01 Alkaloid ALL 22 OCT 2020 Eng Final

Content
ALKALOID VÀ DƯỢC LIỆU CHỨA ALKALOID
1. Thuật ngữ ‐ Glossary 13. Chiết xuất alkaloid (Alkaloid extraction)
14. Phân lập alkaloid (alkaloid isolation)
(ALKALOIDS AND ALKALOID‐BEARING PLANTS) 2. Alkaloids and Alkaloidal Plants for
15. Định nh alkaloid (test for alkaloid)
"Murder" and "Magic“ 16. Phân ch alkaloid bằng SKLM (TLC for
HO O 3. History of alkaloid alkaloids)
4. Alkaloid‐bearing plant in history 17. ĐỊNH LƯỢNG ALKALOID (Assay of alkaloids)
N
O 5. Alkaloid definition 18. Sinh thái của alkaloid‐Ecological Role of
O H Alkaloids
6. Phân loại alkaloid (typology of alkaloids)
19. Tác dụng alkaloid (Alkaloid bioactivities)
N 7. Biosynthesis of alkaloid – Sinh tổng hợp 20. Công dụng một số alkaloid (Uses of alkaloids)
O 8. Phân bố (Occurrence)
HO 21. Các nhóm alkaloid quan trọng (Important
O 9. LÝ TÍNH (PHYSICAL PROPERTIES) alkaloids)
10. Hóa nh (Chemical properties) 22. Chất gây nghiện – Hallucinogens
23. Các dược liệu chứa alkaloid (alkaloid‐bearing
TS DS HUỲNH LỜI 11. Phổ học alkaloid (UV, IR, MS, MNR)
plants)
12. Xác định cấu trúc các alkaloid (Structure 24. Tài liệu tham khảo
huynhloivn@gmail.com Elucidation of Alkaloid)
16‐10‐2020 1 2
Mục tiêu bài giảng Glossary

– Nắm được các khái niệm liên quan alkaloid – Extraction: A means of extracting specific compounds (such as alkaloids) from food by
treatment (usually shaking) with a solvent.
– Đặc điểm lý hóa của alkaloid
– Gas chromatography (GC): A means of separating volatile compounds by passing in a stream of
– Đặc điểm phổ học liên quan alkaloid gas through a very narrow heated glass tube coated with an absorptive phase.
– Các phương pháp chiết xuất phân lập, xác định cấu trúc alkaloid – High‐performance liquid chromatography (HPLC): A means of separating non‐volatile
– Các phương pháp định tính, định lượng alkaloid compounds by passing in a solvent under pressure through a column packed with an absorptive
phase.
– Tác dụng công dụng các alkaloid
– Mass spectrometry (MS): An instrumental means of detecting, identifying, and measuring
– Các dược liệu chứa alkaloid compounds by producing and separating ions. Used as a detector for gas chromatography (GC–
MS) or for high‐performance liquid chromatography (LC–MS).
– Solid phase extraction (SPE): A means of extracting specific compounds (such as alkaloids) from
a solvent extract of food onto a solid medium as a means of separation from food. Alternatively,
unwanted compounds can be removed from the extract
3 C Crews. 2014 4
10/2/2019 (tức mồng 6 Tết Kỷ Hợi)
Chỉ tính từ đầu năm 2019, quân y Đồn biên phòng

THỨ 6, 4/01/2019 Tri Lễ đã cứu chữa thành công 3 trường hợp ăn lá
ngón tự tử trên địa bàn xã.
5 6
History of alkaloids History of alkaloids
– The earliest evidence that humans used alkaloid‐producing plants is derived from Assyrian clay – Galen (129‐199 A.D.): 304 medicinal plants, founder of "galenics“
tablets, written in cuneiform characters. On these 4000 year old plates, about 250 different
plants are mentioned, e.g., Papaver somniferum, Atropa belladonna , and Mandragora – Avicenna (980‐1037 A.D.) (Arabia)
officinarum. – Ibn al‐Baitar (1197‐1248) (Andalusian Arab): 1400 drugs and medicinal plants
– Shen Nong described 365 drugs in about 3000 B.C.
– Paracelsus (Theophrastus Bombast von Hohenheim; 1493‐1541): active substances (the
– About 1550 B.C. medicinal plants were described in the Ebers papyrus (Egypt): Henbane
(Hyoscyamus niger), Pomegranate (Punica granatum), and Poppy (Papaver somniferum). "Arkanum“). Paracelsus favored "Simplice“ instead of using complex mixtures
– In India the traditional medicine was documented in the Ayurveda in about 900 B.C – In 1803, Charles Louis Derosne (1779‐1855) (French) isolated a semipure alkaloid from
– Hippocrates (460‐377 B.C.) (Greek physician) reviewed more than 200 medicinal plants opium. ‘crystallisable’ properties of the new substance (Principium somniferum), weak
– Aristotle (384‐322 B.C.) (Greek), important philosopher base, soluble in acidic solutions, self‐administered for toothache, 15 mg of the drug as
– Theophrastus of Eresos (372‐287 B.C.) (Greek): Historia Plantarum (450 plant species) the optimal dose and named the substance ‘Morphium’ after the Greek god of sleep
– Pedanius Dioscorides (ca. 40‐90 A.D.) (Greek): De materia medica (in 78 A.D.) described more and dreams.
than 500 medicinal plants
Margaret F. Roberts et al. 1998 (Hannu Hotti. 2017). Margaret F. Roberts et al. 1998
7 8
History of alkaloids History of alkaloids
– 1805, Friedrich Wilhelm Adam Sertürner (1783–1841) (Austrian) isolated firstly and – 1839–1842: Opium Wars I (China‐British). 1856–1860: Opium Wars II (China – France)
characterized morphine and recognized its basic nature. (Wikipedia)
– 1819, Carl Friedrich Wilhelm Meißner (1792‐1853): The first definition of alkaloids was – 1870, Coniine was the first alkaloid to have its structure established (Schiff, 1870) and
introduced: all organic compounds of plant origin characterized by basic character. to be synthesized (Ladenburg, 1889).
– 1817 – 1826: Pelletier and Caventou (Faculty of Pharmacy in Paris): strychnine (1817), – 1939 the number of alkaloids isolated and structurally identified: 200
emetine (1817), brucine (1819), piperine (1819), caffeine (1819), quinine (1820), – 1989, the Dictionary of Alkaloids listed details of 10,000 alkaloids.
colchicine (1820) and coniine (1826). – 2010, the Dictionary of Alkaloids is a comprehensive database containing over 40,000
– 1826, Factory of Pelletier used 150 000 kg of Cinchona to produce 3600 kg of Quinine compounds [2] among 326,000 natural products [3]
sulfate. (Walter Sneader. 2005).
Margaret F. Roberts et al. 1998 W. C.Evans. 2009
9 1. Margaret F. Roberts et al. 1998. 2. J. Buckingham. 2010. [3]. Wikipedia (2020) 10
History of alkaloids Lịch sử
– Thiền Sư Nguyễn Bá Tĩnh (1330‐?) (Tuệ Tĩnh) trong sách (Nam Dược Thần Hiệu, Hồng
Nghĩa Giác Tư Y Thư, Thập Tam Phuơng Gia Giảm, Thương Hàn Tam Thập Thất
Chùy) có nhiều vị thuốc có alkaloid (Hồ êu, Liên ý, Tân lang tử (hạt Cau), Bách bộ…).
– Hải Thượng Lãn Ông (1720‐1791): Bộ Hải Thượng Y Tông Tâm Lĩnh 28 tập, 66 quyển.
Nhiều dược liệu alkaloid: Binh lang, Ma hoàng, Ích mẫu, Hoàng liên, Phụ tử…
– 20 giờ, 27/6/1908, biến cố Hà Thành đầu độc với Cà độc duợc. 13 người bị chém, 4
người chung thân, tổng cộng 59 người (Nguồn: Wikipedia)
(Hải Thượng Lãn Ông Y Tông Tâm Lĩnh. NXB Y Học. 2005)
Wikipedia (Tuệ Tĩnh Toàn Tập.NXB Y Học. 2007)
11 12
Lịch sử: Sự nghiệp Tuệ Tĩnh Lịch sử: Sự nghiệp Tuệ Tĩnh
Nam dược quốc ngữ phú
2. Nhớ xưa: BÀI PHÚ CHỈ DẦN TÍNH NĂNG CÁC BÀI THUỐC (Trục giải chỉ nam dược tính
Bàn cổ hóa nên phú)
1. Chín khéo thiêng
Thần Nông nếm biết Muôn giúp nhân dân,
Trời sinh một tính Trước tìm vị thuốc,
Nghĩa đặt có tá sứ quân thần,
Đất hóa muôn loài Sách trời đã định cõi Nam Bang
Tính xét biết òn lương hàn nhiệt
Đôi khí âm dương chuyển vận Thổ sản cùa khác miền Bắc quốc
Thương yêu dân yểu trát, tiên thánh đã chép
Tứ mùa hàn thử vãng lai Mạnh tính thần, trừ tà khí: Lửa luyện hoàng kim
để đồ kinh.
Cứng gán cốt được sống lâu: sương hòa Bạch ngọc
Người chịu khí trung hòa, nhân thở cảm Vui đạo dưỡng sinh, hậu học sá (hãy) tim nơi
An thần tìm Đại mạo sáng tươi,
thương xảy phải diệu quyết.
Thông khiếu uống Xạ hương thơm phức,
Thuốc đôi phương gia giảm dùng thì thực Tôi tiên sư kính đạo tiên sư,
Càn cát, Qua lâu giải khát, công vẫn là nhiều,
hiệu chẳng sai Thuốc Nam Việt chữa người Nam Việt. Bạc hà, kinh giới khu phong, hiệu thu tức tốc,
Thanh yết hầu, nhờ ngậm ô mai,
Giải tâm phiền, nên tìm Bạch trúc
Tuệ Tĩnh Toàn Tập. NXB Y Học. 2007 13 Trích: Hồng Nghĩa Giác Tư Y Thư 14
Alkaloid definition Alkaloid definition
– The definition of the term alkaloid is not a simple one, and is in many cases a source of – The definition of biologist
academic controversy. • Biologically active and heterocyclic chemical compound that contains nitrogen
– The term alkaloid was first mentioned in 1819 by W. Meißner, an apothecary from • May have some pharmacological activity
Halle. He observed that these compounds appeared “like alkali” and so named them • In many cases, medicinal or ecological use.
alkaloids (oid = like). ("alkali" is derived from Arabic al qalīy (or alkali), meaning the – Winterstein and Tier (1910):
calcined ashes). 1. Greater or lesser toxicity, which acts primarily on the central nervous system (CNS);
– The first definition of alkaloids was attributed to all organic compounds of plant origin 2. The basic character of a chemical construction;
characterized by basic character. (W.A. Kukula‐Koch. 2017). 3. Heterocyclic nitrogen as an ingredient;
4. Synthesis from amino acids or their immediate derivatives; and
5. Limited distribution in nature.
(Tadeusz Aniszewski . 2015). 15 (Tadeusz Aniszewski . 2015). 16
– Waller and Nowacki (1978): –Medical scientist definition:
• Nitrogen in the molecule and are connected to at least two carbon • Nitrogenous substances of vegetable origin, often of complex
atoms. structure and high molecular mass.
• At least one ring in the molecule, and its ring is not necessarily • Heterocyclic and may have primary, secondary, or tertiary bases or
heterocyclic. may contain quaternary ammonium groups.
So, alkaloids could not be structural units of macromolecular cellular • Slightly soluble in water but soluble in ethanol, benzene, ether, and
substances (nucleic acids, protein, chitosan), vitamins (Biotin, Thiamine, chloroform.
Pyridoxine, Nicotinic acid), or hormones (Prolactin, oxytoxin, insulin, • Coloration or precipitation in alkaloid reagents (Dragendorff…).
melatonin, thyroxine, adrenaline…). • Intense physiological action, widely used in the medical fields as
curative drugs, can also be highly toxic, even in very small doses.
– Definition of Chemist – Pelletier (1983):
• Biogenic, nitrogen‐containing, mostly N‐heterocyclic compounds. • Cyclic compound containing nitrogen in a negative oxidation state,
So, amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine,
which is of limited distribution among living organisms.
So, compounds would be excluded by this definition: Spermine, spermidine (acyclic),
tryptophan, valine, Tyrosine, Proline…), peptides, nucleosides (cytidine, uridine, adenosine,
aristolochic acid (N oxydation state +3), isoquinoline N‐oxide alkaloids….
guanosine, thymidine) amino sugars (chitin, chitosan...), synthetics (promethazine, alimemazine,
phenothiazine...) and antibiotics (‐lactam, aminoside…) are not considered as to be alkaloids.
NH2
H2N N +
H -
spermidin
chitin chitosan isoquinoline N‐oxide
(Tadeusz Aniszewski . 2015). 19 Segler.1998 Aristolochic acid 20
– The term was originally ascribed to pharmacologically active bases of plant origin, but
– At the other extreme, many scientists in the life sciences/nutrition area tend to
the definition has subsequently been broadened so that it is now generally
considered to include the majority of nitrogen‐containing natural products with the define an alkaloid as any nitrogenous toxin, including proteinaceous substances such
exception of the simple amino acids and proteins, and nitrogen‐containing glycosidic
substances such as the aminoglycoside antibiotics. Alkaloids may be of plant, animal, as ptomaines (formed by the action of putrefactive bacteria on nitrogenous matter
insect or microbial origin. Basic properties may be weak or absent as in the various
and some of which are poisonous)
types of amide alkaloids. Not all higher plants produce alkaloids, but they are fairly
widely distributed. An estimated 40% of plant families contain at least one species
that is known to produce alkaloids. Traditional screening methods, e.g. using
Dragendorff’s reagent, may fail to detect weakly basic alkaloids.
J. Buckingham. 2010. Dictionary of Alkaloids
J. Buckingham. 2010. Dictionary of Alkaloids 21 22
Nomenclature of alkaloids Nomenclature of alkaloids
ELEMENT Oxygen Sulfur Selenium Nitrogen Phosphorous Silicon Boron
– Gay‐Lussac (1778‐1850) recommended suffix –ine; moprhium ‐> Morphine. (W. Sneader.
Valence II II II III III IV III 2005)
Prefix Oxa Thia Selena Aza Phospha Sila Bora – Suffix: ‐idine (Cinchona alkaloid: quinine, quinidine, cinchonine, cinchonidine); ‐anine
(suturated); ‐enine (unsaturated); ‐amidine (febs.onlinelibrary.wiley.com)
Ring Size 3 4 5 6 7 8 9 10
– Prefix Nor‐ :The nor‐compound can be derived by removal of a CH3, CH2, or CH group, or of a
Suffix C atom. (e.g. Ephedrine ‐> Norephedrine, nicotine  nornicotine; (S. W. Pelletier. 1999).
Unsaturated irene ete ole ine epine ocine onine ecine
Saturated irane etane olane inane epane ocane onane ecane – Desmethyl‐ or demethyl‐ are synonyms of "nor‐".
– Prefix: homo‐: Lengthening by insertion of one methylene groups (CH2); Homoharzianic acid
Tri Tetra Hepta Octa Nona Deca
Latin numerals OL IN (C20H29NO6); Harzianic acid (C19H27NO6) (John Buckingham. 2010)
(IR) (ET) (EP) (OC) (ON) (EC)
– Prefix Apo‐: Dehydration e.g .apomorphine, apo‐atropine (Prefix Apo‐: off, separate, formed
 The terminal "e" in the suffix is optional though recommended. from : related to) (M. A. El‐Sakka. 2010)
 Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine", "etidine" &
"olidine" suffix. – Prefix: Seco‐: Cleavage of a ring with addition of one or more hydrogen atoms at each
 Unsaturated nitrogen 3-membered heterocycles may use the traditional "irine" suffix. terminal. E.g. 1‐methyl‐2,7‐dihydro‐5,16:7,17‐dicyclo‐17‐secoyohimban.
 Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered unsaturated heterocycles is prevented by
– Prefix: epi‐, iso‐, neo‐, pseudo‐ or Greek letter: Isomeric alkaloids or slightly modified
their former use for similar sized nitrogen heterocycles.
structure. Pseudoephedrine. (N K Vishnoi. 1999) (Tewari, K.S. 2017)
https://www2.chemistry.msu.edu 23 24
– Name of chief investigator: Pelletierine (Pelletier), Nicotine (Jean Nicot, 1530‐1604,
– Trivial names: Example; Corynoxine; no structural information; if the structure of the alkaloid
has not been determined, this will be the only name available. Derived from the Latin
bring tobacco to France)
binomial or other name for the originating species, e.g. Strychnine from Strychnos – Botanical name: (Genus, species): Papaverine (Papaver somniferum), Coniine
nuxvomica. Traditionally ended in –ine. (Conium maculatum); strychnine (Strychnos); berberine (Berberis); stemonine
– Systematic names: Example: Methyl 6’‐ethyl 1,2,2’,3,6’,7’,8’,8’a‐octahydro‐‐ (Stemona); rotundine (S. rotunda); serpentine (R. serpentina ); baccatine (T. baccata),
(methoxymethylene)‐2‐oxospiro[3H‐indole3,1’(5’Hindolizine]‐7’‐acetate, (E,1S,6’S,7’S,8’aS)‐ cocaine (E. coca)…
is the current CAS (Chemical Abstracts Service) name for Corynoxine.
– Semisystematic names: semisystematic parents can be modified by operators such as nor‐, – Common name: Ergotamine (Ergot) (Nấm cựa gà)
abeo‐, and seco‐, etc. – Property: Hygrine (Hygroscopic) (M. A. El‐Sakka. 2010)
– ‘Semitrivial’ names: derived by appending a systematically‐derived operator to a trivial – Effect: Emetine (Causing vomiting), Vomicine (vomiting), febrifugine
parent. Examples are 8‐(1,1‐Dimethylallyl)confusameline and N‐Cyano‐sec‐pseudostrychnine.
(reduces fever, antipyretic), d‐tubocurarine (Curaré in Indian = “poison”);
semitrivial name is no longer accurate because there has been a structure revision, a note is
given in the dictionary entry, and reference is often given to the possibility of confusion – Mythology: Morphine (Morpheus), Atropine (Atropos). (N K Vishnoi. 1999).
caused by the use of different numbering schemes.
John Buckingham. 2010 25 26
– Name of Ergot alkaloids: – Name of Ergot alkaloids:
• The nomenclature of this group of alkaloids is quite complex • Lysergic acid received its name because it was a product of the lysis of various
ergot alkaloids.
• Botanical names of the host plant or producer, as ergosecaline (Secale spp),
pyroclavine (Agropyrum); elymoclavine, molliclavine (Elymus mollus); setoclavine, • Ergometrine for its actions on the uterus (endometrium uteri), ergotoxine,
ergotaminine is less potent than Ergotamine) [1] (pharmacological properties)
penniclavine (Pennisetum); paspalic acid (Paspalum); festuclavine (Festuca);
ergoclavine (Sclerotium clavus: Thể quả), • Ergocristine for Cristine Stoll, daughter of the scientist Arthur Stoll who isolated
ergotamine, Ergoanname (Anna); Ergoladinine (Ladiclav Cvak); Ergogaline
• Ergokryp ne, an alkaloid that remained elusive (khó hiểu, khó m) (cryptic; (Galena) (personal attachment)
kryptos [Gr]) and obscured for many years.
• 3 forms of systematic nomenclature reflecting different chemistry:
• Ergobasine was so named because of its basic properties.  Ergoline as the name for the tetracyclic system present in most ergot alkaloids
 Ergotaman for the heptacyclic system occurring in most of the peptidic alkaloids
 IUPAC system (International Union of Pure and Applied Chemistry)
Vladimir Kren. 1999 27 Vladimir Kren. 1999 28
Typology of alkaloids Typology of alkaloids
A. Bioecological classification of alkaloids
1. Biological and ecological activity,
1. Neutral or weakly basic molecules (e.g., lactams such as ricinine, certain N‐
oxides such as indicine),
2. Relation to chemical and technological innovations,
2. Animal‐derived alkaloids (e.g., anuran (lưỡng cư), mammalian (có vú) and
arthropod alkaloids (chân đốt),
3. Chemical structure,
3. Marine alkaloids,
4. Biosynthetic pathway. 4. Moss alkaloids (rêu),
5. Fungal and bacterial alkaloids,
6. Non‐natural alkaloids (structurally modified or analogues).
C. Chemo‐molecular classification of alkaloids
B. Chemotechnological classification of alkaloids
1. Acridones,
1. Natural alkaloids, 11. Quinozolines. 21. Oxindoles,
2. Aromatics,
2. Biomime c and bionic alkaloids (mô phỏng sinh học)
3. Carbolines,
12. Quinolizidines, 22. Quinolines
Biomimetic alkaloids are natural alkaloids copied artificially by chemists in the laboratories. They are
4. Ephedras, 13. Phenylisoquinolines, 23. Simple tetrahydroisoquinolines,
identical in structure to natural alkaloids. Bionic alkaloids are those biomimetic molecules being novelized
by the chemists and engineers using natural models and high‐level technology. Bionic alkaloids are not 5. Ergots, 14. Phenylethylamines 24. Sesquiterpenes,
identical analogues to natural alkaloids. [Bionics = bio (logy) + (electro) nics] 25. Stereoids,
6. Imidazoles, 15. Piperidines,
3. Synthetic alkaloids
7. Indoles, 26. Tropanes,
16. Purines,
8. Bisindoles, 27. Terpenoids,
17. Pyrolidines,
9. Indolizidines, 28. Diterpenes,
10. Manzamines, 18. Pyrrolizidines,
29. Triterpenes
19. Pyrroloindoles,
(Tadeusz Aniszewski . 2015). 31 20. Pyrydines, (Tadeusz Aniszewski . 2015). 32
D. Classification established upon the ring structure D. Classification established upon the ring structure
1. Tropane alkaloid 3. Piperidine alkaloids
• Abundant in Solanaceae family. • Odor is the common feature of piperidine alkaloids.
• From ornithine and acetoacetate • Exert chronic neurotoxicity
• Cocaine, atropine, scopolamine, and their derivatives • From Lysine, acetate, acetoacetate
2. Pyrrolizidine alkaloids • Lobeline is one of the important alkaloids in this group
• From Asteraceae and Fabaceae family. 4. Quinolines alkaloid
• Occurring mainly in the plants as N‐oxides, whose role being lost during the isolation process. • Exclusively from the bark of the Cinchona plant. Simple heteroaromatic quinolines are isolated
• Toxic effects, especially liver damage. from various marine sources (4,8‐quinolinediol from cephalopod ink and 2‐heptyl‐4‐
hydroxyquinoline from a marine pseudomonas).
• Senecionine is the popular alkaloid of this type
• Cinchonine, cinchonidine, quinine, and quinidine
Prasanta Dey. 2020 33 Prasanta Dey. 2020 34
5. Isoquinoline alkaloids 6. Indole alkaloids
• Extremely large group of alkaloids mostly occurring in higher plants, few in marine. • From tryptophan
• From tyrosine or phenylalanine.
• Terrestrial, marine, fungal source
• Antiviral, antifungal, anticancer, antioxidant, antispasmodic, and an enzyme inhibitor.
• Morphine and codeine • Polyhalogenation is a common feature
• Types: • Types:
 Simple isoquinoline alkaloids (e.g., salsoline, mimosamycin),  Simple indole alkaloids (e.g., Aplysinopsin, Gramine),
 Benzylisoquinoline alkaloids (e.g., reticuline, imbricatine),  Bisindoles (e.g., Indirubin, 6,60‐Dibromoindigotin),
 Bisbenzylisoquinoline alkaloids (e.g., fumaricine),  Simple tryptamine alkaloids (e.g., Tryptamine),
 Manzamine alkaloids (e.g., manzamine a),  Cyclotryptamine alkaloids (e.g., Physostigmine),
 Pseudobenzylisoquinoline alkaloids (e.g., polycarpine, ledecorine),
 Quinazolinocarbazole alkaloids (e.g., Rutaecarpine),
 Secobisbenzylisoquinoline alkaloids (e.g., baluchistanamine),
 Bisbenzylisoquinoline alkaloids containing one ether link (e.g., dauricine), Bisbenzylisoquinoline alkaloids  β‐Carboline alkaloids (e.g., Harman),
containing two ether links (e.g., berbamine), bisbenzylisoquinoline alkaloids containing aryl links only (e.g.,  Carbazole alkaloids (e.g., Ekeberginine),
pisopowetine), bisbenzylisoquinoline alkaloids containing one aromatic link and one or two ether links (e.g.,  Indolonaphthyridine alkaloids (e.g., Canthin‐6‐one),
Vinblastine
rodiasine)  Ergot alkaloids (e.g., ergotamine)
7. Steroidal alkaloids 8. Imidazole alkaloid
• 1,2‐Cyclopentane phenanthrene ring • Numerous structurally different examples, particularly among marine and microbial alkaloids.
• Display a wide array of biological activities and significant pharmaceutical potential.
• From higher plants (Liliaceae, Solanaceae, Apocynaceae, Buxaceae), some from amphibians
• Pilocarpine is the most pharmaceutically significant imidazole alkaloid
• Types:
9. Purine alkaloids
 Aminopregnanes (simplest)
H • Caffeine, Theophylline and Theobromine
 Steroidal alkaloids H • Plant and marine organisms with substituted purines (e.g.,Phidolopin) and a variety of terpenoid‐
• Salamandra type (e.g.,cycloneosamandione),
N purine alkaloids, such as the agelines and others
• Jerveratrum type (e.g., jervine), H
• Spirosolane type (e.g., soladulcidine), H 10. Pyrrolidine alkaloids
• Solanidine type (e.g., rubijervine), H H • From plants.
• Cerveratrum type (e.g., 3,6‐cevanediol), HO • Hygrine (biosynthesized from ornithine), ficine (where the pyrrolidine ring is involved to a flavone
• Conanine type (e.g., didymeline), Solanidine nucleus), and brevicolline (wherein it is attached to a β‐carboline unit) are some examples of this type
• Buxus type (e.g., cyclobuxine), of alkaloids
• Pregnane type (e.g., 20α‐dimethylamino3β‐senecioylamino‐16β‐hydroxy‐pregn‐5‐ene),
cephalostatins/ritterazines (e.g., ritterazines a),
• Miscellaneous steroidal alkaloids (e.g., bufotoxin)
E. Biosynthetic shape‐classification of alkaloids  True alkaloid
1. L‐Ornithine: Pyrrolidine (Cuscohygrine; Hygrine); Tropane (Atropine; Hyoscyamine; Cocaine;
1. True Alkaloids: True alkaloids derive from amino acid and share a heterocyclic ring with Scopolamine/Hyoscine); Pyrrolizidine (Senecionine; Retrorsine).
2. L‐Lysine: Piperidine (Pelletierine; Lobeline; Piperine); Quinolizidine (Cytisine; Sparteine); Indolizidine
nitrogen. Cocaine, quinine, dopamine, morphine and usambarensine. (Castanospermine)
3. L‐Tyrosine, Phenylalanine: Tetrahydro‐isoquinoline (Codeine; Morphine; Papaverine; Thebaine;
2. Proto‐alkaloids: N from an amino acid is not a part of the heterocyclic bond, include compounds Tubocurarine); Phenethyl‐isoquinoline (Galanthamine)
4. L‐Tryptophan: Indole (Psylocybin, Serotonin; Harmine; Vinblastine); Quinoline (Quinine,
derived from tyrosine, ornithine and tryptophan. Hordenine, Mescaline, yohimbine Camptothecine); Pyrroloindole (Physostigmine); Ergot (ergotamine)
5. L‐Histidine: Imidazole (pilocarpine); Manzamine (marine sponge)
3. Pseudo‐alkaloids: not derived from amino acids: acetate and phenylalanine‐derived or
6. L‐Arginine: β‐carboline (Marine alkaloid): Saxitoxin, Tetrodotoxin
terpenoid, steroidal alkaloids: coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine, 7. Anthranilic acid: Quinazoline (Peganine); Quinoline (Skimmianine); Acridone (Rutacridone)
8. Nicotinic acid: Pyridine/pyrrolidine (Nicotine)
and pinidine.
(Tadeusz Aniszewski . 2015). 39 40
True Alkaloids
True Alkaloids L‐ornithine
Senecionine
Hygrine
Pyrrolidine Tropane Pyrrolizidine HEPATOTOXICITY
Erythroxylum coca, Atropa
GENOTOXICITY
Cuscohygrine Atropine Senecionine CYTOTOXICITY

TUMORIGENICITY
Retrorsine Retrorsine
Hygrine Hyoscyamine NEUROTOXICITY
Indicine‐N‐oxide COOCH3
COOCH3
Cocaine Cuscohygrine
CLivorine N OH
N O
Scopolamine/Hyoscine Retronecine Erythroxylum coca, Atropa HO
O
O
N
Ecgonine Acid benzoic Cocaine
Joaquín Tamariz . 2018
Clivorine
(Tadeusz Aniszewski . 2015). 41 (Tadeusz Aniszewski . 2015). Joaquín Tamariz . 2018
42
True Alkaloids
True Alkaloids L‐Lysine
Pelletierine Cytisine
Piperidine Quinolizidine Indolizidine
Castanospermine
Pelletierine Castanospermine
Cytisine
Lobeline Swansonine smoking cessation aid
Lupanine narrow therapeutic index
Sparteine
Piperine Sparteine
Swansonine
(Tadeusz Aniszewski . 2015). 43 Piperine
(Tadeusz Aniszewski . 2015).
44
Typology of alkaloids O
O
Typology of alkaloids
OH
True Alkaloids
L‐Tyrosine NH2
OH NH2
True Alkaloids
HO O
Phenylalanine L-Tyrosine
Phenylalanine
Phenethyl‐isoquinoline N
Tetrahydro‐isoquinoline O Galanthamine
Crinine
Amaryllidaceae thebaine Vascular dementia
alkaloids and Alzheimer's
Floramultine O
Codeine
Galanthamine
Morphine O
Galanthine
O H
Papaverine Haemanthamine O
Lycorine N
Thebaine O
Maritidine
Tubocurarine Oxomaritidine
heroine
Lycorine
Vittatine 45 (Tadeusz Aniszewski . 2015). 46
H
Typology of alkaloids N Typology of alkaloids
True Alkaloids NH2
True Alkaloids
L‐Tryptophan OH 8
O 8
9 9
Ventricular
pre‐excitation
Indole Quinoline Pyrroloindole Ergot cardiac
Ergobine dysrhythmias
Physostigmine Ergotamine
Simple indole Simple β‐carboline Terpenoid indole Ergocomine
(Eserine) Psilocybe cubensis, Psilocybe tampanensis, Antimalarial
Ergocristine
Panaelous cyanescens (Magic Mushroom)
Arundacine Ergocryptine
Elaeagnine Chloroquinine α‐ergocryptine
Arundamine Ajmalicine 8 8
Harmine Cinchonine N β‐ergocryptine
Psilocin, Catharanthine N
Cinchonidine H H 9 9
Psylocybin Tabersonine Ergometrine
Quinine Ergonovine
Serotonin Vinblastine
Quinidine Ergosine
Tryptamine Camptothecine
Zolmitriptan Ergostine
Fumigaclavine D Camptothecine
Harmine Anticancer
N
H (Tadeusz Aniszewski . 2015). 47 48
O
Typology of alkaloids Typology of alkaloids N
OH
L‐Histidine HN NH2
True Alkaloids
True Alkaloids histidin
Manzamine
Imidazole
Xestomanzamine A
Treat glaucoma and delayed gastric emptying Xestomanzamine B
treat anticholinergic poisoning Ergotamine Histamine (from Marine Sponges)
For acute migraine attacks Pilocarpine
‐Ergocriptine
Pilosine
Pilosine
Treatment of dry mouth

Vinblastine antiarrhythmic by radiation (oral), glaucoma (drops)
Ajmalicine (Raubasine) 49
Anticancer 50
Typology of alkaloids Typology of alkaloids O
OH
– True alkaloid
L‐Arginine True Alkaloids NH2
Anthranilic acid
N Anthranilic acid
β‐carboline N
(Marine alkaloid) quinazolin Quinazoline Quinoline Acridone
Tetrodotoxin
Saxitoxin (Neurotoxin) Peganine Acetylfolidine Acronycine
Tetrodotoxin Rutacridone
Acutine
1‐acetyl‐β‐carboline
Saxitoxin Bucharine
(Algae, Cyanobacteria, shellfish) 7‐bromo‐1‐ethyl‐β‐ carboline
O
Neurotoxin Marinacarboline A Peganine Perforine Acronycine
Eudistomidin B Polifidine
Seragadine A O N O Skimmianine Rutacridone
Veriabine A Tetraodontidae O
Veriabine B
51 Skimmianine (Tadeusz Aniszewski . 2015). 52
N from an amino acid is not a part of the heterocyclic bond
True Alkaloids
Nicotinic acid
Protoalkaloid: O
OH
 L‐Tyrosine: Phenylethylamin: HO
NH2
Pyridine/pyrrolidine Hordenine; L-Tyrosine
Anabasine H
N Mescaline N
Cassinine
N
Nicotine
Celapanin  Tryptophan: Terpenoid indole alkaloids: NH2
Evoline
Evonoline  Yohimbine OH
O
Evorine  Ornithine: Pyrrolizidine:
Maymyrsine
Nicotine 4‐hydroxy‐stachydrine;
Regelidine
Wilforine
Stachydrine
N from an amino acid is not a part of the heterocyclic bond not derived from amino acids
Pseudoalkaloids
Protoalkaloid:
Acetate Pyruvic Ferulic Geraniol Steroid Adenine/guanine
Hordenine stachydrine Piperidine Sesquiterpene Phenyl alkyl Phenyl terpenoid Purine

(Hordeum) Leonurus japonicus
Cassinine Cathine Capsaicin Conessine

Coniine Aconitine Caffeine
Cathinone
-
Coniceine Celapanin Actinidine Solanidine Theacrine
+ Evonine Ephedrine Solasodine
Pinidine Atisine Theobromine
Evonoline Pseudoephedrine Squalamine
Gentianine Theophylline
Yohimbine Evorine Norephedrine Tomatidine
Mescaline (Rauwolfia) 4‐hydroxy‐stachydrine O
(Cactaceae) (erectile dysfunction) (ED) O
OH
(hallucinogenic) CH3COO‐ C15H24 HO
(Tadeusz Aniszewski . 2015). 55 ferulic acid (Tadeusz Aniszewski . 2015). 56
Pseudoalkaloids
OH
H
OH
H
Pseudoalkaloids
* S N * N
R S
* R *
(+)-Ephedrine
(-)-Ephedrine Conessine
(1S,2R) N N O
(1R,2S)
Coniine OH OH N N
H H
Conium maculatum * R N * S N H
R R O
Apiaceae * *
HN theophylline
H
Evonine (-)-Pseudo-ephedrine (+)-Pseudo-ephedrine Asthma, bronchospasm,
OH O
H (1R,2R) (1S,2S) H and COPD.
N H
O H H N N O
Decongestant
O HO Apnea of prematurity
capsaicin
H solasodine in infants & N NH
Neuropathic pain associated Drugbank.ca Aconitine pain relief O
with post‐herpetic neuralgia.
(Tadeusz Aniszewski . 2015). 57 theobromine 58
CH3
Flavoalkaloid Flavoalkaloid N
OH
– Flavonoid backbone + nitrogen containing moiety, a usually at the C (6) or C (8) position HO O CH3
of the flavonoid core.
– Type: OH O
Rohitukine
• FLAVOALKALOIDS WITH PYRROLIDINE MOIETY: Ficine and Isoficine Amoora rohituka, Dysoxylum
• FLAVOALKALOIDS WITH PIPERIDINE MOIETY: Capitavine, Buchenavianine, Kopsirachin General structure of flavonoid alkaloids with numbering binectariferum Meliacee
CH3
Schumanniophyton magnificum;
• SPECIAL FLAVONOID ALKALOIDS: Aquiledine, Isoaquiledine, and Cheliensisine Schumanniophyton problematicum
N
Rubiaceae
OH P. MohanaKumara. 2014
HO O
Cl
OH O
Flavopiridol (Alvocidib)
Viktor Ilkei. 2018 59 Cyclin‐dependent kinase inhibitor for acute myeloid leukaemia Viktor Ilkei. 2018 60
N
Biosynthesis of alkaloid – Sinh tổng hợp Biosynthesis – Sinh tổng hợp
N
histamine, histidine, procarpine, pilocarpine, and pilosine
Cactaceae and Rutaceae Quninazoline (C6C2N)
COOH
N
H
COOH
Pyrrolidine (C4N) NH2
NH2 NH2 hygrine, cuscohygrine N
Anthranilic acid
Quinoline (C6C2N)
L-Ornithine
N
Me
N
Tropane (C4N+ ..)
hyoscyamine, cocaine Acridine (C6C2N)
peganine (vasicine), dictamine, skimmianine,
melicopicine, acronycine, and rutacridone
Peganum harmala,Dictamus albus,
Skimmia japonica, and Ruta graveolens.
marine sponges
Biosynthesis – Sinh tổng hợp Biosynthesis – Sinh tổng hợp
O NH2
Nicotiana tabacum, Ricinus communis,
NH2
Areca catechu O OH Phenyl nucleus (C6C2N)
OH Phenyl nucleus (C6C2N) NH2
NH2
HO
L-Tyrosine
phenylalanine
COOH N D‐Tubocurarine
Pyridine (C5N) Phenyl propyl nucleus (C6C3)) Phenyl propyl nucleus (C6C3))
anabasine, anatabine, nicotine, nornicotine,
N ricine, and arecoline cathionine, cathine, ephedrine, Mescaline, anhalamine, papaverine, curare, and morphine
Nicotinic acid (Niacin, Vit. B3) pseudoephedrine, and norpseudoephedrine
Ephedra.
N
Sesquiterpene pyridine
(Niacin + acetate)
Papaverine Mescaline
Morphine
Biosynthesis – Sinh tổng hợp Occurrence of alkaloids
– Fungi and bacter
N
– Plant
N
N
H • Algae
Indole Quinoline (C9N)
• Tracheophytes (Vascular plant)
N  Lycopodiacae
COOH
N  Spermatophytes
NH2
• Gymnosperms
-Carboline (C8NC3N)
N • Magnoliophyta (flowering plants)
H
tryptophan
N
–Animal (Tadeusz Aniszewski . 2015).
N
H H
Pyrrolo-indole (C10N2) – ca. 27000 alkaloid were known. (William Charles Evans. 2009)

– 150 families (ca. 20% of the ‘species of flowering plants’ contain alkaloids) (Tristan Richard et
psilocin, psilocybin, harmine, catharanthine, reserpine, ajmalicine, vindoline, vincristine, strychnine, quinine,
al. 2013).
ergotamine, and other ergot alkaloids
Occurrence of alkaloids Occurrence of alkaloids
– Fungi: – Fungi: Hericirine, serotonin, psilocin, and psilocybin. Powerful psychoactive.
• Aspergillus, • Hericium erinaceum
• Rhizopus, • Psilocybe semilanceata ("magic" mushroom)
• Penicillium, • Conocybe
• Claviceps purpurea (Ergot) (Ergotamine, (+)‐ • Panaeolus subbalteatus
lysergic acid ‐> lysergic acid diethylamine (LSD) • Stoparia
(hallucinogenic), for schizophrenia (small dose)
• Amanita muscaria (Fly agaric)
(Muscarine, ibotenic acid, muscimol)
Ibotenic acid
Acetyl choline
Muscarine
Amanita muscaria (fly agaric), Inocybe and Clitocybe
species (e.g., Inocybe geophylla, Clitocybe dealbata)
Amanita muscaria
Agonising muscarinic acetylcholine receptors Psilocybe semilanceata
Panaeolus subbalteatus (Wikipedia)
(Wikipedia)
(Wikipedia)
Miosis, blurred vision, increased salivation, excessive sweating, Nấm tản
Muscimol
lacrimation, bronchial secretions, bronchoconstriction, bradycardia,
abdominal cramping, increased gastric acid secretion, diarrhea
and polyuria.
Magic mushrooms are sold in bags. Photo: Tuoi Tre
Spores of magic mushrooms are kept in a fluid

71 mixture inside hypodermic syringes. Photo: Tuoi Tre 72
– Plant:
–Bacter:
• Marine Algae (Tảo biển): brown, red, green alga. 44 alkaloids: 1
• Alkaloids by bacteria is not common in nature phenylethylamine, 41 indole, and 1 naphthyridine derivates. Halogenated
alkaloids (bromine‐ and chloride) are specific for algae. (Kasım Cemal Güven,
• Pseudomonas: tabtoxin and pyocyanine
2013).
• Pantoea agglomerans P20‐14: indole alkaloids • Lycopodiophyta: Lycopodiaceae (Thông đất) (Non‐seed‐bearing plants):
• Pseudomonas brassicaceareum ssp. neoaurantiaca isolated from Salvia  Lycopodium: annotinine, lycopodine, cernuine, lyconadins, and complanadine.
 Huperzia serrata: huperzine A (for Alzheimer)
miltiorrhiza produces 11 alkaloids.
• Pinophyta: Taxaceae: Taxus brevifolia (Taxol: anticancer)
• Gnetophyta:
 Gnetaceae (Gắm)
 Ephedraceae (Ma hoàng): (Gnetophyta): Ephedra sp. Ephedrine (Wink, 2016)
– TAXONOMIC RELEVANCE:
– Plant:
• Simple isoquinoline: Cactaceae, Chenopodiaceae
• Cycadophyta: Cycadaceae: Cycas (Thiên tuế): Cycasin
• Chromo‐alkaloids (betalains): Caryophyllales (Cẩm chuớng): Cactaceae
• Magnoliophyta (Angiosperms): (Hylocereus undatus‐thanh long), Nyctaginaceae, Portulacaceae,
 Monocot: Amaryllidaceae and Liliaceae, Stemonaceae, Dioscoreaceae, Arecaceae, Poaceae Chenopodiaceae, Arnaranthaceae (Beta vulgaris, Cải ngọt)
and Orchidaceae. • Ergoline (Indole): Fungi, Convolvulaceae
 Dicot: Papaveraceae, Berberidaceae, Fabaceae, Boraginaceae, Apocynaceae, Asclepiadaceae, • Complex indole: Loganiaceae, Apocyanaceae and Rubiaceae.
Menispermaceae, Asteraceae, Ranunculaceae, Rubiaceae, Solanaceae, and Rutaceae. • Quinolines: Rutaceae
(M. Wink, 2003).
• Diterpenoids: Aconitum, Delphinium, Garrya.
 The dicotyledon orders Salicales, Fagales, Cucurbitales and Oleales at present appear to be
• Steroid: pregnanes skeleton: Apocynaceae. Buxaceae.
alkaloid‐free.
C27‐steroid: Solanum, Veratrum (Glycoalkaloid)
(Tadeusz Aniszewski . 2015). Evans.2009 75 HEGNAUER. 1988 76

– TAXONOMIC RELEVANCE: Plant family Precursor Type Genus, species Compound
• Tropane alkaloid: mainly occur in the Solanaceae. but are also found in Indole, quinoline, Rauvolfia serpentina, Quinine, Reserpine, Ajmalicine,
Catharanthus roseus, Reserpine, Vinblastine
Convolvulaceae, Erythroxylaceae, Proteaceae and Rhizophoraceae. Less Apocynaceae Tryptophan Terpenoid
Holarrhena antidysenterica; Vincristine, Camptothecin
alkaloids Strophanthus, Vinca (Ervatmia heyneana), Conessine
frequently, in the Euphorbiaceae, Brassicaceae and Olacaceae [P. Christen, 2000]
Senecio, Centaurea,
• Berberine: Annonaceae (Annickia, Rollinia, Xylopia), Berberidaceae (Berberis, Asteraceae ornithine pyrrolizidine Senecionine, retrorsine
Petasites hybridus.
Caulophyllum, Jeffersonia, Mahonia), Menispermaceae (Tinospora, Coscinium, Tyrosine, Isoquinoline,
Strychnos nux‐vomica, S.
strychnine, brucine, and curare
Loganiaceae Ignatii; S. wallichiana;
Fibraurea), Papaveraceae (Argemone, Bocconia, Chelidonium, Corydalis, tryptophan Indole (C‐toxiferine)
Strychnos toxifera
Eschscholzia, Papaver…), Ranunculaceae (Coptis, Hydrastis, Xanthorhiza), Rutaceae morphine, codeine, thebanine,
Papaver somniferum,
(Phellodendron, Zanthoxylum). [Maria A. Neag. 2018] Papaveraceae tyrosine isoquinoline papaverine, narcotine, narceine,
Chelidonium, Corydalis
isoboldine, and salsolinol
• Caffeine: Rubiaceae (Coffea), Theaceae (Camellia), Aquifoliaceae (Ilex),
Phenylalkylamin Mescaline, Anhalamine
Sterculiaceae (Cola, Theobroma) [Tadeusz. 2015] Cactaceae tyrosine Lophophora williamsii
Isoquinoline Anhalonine, Anhalonidine
77 (Tadeusz Aniszewski . 2015).
78
Plant family Precursor Type Genus, species Compound
quinazoline,
quinoline, europine and ilamine and their
Dictamnus, Pilocarpus, Ruta dictamnine, skimmianine,
Anthranilic acid Acridine Heliotropium indicum (Vòi voi), N‐oxides (strong toxic effects)
Rutaceae (Anthranilic)
graveolens, Zanthoxylum, Evodia, Semecarpine, Rutacridone, Boraginaceae
histidine ornithine pyrrolizidine Cynoglosum creticum, Indicine‐N‐oxide, Acetyl‐
Glycosmis, Pilocarpine, Pilosine (Họ Vòi voi).
Imidazole Symphytum officinale intermedine, Acetyl‐
(histidine)
lycopsamine
ornithine, Senecionine, lupinine,
Atropa belladonna, Datura, Hyoscyamine, Atropine, hyoscine Crotalaria, Baptisia, Lupinus,
nicotinic acid, Tropane, Mandragora, Duboisia, Scopolia, Cuscohygrine, (‐)‐nicotine, pyrrolizidine, sparteine, Swainsonine,
Solanaceae Phenylalanine pyridine, Ornithine, Cytisus, Swainsona,
Hyosciamus, Nicotiana, Capsicum Anabasine, Capsiacin, Solanidine, Quinolizidine, Castanospermine, Eserine
Steroid saponin Fabaceae Lysine, Castanospermum, Arachis,
annuum, Solanum, Lycopersicon. Tomatine indolizidine, (Physostigmine), Eseramine,
alkaloids Tryptophan Physostigma venenosum,
indole Physovenine, Geneserine,
cocaine, ecgonine, Erythrina
Erysovine
Erythroxylum coca, E. cinnamylcocaine, α‐truxilline,
Chondrodendron tomentosum,
Erythroxylaceae ornithine Tropane truxilense, and E. truxilline, methylecgonine, Curare, Tubocurarine,
novagranatense tropine, hygrine, hygroline, and
Cissampelos, Cyclea, Stephania
Menispermaceae tyrosine Isoquinoline Tetrandrine. Stephanine,
cuscohygrine tetrandra, Stephania
Fangchinoline, rotundine
harnandifolica, S. rotunda
80
Elaeagnaceae
Berberine, Berbamine, tryptophan indole Elaeagnus angustifolia Elaeagnine
Berberidaceae tyrosine Isoquinolie Berberis, Mahonia, Nandina (Nhót)
Hydroxyacanthin, Glaucine
Harman, harmine
Peganum harmala
Zygophyllaceae Tryptophan, Komavine
indole Nitraria komarovii Acetylkomavine
tyrosine and Isoquinoline Hydrastis, Thalictrum, Aconitum, Berberine, Hydrastine, (Gai chống) acetate
Ranunculaceae Nitraria sibirica Dihydroschoberine
terpenoid terpenoid Delphinium Fangchinoline, Aconitine Nitrabirine N‐oxide
Nyssaceae tryptophan quinoline Camptotheca acuminata Camptothecin
Cephaelis ipecacuanha, Emetine, Cephaeline, Yohimbine,
Tyrosine Isoquinoline, Pausinystalia yohimbe, Camptothecin, Quinine, Pelletierine
Rubiaceae tryptophan indole Ophiorrhiza mungos, Quininidine, Cinchonine, Punicaceae lysine pyridine Punica granatum Pseudopelletierine
Purine Ophiorrhiza mungos, Cinchona, Cinchonidine, Caffeine, Methylpelletierine
Purines
Corynanthe, Coffea Theophylline, Theobromine
82
Plant family Precursor Type Genus, species Compound – Animal
• Sponge (San hô): Monanchora unguifera: batzelladine J, ptilomycalin A, ptilocaulin,
Hordenine
Tyrosine Phenylalkylamine
Hordeum vulgare (lúa Tyramine isoptilocaulin.
Poaceae mạch) Gramine (indole)
Tryptophan indole
Arundo donax Arundamine • Saxidomus (Nghêu)
Arundacine
• Salamandra (Kỳ nhông)
Colchicine, Autumnaline
Tyrosine Colchicum, Kreysigia Floramultine, Kreysigine, Jervine • Dendrobates (Ếch): Batrachotoxins
Liliaceae Phenylalkylamine
multiflora, Veratrum Cyclopamine, Cycloposine,
Stereoidal
Protoveratrine A‐B
• Phyllobates (Ếch) (poison dart frogs): Batrachotoxins (Toxic) (Terri L. Postma, 2009).
Amaryllidaceae tyrosine Isoquinoline Lycorus, Galanthus Lycorine, galanthamine

• Oophaga pumilio (Ếch): Pumiliotoxins (indolizidine alkaloids) (neurotoxic)
(Matthew Gronquist, 2010)
Arecaceae Nicotinic acid pyridine Areca catechu arecolin
• Bufo toads contain bufotenine (5‐OH‐DMT) and an alkaloid tryptamine (5‐MeO‐
DMT), a potent hallucinogenic (Terri L. Postma, (2009).
84
Occurrence of alkaloids
Occurrence of alkaloids
– Animal
• Millipedes (sâu chiếu), Human Cases of Tetrodotoxin Intoxication
• Fish: Tetrodotoxin: Takifugu snyderi, T. obscurus, T. niphobles, Fugu poecilonotus, F. obscurus, F. ̶ 100 cases in Taiwan from 1998–2008. (pufferfish).
rubripes, F. vermicularis radiatus. (Jorge Lago. 2015) ̶ 2002: 37 patients. Bangladesh. 8 died after 5 h. (pufferfish). Takifugu (Wikipedia)
• Mollusc cephalopod: Octopus maculosus: Tetrodotoxin. (Jorge Lago. 2015) ̶ 2008: 9 patients. Bangladesh. 2 died and 3 survived by treated with neostigmine and atropine.
• Mollusc gastropod: Niotha Clathrata: Tetrodotoxin. (Jorge Lago. 2015) (pufferfish egg (20g ‐> severe illness).
• Castor (Hải ly) ̶ 71 persons. Thailand. 2 died (crab Carcinoscorpius rotundicauda)
• Moschus (Huơu xạ) ̶ 1986. Hawaii. porcupinefish Diodon hystrix
• Mammals: harman, norharman, tetrahydroharman, harmalan, 6‐metoxyharman, salsolinol, ̶ 2007. 2. Chicago. Tetraodontidae.
norlaudanosoline (THP), dideoxynorlaudanosoline 1‐carboxylic acid and spinaceamines ̶ 2014. New York City. Lagocephalus lunaris (pufferfish).
– Ca. 300 alkaloids in 24 classes occurring in the skins of amphibians along with other
toxins. Potent neurotoxic alkaloids of frogs of the genus Phyllobates, the most
poisonous substances known (W. C. Evans. 2009).
85 Jorge Lago. 2015 86
Friday, October 12, 2012 10:45 Friday, March 09, 2018, 11:58 GMT+7
Five farmers were rushed to a hospital in Vietnam after enjoying a pufferfish hotpot on

Two fishermen died and three others were hospitalized with serious poisoning after eating pufferfish
Wednesday evening.
in the central province of Binh Thuan on Thursday.
Shortly after consuming the hotpot, the victims became paralytic and were unable to speak.
One of the survivors' wife told Thanh Nien that the fishermen had the fish for lunch that day when they
All five farmers, from Hau Giang Province, were comatose and suffering from cardiac arrest, suspended
were working on a boat some 40 sea miles off the coast of Phan Thiet Town.
Around 30 minutes later, they all started vomiting and feeling dizziness, she said. breathing, and unstable blood pressure
Pham Van Hoang, 21, and Tran Van Manh, 20, died on the way.
87 88
27‐7‐2019
Mạng xã hội rộ lên thông tin một

loại cua độc xuất hiện rải rác với tần
xuất nhiều ở Côn Đảo.
Cua mặt quỷ sống nhiều ở các rạn san
hô và phân bố khá rộng trên nhiều
vùng biển.
After ingestion of a specimen of the crab Zosimus aeneus (Xanthidae), an East
Năm 2015, một nhóm công nhân bắt cua mặt quỷ dọc bờ
Timorese adult male died within several hours. Xanthid crabs are known to biển Quảng Ngãi về nhậu. Một giờ sau, 3 người tê cứng chân
harbour paralytic shellfish toxins (PSTs), tetrodotoxin and palytoxin tay, khó thở, đau đầu.
89 90
– Depending on the type of plants, the maximum concentration is observed in the:
– Yield (Hàm lượng):
• Leaves: Hyoscyamus niger (black henbane), Belladon, Erythroxylum coca, Nicotiana tabacum,
Camellia sinensis. • High: 1‐3%
• Seeds: Strychnos nux‐vomica, Coffea, Colchicum autumnale
• Root: Rauwolfia serpentine, Punica granatum • Cinchona: 6‐10%
• Tuber: Aconitum, Stephania rotunda, Stemona tuberosa

• Opium: 20‐30%
• Bark: Cinchona, Holarrhena antidysenterica, Phellodendron amurense
• Flower: Datura metel
• Fruits: Capsicum, Piper nigrum, Papaver somniferum
• Trunk: Ephera sinica
Phạm Thanh Kỳ. 2015 Grinkevich NI. (1983) 91 Phạm Thanh Kỳ. 2015 92
PHYSICAL PROPERTIES PHYSICAL PROPERTIES
1. Physicochemical Properties • In plant tissues as water‐soluble salts of organic acids (tartaric, acetic,
oxalic, citric, malic, and lactic acids), esters (e.g., atropine, scopolamine,
2. Solubility ( nh tan)
cocaine, aconitine), or combined with tannins (Cinchona bark) or sugars
3. Color and taste (e.g., the glycoalkaloids of Solanum species) rather than as free bases.
• Additionally, N‐oxide alkaloids (e.g Harmanine) also occurs naturally. (J.
4. Basicity (Tính kiềm)
D. Phillipson, 1971)
W.A. Kukula‐Koch. 2017 W.A. Kukula‐Koch. 2017
93 94
–Solubility
• Most alkaloids: Oxygen‐containing, crystalline, amorphous, non‐
• The free bases of alkaloids are soluble in nonpolar organic solvents
odorous, and non‐volatile compounds.
(chloroform, methylene chloride, Benzene, ether), while their solubility
• Exception: in water is low.
 Low molecular weight (arecoline and pilocarpine), and alkaloids with no  Exceptions:
oxygen atom (sparteine and nicotine) occur in the volatile, colorless, liquid
• Colchicine, pilocarpine, ephedrine, quartenary alkaloid (berberine,
form.
tubocurarine), caffeine are water soluble. Caffeine extracted from tea with
 Arecoline, guvacoline, nicotine [1], coniine [2] , hyoscyamine, scopolamine, and water.
atropine [3] are volatile
• Narceine, morphine, psychotrine and pilocarpine are insoluble in organic
solvents. Theobromine and theophylline almost insoluble in benzene
[1] D.K.Holdsworth. 1998. [2]. G. Biswas. 2012. [3]. D. M. Culbreth ‐ 1996 W.A. Kukula‐Koch. 2017 95 Mazen A. El‐Sakka.2010 W.A. Kukula‐Koch. 2017 96

Solubility Solubility
– In contrast, the salts of alkaloids are soluble in water or dilute acids, whereas – Octanol/water partition coefficient (Pow, log Pow)
they are insoluble or sparingly soluble in organic solvents. Coctanol Coctanol
 Exception: log Pow = log
Cnước
• Salts insoluble in water: quinine sulphate, berberine chloride
• Salts soluble in organic solvents: Lobeline HCl and apoatropine HCl soluble in chloroform.
High log Pow Dissolve easily in non-polar solvent CH2O
• Both alkaloidal bases and their salts are soluble in alcohol (MeOH, EtOH).
• Water soluble alkaloid: Quartenary alkaloid salts (except: Berberine
chloride), N‐oxide alkaloids, polyhydroxy alkaloids [1]
– These differences in the solubility of alkaloids, depending on their The octanol/water partition coefficient can be determined experimentally by liquid‐
form, are used in the pharmaceutical industry for their purification. liquid extraction and by high‐performance liquid chromatography (HPLC) and can also
be theoretically calculated from parameters related to the structure of molecules
Mazen A. El‐Sakka.2010 W.A. Kukula‐Koch. 2017 97 Joaquín Isac‐García. 2016 98
– Solubility – logPow
logPow
alkaloid log Pow pKa
Hyoscyamin 1,53 Cocain 3,08
morphin 0.87 8.2 Morphinan alkaloids dissolve
Scopolamin 1,34 Apoatropin 3,21 easily in water (low log Pow)
oxymorphon 1.15 9.3
Pelletierin 0,45 Truxillins 4,30
hydromorphon 1.06 8.2
Ψ-Pelletierin 0,63 Quinin 3,44
hydrocodon 1.83 8.9
Ecgonin -0,60 Reserpin 4,40
oxycodon 1.87 8.9
codein 1.39 8.2
nor-codein 0.89 9.2
99 100
– Optical rotation (D)
– Color and taste
• Many alkaloids are optically active, with counterclockwise isomers (e.g., (‐)‐
• Majority of alkaloids are colorless with a bitter taste[1]. Burning (hot) taste: Capsaicin,
hyoscyamine) and are more pharmacologically active in contrast to the
Piperine, chavicine [2]. Sweet taste: (4S,2R)‐4‐Hydroxy‐2‐pyrrolidine carboxylic
corresponding racemic mixtures which are characterized by lower activity, or a
(Amanita) [3]
quite different activity.
Exception:
 (‐)‐Morphine: Analgesic, the enantiomers of morphine ((+)‐Morphine: non‐ analgesic) [1]
 Berberine, colchicine (orange‐yellow),
 L‐ephedrine is 3.5 times more active than d‐ephedrine.
 Canadine, serpentine) (yellow),
• Exceptions:
 Sanguinarine (red)
 d‐Tubocurarine is more active than the corresponding L‐from.
 Strong fluorescence (e.g., quinine)
 Both quinine (L‐from ) and its D‐isomer quinidine are active.
 Some pyrrolizidine and indolizidine alkaloids are not bitter in their pure forms.
 The racemic dl‐atropine is physiologically active.
 Caffeine and quinine solutions: as reference standards for bitter taste
(1. Arnold Brossi. 1998).
[3]W. Southon. 1989 Mazen A. El‐Sakka.2010 [1]W.A. Kukula‐Koch. 2017 101 Mazen A. El‐Sakka.2010 W.A. Kukula‐Koch. 2017 102
PHYSICAL PROPERTIES PHYSICAL PROPERTIES pKa of some alkaloids

Compounds pKa pKa
Basicity: 1 2
Harmine 7.61 Quinidine 8.77 4.2
Caffeine 1.0
BH+ = H+ + B Nicotine 8.02 3.12 Retronecine 8.88
Theobromine 1.0
pH = pKa + log[B]/[BH+] (Henderson‐Hasselbalch Equation). Theophylline 1.0 Cytisine 8.12 1.20 Arecaidine 9.07
Colchicine 1.85 Thebaine 8.15 NH4OH 9.25
[BH+]/[B] = antilog(pKa‐pH) Piperine 1.98 D,L‐Pelletierine 9.40
Brucine 8.16 2.50
% Ionized = 100/{1+antilog(pH‐pKa)} Narceine 3.3 Codeine 8.21 L‐Hyoscyamine 9.65
Nicotyrine 4.76 Morphine 8.21 Atropine 9.85
 99.9% ionized: pH = pKa ‐ 3 Acetic acid 4.76
Strychnine 8.26 2.5 Tropacocaine 9.88
 99% ionized: pH = pKa – 2 Protopine 5.99 Tropine 10.33
Quinine 8.34 4.3
a‐Narcotine 6.37
 90% ionized: pH = pKa ‐ 1 Cinchonine 8.35 4.28 Heliotridine 10.55
Papaverine 6.40
Ergometrine 6.73 Aconitine 8.35 D‐Coniine 10.9
 50% ionized: pH = pKa (50% free base) Cocaine 8.39 Berberine 11.73
Pilocarpine 6.87
 10% ionized: pH = pKa +1 (90% free base) lsopilocarpine 7.18 Cinchonidine 8.40 4.17 Benzoylecgonine 11.8
Arecoline 7.41 Emetine 8.43 7.56 Sparteine 11.96 4.8
 1% ionized: pH = pKa + 2 (99% free base) Yohimbine 7.45 3.0
 0.1% ionized: pH = pKa + 3 (99.9% free base) Solanine 7.54 Na2CO3: pH of 11.6 for a 0.1 M
L‐Scopolamine 7.55
David W. Newton. 1978 103 Heroine 7.6 Milan Popl. 1990 104
Basicity: Basicity:
– The basicity of alkaloids is due to the presence of a lone pair of electrons on the • Primary amines (R–NH2, mescaline, tryptamine, spermine, spermidine),
amino nitrogen atom. [M. A. El‐Sakka. 2010] • Secondary amines (R–NH‐R’, ephedrine),
– Most alkaloids have basic properties. The pKa values vary from 6 to 12, with most • Tertiary‐amines (R3N, atropine)
alkaloids in the range of 7–9. [A. Conqueiro. 2015] • Quaternary ammonium salts (R4N+, D‐tubocurarine)
 R –NH2 > R‐NH‐R1 > R3 –N.
 Weak bases: Colchicine (amide alkaloid), piperine, quaternary alkaloid (tubocurarine, berberine,
2 2 3
Coptisine, Palmatine, Jatrorrhizine, Columbamine, Sanguinarine…); caffeine, N‐oxide alkaloid  Saturated heterocyclic amines are more basic than aromatic amines (piperidine > pyridine)
(Retrorsine oxide, Senecionine N‐oxide, pyrrolizidine alkaloids N‐oxides…) [1]  Alkyl groups, increase the basicity
 Strong bases: Atropine  Carbonyl groups decrease the basicity (e. g Amide alkaloid, ricinine, purine alkaloid…)
 Amphoteric (phenolic alkaloid): Morphine, narceine.  Amphoteric alkaloids have phenolic group or carboxylic group (Morphine, psycotrine, cephaline
 Neutral: colchicine (phenolic); narceine (carboxylic).
A.N.M. Alamgir. 2018 105 [M. A. El‐Sakka. 2010] A.N.M. Alamgir. 2018 106
PHYSICAL PROPERTIES CHEMICAL PROPERTIES
Basicity: – The influence of different factors such as exposure to light, heat, oxygen,
HO
O acids and alkalis.
O Me Me
H H
O N N O – Alkaloids are less stable in solution than that in the dry state.
N O N N – Alkaloids are decomposed by heat; except caffeine that sublimes without
N Me
HO
O H H Me
decomposition.
piperin/ hồ tiêu Caffeine Morphine
– Most tertiary amine alkaloids are easily transformed to the N‐oxides when
O
MeO
O N exposed to light and oxygen at elevated temperature. N‐oxides are usually
NH
MeO O COOH
water‐soluble, low toxicity and low addictive properties as compared to
MeO H3CO OCH3
O
O the parent tertiary alkaloids.
OMe OCH3
Narceine
Colchicine
107 [M. A. El‐Sakka. 2010] 108
CHEMICAL PROPERTIES CHEMICAL PROPERTIES
– Effect of acids: Hot dilute acids & conc. mineral acids – Effect of alkalines
• Dehydration: form apo‐alkaloid (apomorphine, apo‐atropine)
– O‐demethyl: quinine, narcotine, codeine  phenolic alkaloids by HI (e.g . codeine  • Weak bases (NH4OH): free base from salt
morphine). • Strong bases (KOH, NaOH): Phenolic alkaloid (e. g Morphine)  Phenolate
– Hydrolysis: các ester, glycoside. e.g Atropine, cocaine, reserpine, gluco‐alkaloids (solanine).
• Hot bases: Hydrolysis of ester alkaloid (atropine, cocaine, physostigmine…), cleavage
ATROPINE + H2O ‐> TROPINE + TROPIC ACID
COCAINE + 2H2O ‐> ECGONINE + BENZOIC ACID + METHANOL
of lactone (pilocarpine ‐> pilocarpic acid)
HO
• Isomerization: L‐hyoscyamine  D,L‐Atropine
HO
O O
O H HO
-H2O N O N O-
N
N OH-
HO Conc. HCl N N OH
Morphine Apomorphine
C17H19NO3 C17H17NO2 Pilocarpine Pilocarpate
[Muhtadi.1991]
[M. A. El‐Sakka. 2010] 109 [M. A. El‐Sakka. 2010] 110
NO2
CHEMICAL PROPERTIES O2N
O
N CHEMICAL PROPERTIES
N
H3C
picrolonic acid
– Precipitating reagents (non‐specific reagents): – Precipitation reagents (non‐specific reagents):
• Precipitates do not dissolve in water (Qualitative and quantitative analyses)
1. Dragendroff’s test
 Mayer’s reagent (K2HgI4): Cream, white, pale yellow. Detection: 1/2700 for Morphine, 1/125000 for Quinine
To a few milliliters of the extract, add 2 ml of Dragendroff’s reagent (potassium bismuth iodide). A
 Bouchardat (Wagner)’s reagent (KI3): Brown. 1/10000 for Caffeine
reddish brown precipitate confirms the test as positive.
 Dragendorff (KBiI4): Reddish‐brown (TLC detection). 1/600 (Caffeine)
2. Mayer’s test
 Reinecke salt [NH4[Cr(SCN)4(NH3)2].H2O (Quantitative)
 Scheibler’s reagent(H3P(W3O10)4 (Quantitative)
To a few milliliters of the extract, add a few drops of Mayer’s reagent (potassiomercuric iodide). A
cream colored precipitate indicates a positive test.
 Godeffroy’s reagent (H3Si(W3O10)4
 Sonnenschein’s reagent ((H3P(M3O10)4 (Định lượng) 3. Wagner’s test
 Bertrand’s reagent (Silicotungstic Acid). White to pale yellow To a few milliliters of the extract, add a few drops of Wagner’s reagent (solution of iodine in
 Tannic acid potassium iodide). A reddish brown precipitate indicates a positive test.
• Crystalline precipitates: HAuCl4 ; H2PtCl6; picric acid (Hager’s reagent); picrolonic acid; styphnic acid
W. C. Evans.2009 Phạm Thanh Kỳ. 2015 111 Subhash C. Mandal. 2015 112

– Precipitation reagents (non‐specific reagents):
– Precipitation reagents (non‐specific reagents): • Purine alkaloids (Caffeine) and some other alkaloids do not give precipitates
4. Hager’s test • Care must be taken in the application of these alkaloidal tests, as the reagents also give precipitates with
To a few milliliters of the extract, add a few drops of Hager’s reagent (saturated solution of picric acid). A yellow proteins.
precipitate indicates a positive test. • A variety of non‐nitrogenous oxygenated compounds gave false‐positive alkaloid reactions with
5. Marme’s test Dragendorff's spray reagent. These compounds reacted positively if the oxygen function and the β‐
carbon bonded to the oxygen had high electron density. Thus, aldehydes, ketones, lactones, ethers,
To a few milliliters of the extract, add Marme’s reagent (cadmium iodide + potassium iodide + water). A
esters, epoxides, and peroxides with an ethylene bond or free alkyl groups at the β‐carbon gave a
precipitate is formed. positive reaction, provided that the availability of electrons at the oxygen and the β‐carbon was not
6. Scheibler’s test altered by electron withdrawal or hydrogen bonding.
To a few milliliters of the extract, add Scheibler’s reagent (sodium tungstate + disodium phosphate + water). A  Conjugated aldehydes and ketones: Acrolein, furfural, citral, chakcone, cortisone, cinnamaldehyde
precipitate is formed.  Conjugated lactones: Coumarin; umbelliferone, Digitoxin, Digoxin, Strophanthin, 0uabain.
7. Reineckate test  With additional reactive ether or ester functions: anisaldehyde, vanillin, santonin
 Nonconjugated aldehydes and ketones: menthone, camphor
To a few milliters of the extract, add a few drops of reineckate solution (1 g of ammonium reineckate in water
and 0.3 g of hydroxylamine hydrochloride in 100 ml ethanol). A precipitate is formed.  Phenol, phenolic ethers, and esters: Eugenol, Acetyleugenol, Anethole; Guaiacol; Thymol
Subhash C. Mandal. 2015 113 W. C. Evans.2009 Abdel‐Azim M. Habib. 1980 114
– Precipitation reagents (non‐specific reagents):
– Colour tests for identification of alkaloids (specific reagents)
• False‐positive alkaloid reactions with Dragendorff's spray reagent.
• H2SO4
• HNO3 : Brucine, Belladon…
• Erdmann (Sulfonitric): Brucine…
• Fröhde (Sulfomolypdic acid): Morphine, Ipeca…
• Marquis (Sulfoformol). Morphine…
• Mandelin (sulfovanadic): Strychnine…
• Wasicky (p‐dimethylaminobenzaldehyd/H2SO4) (Van Urk) (Ehrlich). For test of Indole alk. (Ergot)
• Merke (Sulfoselenic)
– Alkaloids must be pured in color test and standards needed for TLC analyses
Abdel‐Azim M. Habib. 1980 115 Phạm Thanh Kỳ. 2008 116

– Colour tests for identification of alkaloids (specific reagents) – Colour tests for identification of alkaloids (specific reagents)
• Cinchona alkaloids
• Caffeine and other purine derivatives
Thalleioquin test: To a dilute alkaloidal solution, add a few drops of bromine water. Shake well
Murexide test: mixing with a very small amount of potassium chlorate and a and then add a drop of strong ammonia solution. An emerald color is produced, which develops
drop of hydrochloric acid, evaporating to dryness and exposing the residue to a red color upon treatment with sulfuric acid.
to ammonia vapour. A purple colour is produced with caffeine and other Erythroquinine test: To a dilute acidic solution of quinine, add a few drops of bromine water, a
drop of 10% solution of potassium ferrocyanide, a drop of strong ammonia solution. A red color
purine derivatives. is formed.
• Colchicine with mineral acids gives yellow colour • Nuxvomica
• Indole alkaloids treated with sulphuric acid and p‐  Mandelin’s test: To the sample solution, add Mandelin’s reagent (sulfuric acid and
ammonium vanadate). A violet blue color develops, which slowly changes to an orange
dimethylaminobenzaldehyde gives bluish‐violet to red colour color. The test is specific for strychnine
• Ipecacuanha alkaloids: Frohde’s test: This gives a greenish color with an  Malaquin’s test: To a dilute solution, add hydrochloride acid, zinc granules, and heat on a
water bath at 100 °C for 5 min. Filter the solution and add a small crystal of sodium nitrate. A
alkaloidal solution. red color is formed
Subhash C. Mandal. 2015 117 Subhash C. Mandal. 2015 118
CHEMICAL PROPERTIES
Spectroscopy of alkaloids
– Colour tests for identification of alkaloids (specific reagents)
• Tropane alkaloids – UV‐Vis
 Vitali–Morin’s test: The extract is treated with fuming nitric acid and is evaporated to dryness on a – IR
water bath. The residue is then treated with 3% caustic potash. A deep purple color is formed.
 Rathenasinkam’s test: In this test, nitric acid is used to effect the nitration of the benzene ring in – MS
atropine, hyoscyamine, and hyoscine. To the residue, add a few drops of ammonia and extract
with chloroform. The chloroform extract is evaporated, and the residue is dissolved in acetone. A – NMR
few drops of 10% sodium hydroxide is then added. A bluish‐purple color is formed.
• Morphine
 Marquis’ reagent: Formaldehyde in concentrated sulfuric acid. Purple red changing to purple is
observed. Frshde’s reagent: Molybdate in concentrated sulfuric acid. Violet, quickly changing to
strong purplish red, fading out to weaker brown or brownish, then developing green. Mecke’s (or
Lafon’s) reagent (Selenious acid in concentrated sulfuric acid). Green, quickly greenish blue,
changing to blue, slowly to bluish green with a yellow–brown edge, then olivaceous green.
Subhash C. Mandal. 2015 119 120

Spectroscopy of alkaloids Spectroscopy of alkaloids
Diagram of the electromagnetic spectrum, showing various
properties across the range of frequencies and wavelengths
Wikipedia. 2007 121 Wikipedia. 2007 122
Spectroscopy of alkaloids UV‐Vis
UV‐Vis
– Energy changes of electronic transitions
– Highest occupied molecular
orbital (HOMO) (2)
– Lowest unoccupied
molecular orbital (LUMO)
(*3)
Timothy Soderberg. 2016 123 Richard Koplík. https://web.vscht.cz 124

UV‐Vis UV‐Vis
– Molecular absorption of electromagnetic radiation –Spectral regions
• Changes of energy state of the molecule include
 Electronic state: ΔEe =150‐600 kJ/mol ((electron transitions between orbitals) Region λ Absorbing compounds
 Vibrational state: ΔEv =2‐60 kJ/mol
Far ultraviolet (vacuum UV saturated and mono‐
 Rotational state: ΔEr ≈ 3 kJ/mol <190 nm
region) unsaturated
• Relation to the absorbed radiation wavelength poly‐unsaturated and
(Near) ultraviolet 190‐380 nm
 ΔE = ΔEe + ΔEv + ΔEr = h . ν = h . c / λ (h = 6.626 . 10‐34 J s (Planck’s constant) aromatic
Visible light region 380‐780 nm coloured
Richard Koplík. https://web.vscht.cz 125 Richard Koplík. https://web.vscht.cz 126
UV‐Vis UV‐Vis
– Visible light absorption
λ (nm) Colour of light Colour of absorbing body –Lambert‐Beer law

400–435 violet yellow‐green • Transmittance T = I/I0
435–480 blue yellow
• in a diluted solution the value of absorbance A measured at the
480–490 green‐blue orange
490–500 blue‐green red‐orange specific wavelength is proportional to the concentration of absorbing
500–560 green red compound
560–580 green‐yellow violet • Aλ = ‐ log T = log (I0/I) = ελ . b . C
580–595 yellow‐orange blue
• εmax ≈ 103–105 l.mol‐1.cm‐1
595–620 red‐orange green‐blue
620–760 red blue‐green
UV‐Vis UV‐Vis
– Terms used in UV/VIS spectrometry – Shifts in absorption position and intensity
• Chromophore: a group of atoms responsible for UV/VIS absorption of the molecule, e.g. double
bonds C=C, C=C‐C=C, C=O, N=N, aromatic rings etc
• Auxochrome: a substituent that increases absorption of a molecule, typically ‐CH3, ‐OH, alkoxyl or
amino group or an atom of halogen; when the auxochrome is conjugated with a π‐electron
system, the λmax value is shifted to a longer wavelength (bathochromic efect)
• Bathochromic effect (red shift): a shift of λmax to longer wavelength caused by molecule
modification or a change of solvent
• Hypsochromic effect (blue shift): a shift to shorter wavelength
• Hyperchromic effect: an increase of absorption
• Hypochromic effect: a decrease of absorption
Richard Koplík. https://web.vscht.cz 129 L.D.S. Yadav. 2005 130
UV‐Vis UV‐Vis
Some chromophores and the corresponding transitions
– Conjugated polyenes
Chromophore Transition λmax (nm)
an example of compound
H2O σ→σ* 183
C-C a C-H, CH4 σ→σ* cca 170, 173 n H−(CH=CH)n−H CH3−(CH=CH)n−CH3
C-X, CH3OH, CH3NH2, CH3I n→σ* 180-260, 187, 215, 258
C=C, H2C=CH2 π→π* 160-190, 162 λmax (nm) log ε λmax (nm) log ε
H2C=CH−CH=CH2 π→π* 217 2 217 4.3 223 4.4
C=O, H−CH=O n→π*, π→π* 270, 170-200, 270, 185
H2C=CH−CH=O n→π*, π→π* 328, 208 3 268 4.7 275 4.5
C=N n→σ*, n→π* 190, 300
N=N n→π* 340 4 304 ? 310 4.9
C=S n→π* 500 5 334 5.1 341 5.1
NO2 n→π* 420-450
N=O n→π* 630-700
UV‐Vis UV‐Vis
– Benzene and its derivatives – Heterocyclic compounds
• 5‐membered
Compound λmax (nm) log ε λmax (nm) log ε λmax (nm) log ε
benzene 204 3.9 254 2.0 ‐ ‐
toluene 207 3.8 261 2.4 ‐ ‐ Compound λmax (nm) log ε λmax (nm) log ε
brombenzene 210 3.9 261 2.3 ‐ ‐ furan 200 4.0 ‐ ‐
phenol 211 3.8 270 3.2 ‐ ‐
2‐furaldehyde 227 3.3 272 4.1
benzaldehyde 250 4.1 280 3.0 320 1.7
acetophenone 246 4.0 280 3.0 320 1.7 2‐acetylfuran 225 3.4 269 4.1
benzoic acid 230 4.1 273 3.0 ‐ ‐ pyrrole 210 4.2 240 2.5
aniline 230 3.9 280 3.5 ‐ ‐ 2‐acetylpyrrole 250 3.6 287 4.2
styrene 247 4.0 281 2.0 ‐ ‐ thiophene ‐ ‐ 235 3.7
cinnamaldehyde 285 4.4 ‐ ‐ ‐ ‐ 2‐acetylthiophene 260 3.9 285 3.7
cinnamic acid 273 4.3 ‐ ‐ ‐ ‐ thiazole ‐ ‐ 240 3.6
biphenyl 248 4.2 ‐ ‐ ‐ ‐
UV‐Vis N UV‐Vis
HợP chất không có chromophore khi dùng HPLC
– Heterocyclic compounds – Solvents for UV spectrometry dùng dm là acetonitrile như saponin
• 6‐membered 2-Picoline
Solvent λ (nm) Solvent λ (nm)
acetonitrile, water 190 chloroform 240
Compound λmax (nm) log ε λmax (nm) log ε λmax (nm) log ε
isooctane,
195 ethylacetate 260
Pyridine 195 ‐ 250 3.3 ‐ ‐ cyclohexane
2‐Picoline ‐ ‐ 262 3.4 ‐ ‐ hexane 201 dimethylformamide 270
Pyrazine ‐ ‐ 260 3.7 ‐ ‐ methanol, ethanol 205 acetic acid. 270
1,4-dioxane 215 benzene 280
Quinoline 227 4.6 275 3.7 313 3.4 N
diethylether 220 toluene 285
Isoquinoline 218 4.9 262 3.6 317 3.5 N glycerol 230 pyridine 300
Pyrimidine ‐ ‐ ‐ ‐ 343 3.3 Pyrimidine
dichloromethane 233 acetone 330
UV‐Vis: ALKALOID UV‐Vis: ALKALOID
– Large number of alkaloids of varying structural types; for example, most of the
Argyrolobine
Caffeine
pyrrolidine and diterpene alkaloids, which have no ultraviolet spectra. Sparteine
Berberine
Senecionine
– Some structural types are, however, included because of chromophore‐containing Alk. max Alk. max
Sparteine 200 Colchicine 234 sh, 246, 355
substituents; for example, the pyrrolizidine and tropane alkaloids.
Senecionine 215 Berberine 230, 267, 344, 352, 432
Argyrolobine 240 Palmatine 228, 240, 268, 276, 343, 350, 433
Colchicine 234 sh, 246, 355 Jatrorrhizine 228, 241, 267, 352, 440
Caffeine 227 sh, 272 Coptisine 229, 241, 268, 354, 363, 467
Argyrolobine: C=C-N-C=O grouping with a maximum at 240 nm

Lenka Grycova. 2007
A. W. SANGSTER., 1965 A. W. SANGSTER., 1965
137 138
RO
UV‐Vis: ALKALOID Bathochromic UV‐Vis: ALKALOID
O H
– Influence of pH on ultraviolet absorption
of morphine and codeine N UV spectra of some common indole
HO
– By measuring UV spectra at various pH, chromophores (not normalized for
Morphine: R=H
information can be obtained about the Codeine: R=OCH3 concentrations)
presence of phenolic groups. [R.
VERPOORTE. 1994]
https://www.unodc.org/unodc/en/data‐and‐
analysis/bulletin/bulletin_1955‐01‐01_3_page006.html
United Nations Office on Drugs and Crime
139 140 [R. VERPOORTE. 1994]
Alkaloid max Alkaloid max
Aconitine 273, 280 Emetine 282
UV spectra of some aromatic Ajmaline 292 L‐Ephedrine 257, 263 d‐Coniine
substituted indole alkaloids (not Arecaidine 214 Ergot alkaloids 240, 310
normalized for Arecoline 214 Germine No chromophore
concentrations) Atropine 258, 262 Hygrine No chromophore

Berberine 265; 345 L‐Lobeline 245, 280 Hygrine
Brucine 263, 301 Lupinine No chromophore
Caffeine 271 Morphine 284
Cinchonidine 286, 315 Nicotine 262
Cinchonine 284, 315 Palma tine 347
Cocaine 273 Papaverine 279, 326
Quinine
Codeine 285 Quinine 332
Conhydrine No chromophore Reserpine 267, 295
Milan Popl.1990.
d‐Coniine No chromophore Scopolamine 258, 264
141 [R. VERPOORTE. 1994] Dictamnine 309, 328 Strychnine 254, 289 142
Alkaloid group Dominating chromophore Examples Alkaloid group Dominating chromophore Examples
Phenylethylamine Benzene Mescaline, ephedrine Senecio Isolated double bond Heliotridine, retronecine
Pyridine Pyridine Nicotine, anabasine Lupine Non‐absorbing Lupinine, sparteine
Dihydro‐ and ‐CH=CH‐C=O Arecoline, arecaidine Amaryllidaceae Benzene Lycorine
tetrahydropyridine alk.
Piperidine Nonabsorbing Pelletierine, coniine Purine Purine Caffeine, theophylline,
Benzene (substitution) Lobeline theobromine
Tropane Nonabsorbing Tropine, scopine, methylecgonine Indole Indole Gramine
Benzene (substitution) Atropine, hyoscyamine, cocaine Ergot Lysergic Ergot alk.
Quinoline Quinoline Cusparine, Quinine Diterpene Benzene (substitution) Aconitine, delphinine
Isoquinoline Benzene Anhalamine, Papaverine, Morphine Steroid Nonabsorbing Tomatidine, veracevine,, germine
Isolated double bond Solanidine
Milan Popl.1990. 143 Milan Popl.1990.
144
IR IR
– The IR can be divided into three spectral subregions:
• The near extends from 800 to 2500 nm (NIR),
• The mid from 2500 to 15000 nm (MIR),
• The far‐IR from approximately 15,000 to 100,000 nm (FIR). [Meisam Omidi. 2017]
– To date, most near‐IR spectroscopic studies have focused on two main
areas: blood glucose analysis and haemodynamic monitoring.
[Michael Jackson. 1999]
145 https://www2.chemistry.msu.edu 146
IR IR
– Characteristic IR absorbances
– The region 1400–650
cm−1 is known as the
‘fingerprint region’ and is Characteristic IR
Functional group Source of signal
usually checked for absorbance(s) (cm‐1)
identification as Carbonyl 1650‐1750 (strong) C=O stretching
absorptions in this region Alcohol 3200 ‐ 3600 (broad) O‐H stretching
are characteristic of a 1700‐1725 (strong) C=O stretching
Carboxylic acid
substance. This can be 2500‐3000 (broad) O‐H stretching
compared to infrared Alkene 1620 ‐ 1680 (weak) C=C stretching
3020 ‐ 3080 vinylic C‐H stretching
spectra of known
1620 ‐ 1680 (weak) triple bond stretching
substances for Alkyne
3250‐3350 terminal C‐H stretching
identification.
Sue Clarke. 2008 147 Timothy Soderberg. 2016 148

IR ‐ Bohlmann’s IR criterion IR ‐ Bohlmann’s IR criterion
– IR spectroscopy has been used to assign the stereochemistry and conformational
preferences of quinolizidines, indolizidines, pyrrolizidines, and other fused 6/5 and 5/5
ring systems.
– Bohlmann found that it was possible to distinguish between the cis and trans
configurations of the quinolizidine moiety: the trans‐fused systems exhibited a
characteristic series of bands in the IR spectrum between 2700 and 2800cm‐1, which
were absent when the quinolizidine was cis‐fused.
– It has generally been ascertained that Bohlmann’s IR criterion, originally deduced for
the quinolizidine system, is applicable to other saturated systems with a bridgehead
nitrogen atom. (H‐C‐N‐)
Malgorzata Baranska. 2009 G. W . GRIBBLE. 1973

149 2700 and 2800cm‐1 150
IR (KBr) of conessin
IR ‐ Bohlmann’s IR criterion
– Protons alpha to a nitrogen atom in a rigid ring give rise to characteristic absorptions in
80
the infrared near 2700 cm‐1 when they are situated antiperiplanar to the nitrogen lone
electron pairs. First observed by Wenkert, they are commonly called “Bohlmann Me
N Me
bands”. Their use aided the characterization of the lupin alkaloids, such as sparteine, 60
and matrin. Me
1329
Me
889 799
N 997
40
Me 1175
1456 1377
1433
1040
20
2760
2939
Sparteine Matrin 4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500
151 152
cocain.HCl morphin base
COOMe
HO
ClH N OOC Ph
N Me
HO
153 154
codein base heroin.HCl
O
CH3 C O
MeO
O
O
N Me
CH3 C O H Cl
N Me O
HO
155 156
IR (KBr) of caffein base Mass spectroscopy
– Mass spectrometry (MS) is a powerful analytical technique widely used by chemists,
biologists, medical researchers, and environmental and forensic scientists, among
others.
– Looking at the mass of a molecule, or of different fragments of that molecule.
O
Me Me – Instrument of MS:
N N
1. ionization source, where the molecule is given a positive electrical charge, either by removing
O N N
an electron or by adding a proton. Depending on the ionization method used, the ionized
Me
molecule may or may not break apart into a population of smaller fragments. Some of the
không có
sample molecules remain whole, while others fragment into smaller pieces.
>C-O-
2. Mass analyzer, where the cationic fragments are separated according to their mass.
3. Detector, which detects and quantifies the separated ions.
4. Recorder: Computer
157 Timothy Soderberg. 2016 158
Mass spectroscopy Mass spectroscopy
– MS
− Mass spectrometry
• MS: Mass of a
molecule, or of
different fragments of
that molecule
SOMOGYI, Á. (2008). 159 Timothy Soderberg. 2016 160

– Mass Spectrometer (MS) –MS
• Ionizes a gaseous molecule using enough energy that the resulting ion breaks apart into smaller ions.
• Ionization Methods:
• Ions have different mass‐to‐charge ratios (m/z), so ions separated using a magnetic field or an
1. Gas Phase (‘‘Hard’’) Ionization Methods
electrical field.
• Electron Impact Ionization (EI) This classical ‘‘hard’’ ionization method
• Mass spectrum contains both quantitative and qualitative information employs an electron beam (70 eV) passing through the sample in the gas
• Using the mass spectrum to help identify a mixture’s components phase. can be applied to all volatile and thermally stable compounds.
• Chemical Ionization (CI): Reagent gas such as ammonia or methane is
ionized by electron impact. Molecular ions such as [M+H]+ are obtained
David Harvey. 2019
161 G. Gauglitz. 2014 162
Electron Impact Ionization (EI)
–MS –MS Chemical Ionization (CI)
SOMOGYI, Á. (2008). 163 SOMOGYI, Á. (2008). 164

–MS –MS
• Ionization Methods:
2. ‘‘Soft’’ Ionization Techniques
1. Field desorption (FD): Electron tunneling from an emitter biased at a high electrical potential.
2. Fast Atom Bombardment (FAB): The sample is dissolved in a liquid matrix with low volatility
such as glycerol or m‐nitrobenzyl alcohol and deposited on a target. The target is then
bombarded with a continuous beam of fast atoms (e.g., Xe) or ions (e.g., 131Cs+).
3. Electrospray Ionization (ESI): Analyte is sprayed at atmospheric pressure into an interface to
the vacuum of the mass spectrometer ion source. The sample solution is sprayed across a high
potential difference (1–4 kV) from a needle tip into an orifice of the mass spectrometer.
4. Matrix‐Assisted Laser Desorption/Ionization (MALDI): pulsed laser is typically used to desorb
species from a target surface. Therefore, amass analyzer compatible with pulsed ionization
methods has to be used. Mmore sensitive than ESI, mass range 1–2 MDa, Disadvantages: low
salt tolerance
165 Electrospray Ionization (ESI) 166
G. Gauglitz. 2014 G. Gauglitz. 2014
–MS –MS
Electrospray Ionization (ESI) Matrix‐Assisted Laser Desorption/Ionization (MALDI)
Somoyi A. 2008 167 G. Gauglitz. 2014 168
Mass spectroscopy Magnetic Sector Mass spectroscopy
–MS Magnetic field B

• Mass Spectrometric Analyzers Voltage V
 Magnetic Sector Mass Analyzers TOF
 Quadrupole Mass Analyzers
 Time‐of‐Flight Mass Analyzers (TOF)
 Trapped‐Ion Mass Analyzers
 Hybrid Analyzers: quadrupole analyzer as a gate in conjunction with an
orthogonal TOF analyzer (Q‐TOF analyzer)
G. Gauglitz. 2014 169 Magnetic Sector Mass Analyzers G. Gauglitz. 2014 170
Quadrupole Mass Analyzers
G. Gauglitz. 2014 171 Time‐of‐Flight Mass Analyzers (TOF) Somogyi A. 2008 172
– Detector
• Faraday Cup detector (or Cylinder electrode): relatively insensitive detector but is very
robust. Ideally suited to isotope analysis and Isotope-ratio mass spectrometry.
• Electron Multiplier
• Photomultiplier (or Scintillation Counter)
Trapped‐Ion Mass Analyzers
G. Gauglitz. 2014 173 http://www.chm.bris.ac.uk/ms/detectors.xhtml 174
– Detector – Detector
• Faraday Cup detector (or Cylinder electrode) • Electron Multiplier
http://www.chm.bris.ac.uk/ms/detectors.xhtml 175 http://www.chm.bris.ac.uk/ms/detectors.xhtml 176

– Detector – electron impact
• Photomultiplier
most common detectors
http://www.chm.bris.ac.uk/ms/detectors.xhtml 177 Timothy Soderberg. 2016 178
Tandem mass spectrometry (MS/MS) Tandem mass spectrometry (MS/MS)
O.D. Sparkman et al. (2011) 179 Arpana Vaniya et al. 2015 180

MS MS
– Double Bond Equivalent
• Double Bond Equivalent (DBE)) (degree of unsaturation‐DoU) (IHD: index Hydrogen
Nitrogen rule states that organic compounds
deficiency): pi () or cyclic. E.g. benzene : DBE = 4 (3  and 1 cyclic) containing exclusively hydrogen, carbon, nitrogen,
• DBE = C – (H/2) + (N/2) + 1
 C: Carbon.
oxygen, silicon, phosphorus, sulfur, and the halogens
 H: H or halogen either have
 N: Nitrogen
1. An odd nominal mass that indicates an odd number of
• CH3CH2CH2Br, DBE = 3‐(8/2)+(0/2)+1=0
nitrogen atoms are present or
2. An even nominal mass that indicates an even number of
nitrogen atoms in the molecular formula of the
molecular ion
www.chem.ucla.edu/harding/notes/notes_14C_MS.pdf 181 http://www.chem.ucla.edu 182
MS MS
• Nitrogen rule
– Rule of Thirteen
• The first step in applying the rule is to assume that only carbon and hydrogen are present in
the molecule and that the molecule comprises some number of CH "units" each of which has
a nominal mass of 13.
• A negative value of u indicates the presence of heteroatoms in the molecule and a half‐
integer value of u indicates the presence of an odd number of nitrogen atoms. On addition of
heteroatoms, the molecular formula is adjusted by the equivalent mass of carbon and
hydrogen. For example, adding N (=14) requires removing CH2 (=14) and adding O (=16)
requires removing CH4 (=16)
183 the degree of unsaturation 184

http://www.chem.ucla.edu J. W. Bright. 1983
MS MS
–Rule of Thirteen – Rule of Thirteen
• An alkaloid was isolated from a common household beverage. The • The Drug Enforcement Agency (DEA) confiscated a hallucinogenic substance
during a drug raid. When the DEA chemists subjected the unknown
unknown alkaloid proved to have a molecular mass of 194. Using the
hallucinogen to chemical analysis, they found that the substance had a
Rule of Thirteen, determine a molecular formula and an index of molecular mass of 314. Elemental analysis revealed the presence of carbon
hydrogen deficiency for the unknown. Alkaloids are naturally and hydrogen only. Using the Rule of Thirteen, determine a molecular formula
occurring organic substances that contain nitrogen. (Hint: There are and an index of hydrogen deficiency for this substance. (Hint: The molecular
four nitrogen atoms and two oxygen atoms in the molecular formula. formula of the unknown also contains two oxygen atoms. The unknown is
The unknown is caffeine. Look up the structure of this substance in tetrahydrocannabinol, the active constituent of marijuana. Look up the
structure of tetrahydrocannabinol in The Merck Index and confirm its
The Merck Index and confirm its molecular formula.
molecular formula.)
Donald L. Pavia. 2009
185 Donald L. Pavia. 2009 186
MS MS
General MS/MS – MS/MS mass spectra of (I)
fragmentation pathways aporpine‐, (II)
of aporpine‐ and protoberberine‐, (III)
protoberberine‐ type tetrahydroprotoberberine‐
alkaloids
, and (IV) protopine‐type
alkaloids.
[M + H − CH4]+ (a-type)
[M+ H − CH4 −CH2O]+ (b-type)
[M + H − CH4 − CO − CH2O]+ (c-type),
[M+ H − CH4 − CO]+ (d-type)
187 Hee Jung Shim. 2013 188 Hee Jung Shim. 2013

NMR 1H‐NMR
Timothy Soderberg. 2016 189 http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 190
1H‐NMR 13C‐NMR
http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 191 http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 192

15N‐NMR Structure Elucidation of Alkaloid
– The identification of an alkaloid is first of all a matter of classification.

– From plant material, chemotaxonomy will provide information about the
type of alkaloid commonly found in that particular plant, plant genus, or
family
• Menispermaceae (4000 compounds) : Isoquinoline alkaloids.
• Apocynaceae, Loganiaceae, or Rubiaceae (4100 compounds): Indole alkaloids.
• Some of alkaloids are typical for the genus.
https://en.wikipedia.org/wiki/Nitrogen‐
15_nuclear_magnetic_resonance_spectroscopy 193 R. VERPOORTE. 1994 194
Structure Elucidation of Alkaloid Structure Elucidation of Alkaloid
– Known alkaloids: – Strategy for the identification of known alkaloids
• Complete isolation is not necessary.

• Co‐TLC, co‐GLC, and/or co‐HPLC, mass spectrum (e.g., obtained after GC‐MS of a
crude extract), High Resolution‐MS (HR‐MS), NMR (1H, 13C), 2D‐NMR.
– Unknown alkaloids:
• Derivative of a known alkaloid (M): UV and MS data: hydroxy (M+16), methoxy
(M+30), acetyl (M+42), or N‐oxide (M+16).
• Novel structure: 1H‐NMR, 13C‐NMR, IR, MS..
R. VERPOORTE. 1994 195 R. VERPOORTE. 1994 196

Structure Elucidation of Alkaloid Alkaloid extraction
– Strategy for structure determination of novel alkaloids
–Extraction of alcohol solvent
• Chemotaxonomy: Type of alkaloid
• Both free and salt alkaloids can be dissolved in methanol, ethanol, alcohol reflux,
• UV: Chromophore
percolation or immersed can be used.
• MS: Molecular weight, known fragments, simple derivative of known alkaloid
• The advantage: Different alkaloids or alkaline salts can be suit, water‐soluble
(fragments +14, +16, +30, etc.)
impurities such as polysaccharides, proteins are less extracted.
• 1H‐NMR: Characteristic features, eventually complete assignment with the aid of 2D
• The drawback: More fat‐soluble impurities is extracted. Using acidic water‐ alkaline
methods and nOe
‐ extraction methods to remove fat‐soluble impurities. The specific method is that
• 13C‐NMR: Characteristic features, functional groups, 2D‐methods for e.g. C‐H (long
recover alcohol from alcohol extracts and add dilute acid water and stir, place, filter,
range) couplings
after basifying solution, use an appropriate lipophilic organic solvent to extract,
• IR: Functional groups recover solvent and total alkaloids are obtained.
R. VERPOORTE. 1994 197 JI Yubin. 2014 198
Alkaloid extraction Alkaloid extraction
–Extraction with water or acidic water Stas‐Otto process
• Alkaline alkaloids is present in salt form in the plant
The Powdered plant material was acidified
• Using water or acidic water to extract
with tartaric acid and then extracted with
• Inorganic acidic extraction is used Ethanol (90-95%). The alcohol portion was
• 0.1% to 1% sulfuric acid, hydrochloric acid or acetic acid, tartaric acid solution then distilled off under vacuum condition.
• Maceration or percolation method Later Petroleum ether was added to the
• The advantage: Increasing the solubility in with inorganic acidswater, and relatively aqueous residue to remove fatty components.
simple. Again the aqueous portion was filtered and
• The main drawback: Difficulty concentrating, and has more water‐soluble evaporated in Rotary evaporator
impurities.
Dr. G. Madhumitha. 2015
JI Yubin. 2014 199 200
Alkaloid extraction
Alkaloid extraction
–Extraction with lipophilic organic solvent
– N: Non‐polar compounds • Most of the free alkaloid are lipophilic, so chloroform, benzene
– B: Bases (toxic), ether and methylene chloride (CH2Cl2) can be used to
extract free alkaloid.
• Impregnated, reflux or continuous reflux extraction can be used
Ether
to extract
• Using a small amount of alkaline water wetting medicine and
then extracting so that make the alkaloid free, also may increase
the solvent penetrating the plant cell, then extract with
Water lipophilic organic solvent (CHCl3, CH2Cl2…)
• Strong bases (NaOH, KOH) can be used for tannate alkaloid
(with tannin) (E.g. Cinchona bark, Pomegranate bark)
• The main advantage: Less water soluble impurities
• Disadvantage: High price of the solvent, poor security
https://chem.libretexts.org/Bookshelves/Ancillary_Materials/Demos_Techniques_and_Experiments/Gener
al_Lab_Techniques/Acid‐Base_Extraction
201 JI Yubin. 2014 202
Alkaloid separation Alkaloid separation
– Separation of
– Separation of different classes of alkaloids
different classes of
alkaloids
B
Alkaline layer
JI Yubin. 2014 203 JI Yubin. 2014 204

Alkaloid separation B Alkaloid separation
– Separation of – According to the difference of basicity of alkaloids
different classes of
• PH gradient extraction to separate
alkaloids
• Method 1: Total alkaloids dissolved in the lipophilic organic solvents, then with
different acid buffers to extract in descending order by PH, alkaloids according to its
alkaline from strong to weak formed salt and sequentially to be extracted.
• Method 2: total alkaloids dissolved in acidic water, gradually adding alkaline water
to make PH value from low to high, whenever adjusting PH value, must be
extracted with other organic solvents such as chloroform, each monomer alkaloids
according to its alkaline from strong to weak formed salt sequentially to be
extracted and then separated.
JI Yubin. 2014
JI Yubin. 2014 205 206
– Method 1: Total alkaloids dissolved in the lipophilic
– Method 1
organic solvents Atropin Hyoscyamin Hyoscin
(pKa 9.85) (pKa 9.65) (pKa 6.75)
hòa tan trong HCl loãng
Atropin.HCl Hyoscyamin.HCl Hyoscin.HCl
+ dd. NaHCO3 đến pH 7.5 Lắc phân bố với Et2O
Atropin.HCl Hyoscin base

Hyoscyamin.HCl (trong lớp Et2O)
JI Yubin. 2014 207 JI Yubin. 2014 208

– Method 2: total alkaloids dissolved in acidic water – Method 2
1. Từ alkaloid muối/nước
Hòa cắn alk. base ∑ của rễ Ba gạc / HCl loãng.
- chỉnh về pH 6-7, dd. sẽ hơi đục, chiết (lần 1) = CHCl3

 yohimbin, rererpin, rescinamin (alk kiềm yếu nhất).
- chỉnh về pH 8-9, dd. nước lại đục, chiết (lần 2) = CHCl3

 ajmalin, ajmalicin (alkaloid kiềm mạnh hơn).
- chỉnh về pH 12-13, dd. nước lại đục, chiết (lần 3) = CHCl3

 serpentin, alstonin (alk. NIV, alkaloid kiềm mạnh 1’)
JI Yubin. 2014 209 210
– According to the basic difference of – According to the solubility difference of alkaloids or its salt
alkaloids to separate • Oxymatrine’s polar slightly stronger than matrine, and it is insoluble Oxymatrine
• Fraction L: lipophilic compounds and in ether and matrine is soluble in ether, alkaloids dissolved in
non‐basic alkaloids
chloroform, add ether for more than 10 times, oxymatrine can
• Fraction A: quaternary
benzophenantridine alkaloids, precipitate.
matrine
protopine alkaloids, tertiary bases • Ephedrine, pseudoephedrine separated by oxalic acid, ephedrine
N
soluble in ether H
oxalate precipitate crystals.
H
• Fraction B: citrates of quaternary H H
• Brucine and strychnine separated by EtOH 20% or 50% N
protoberberine alkaloids O
• Fraction E: the rest of fraction A, non‐ O
polar compounds Strychnine
• Fraction I highly polar quaternary
alkaloids (as iodides) JI Yubin. 2014
211 Lenka Grycova. 2007 212
– According to alkaloids special functional group
– According to the solubility difference of alkaloids or its salt
• Phenolic alkaloids form a salt and soluble in water in alkaline conditions, morphine have phenolic
• Strychnine and Brucine
hydroxyl and codeine having no phenolic hydroxyl, with sodium hydroxide solution treating opium
 The mother liquor is concentrated in vacuo on a water bath until most of the alcohol has been alkaloids solution, morphine form salt and dissolve, codeine precipitate.
removed. The residue is acidified to pH 6 with dilute sulfuric acid and then concentrated to a volume
of 3 to 4 ml. After standing in a refrigerator overnight, the product is filtered and washed with cold • Lactone or lactam structure alkaloids can be saponified by heating in an alkaline aqueous solution
water. Brucine sulfate is purified by dissolution in 4.5 volumes of hot distilled water and boiled with a to generate open‐loop and form carboxylic acid salt which is water‐soluble. E.g. Camptothecin.
little charcoal for 1 hr. It is filtered hot and left in a refrigerator for several days. Brucine is recovered
from the sulfate in a manner analogous to that outlined for strychnine; recrystallization from aqueous
acetone yields crystals of mp 178°C.
• Warning! Extreme caution should be exercised in carrying out this experiment. The hands must be
washed thoroughly because of the high toxicity of these alkaloids.
Camptothecin
Raphael Ikan. 1991
213 JI Yubin. 2014 214
– According to difference of polarity – Precipitation method
LogPow: • Water‐soluble alkaloids mainly referring quarter ammonium separated by Reye
• Hexan: 3.13 ammonium salt (Reinecke’s ammonium salt) (NH4[Cr(NCS)4(NH3)2] ).
• CHCl3 = 0.84 • Quaternary ammonium base solution with dilute mineral acid solution to adjust
• Diethyl ether = 0.84 PH 2‐3, add freshly prepared alkaloids Reye salt saturated aqueous solution, the
độ phân cực tăng dần
• CH2Cl2 = 0.84 alkaloids Reye salt precipitate, filtration after complete precipitation, precipitation
• EtOAc = 0.28 was washed with a little water to the washing liquid is not red so far
Serban C.Moldoveanu. 2017
215 JI Yubin. 2014 216
JI Yubin. 2014
– Crystallization: – Isolation of polyhydroxy alkaloid
• Some acids such as hydrochloric, hydrobromic, perchloric, picric, and oxalic to form the
• Monocyclic or bicyclic alkaloids of the pyrrolidine, piperidine, pyrrolizidine,
corresponding salt of alkaloids. Sulfate acid or neutral of some alkaloids can be crystallized in
alcohol or water. indolizidine and tropane classes, bearing two or more hydroxyl groups.
• Hydrochloric or hydrobromic acid in methanol is recommended • Highly water soluble and frequently quite insoluble in non‐hydroxylic solvents
• MeOH used for free base of alkaloids
• Lack of a chromophore
• Solution of alkaloid in MeOH with HX ca be crystallized by adding ether, hot acetone or acetone with
methanol. • Extraction and isolation:
 EtOH or MeOH admixed with 25–50% water. Dilute acid has also been added. EtOAc,
CHCl3
 Ion‐exchange chromatography: anionic or cationic forms, Dowex 50 or Amberlite
CG120.
R. F.MANSKE. 1950 217 Russell J. Molyneux. 2002 218
– Polyhydroxy alkaloid – Artifacts while separation
• Alkaloids are often rather unstable, e.g., N‐oxidation is quite common.
• Heat, light, solvent
• Chloroform (strong proton donor): Phosgene (COCl2) + EtOH ‐> ethyl chloroformate. ethyl
chloroformate + R‐NH‐R1 ‐> ethylcarbamates (C2H5‐OCO‐NH2).
australine • EtOH in chloroform: O‐methyl pseudo strychnine ‐> pseudostrychnine
dihydroxymethyl-dihydroxypyrrolidine 1-deoxynojirimycin
• Ethers: peroxides ‐> N‐oxidations.
• Dichloromethane: quaternary N‐dichlorometho compounds
• Acetone and methylethylketone: e.g Berberine + Acetone
• Acetone + Ammonia ‐> Condensates ‐> Dragendorff (+) (chromatography)
• Ammonia + aldehydes (in plant) ‐> artifact alkaloids. e.g sweroside ‐> gentianine.
calystegine B • Generally, alkaloids are more stable in toluene, ethyl acetate, and alcoholic solutions.
swainsonine castanospermine
Russell J. Molyneux. 2002 219 R. VERPOORTE. 1994 220
Extraction of volatile alkaloids Extraction of volatile alkaloids
• Conium maculatum alkaloids are volatile at 173‐174 0C ‐> nhiệt kế và

N‐methyl coniine and coniine, separated by HBr [R. H. F. bộ tiếp nước
Manske. 2014]
hơi nước sôi Alk base
• Pyridine alkaloids are volatile at high temperature. ngưng tụ
Nicotine (pyridine skeleton) is easy to volatile, other
secondary amine alkaloids (nornicotine, anabasine,
anatabine, myosmine) is hard to volatile.
• Tobacco alkaloids in alkaline solution (NaOH) were dược liệu + kiềm (NaOH)
H2SO4 loãng
distilled and quantitative analysis by spectroscopy. Myosmine
Hans‐Ferdinand Linskens. 2012 221 222
Alkaloid separation 25 g Lá Cà
Alkaloids extraction độc dược
Sublimation:
EtOH – NH4OH ‐ ether (5 : 4 : 10)
• Alkaloids of cinchona and nux vomica are
removed, by microsublimation powdered crude
Bã Dịch
drug which has been treated with sodium
1. H2SO4 0,5 N (5mL) Bốc hơi gần hết ether
carbonate. The procedure can be carried out
2. H2O (2 x 5 mL) + 25 mL H2SO4 0.5 N Dược liệu ≥ 0,12% alcaloid tính
quantitatively. [J.A. Zapotocky. 1949] theo scopolamin (C17H21NO4) tính
dịch Dịch
• Caffeine can be extracted by sublimation theo dược liệu khô kiệt.
Cloroform (10; 5; 5 mL) Bốc hơi hết ether
cloroform H2SO4
+ H2SO4 1 ml H2SO4 0,02 N ̴ 6,068 mg
C17H21NO4. (Scopolamine)
H2SO4
Na2SO4 Bốc hơi Định lượng =
khan NaOH, CT
H2SO4 CHCl3 CHCl3 H2SO4
+ NH4OH methyl da cam
Mohrig, Jerry R. 2010 + H2SO4
thăng hoa 223 DĐVN V + CHCl3
224
Alkaloid isolation Alkaloid isolation
– Strychnine and Brucine – Caffeine extraction
Groundnuts (200 g) are mixed thoroughly with 200 ml suspension of 10% 20 g finely powdered tea leaves are placed in a 400 ml beaker, 5 g sodium carbonate and 100 ml
N
calcium hydroxide in water and left overnight at room temperature. After H
R
water is added, and the mixture is heated by a Bunsen burner for 20 min. Water is occasionally
air drying, the slurry is extracted with chloroform in a Soxhlet extractor for 3 H
H H added to keep the volume of the solution constant. The hot solution is then filtered, and the
hr. The chloroform solution is then extracted several times with 5% sulfuric N O filtrate is neutralized cautiously, with stirring, with sulfuric acid 10% solution. It is then filtered
R
acid solution, and subsequently basified with 10% aqueous sodium through a thin layer of a filter aid (Celite), placed on a Büchner funnel padded with a wet filter
O
hydroxide. After cooling, the crystals are filtered, 1.5 volumes of 50% paper, and washed with 20 ml dichloromethane. The two‐phase filtrate is then placed in a
Strychnine: R=H
ethanol are added, and the mixture is refluxed until most of the solid has Brucine: R=OCH3 separating funnel. The organic lower layer is separated, and the aqueous layer is extracted twice
dissolved. After addition of a little activated charcoal, the solution is filtered with two 40‐ml portions of dichloromethane. The two organic (CH2Cl2) layers are then combined,
l
hot and left overnight. The crystals of strychnine are filtered and washed and the solvent is evaporated. Crude caffeine is crystallized from a very small quantity of hot
with a little 50% ethanol. The mother liquor and washings are kept for the acetone or water. The pure crystalline silky needles of caffeine (0.5 g) melt at 235°C.
isolation of brucine.
Raphael Ikan. 1991 225 Raphael Ikan. 1991 226
(toluene)
– Piperine extraction
• Ten g black pepper is ground to a fine powder and extracted with 150 ml 95%
ethanol in a Soxhlet extractor for 2 hr. The solution is filtered and concentrated in
vacuo on a water bath at 60°C. Alcoholic potassium hydroxide (ten ml 10%)(*) is
added to the filtrate residue and after a while decanted from the insoluble
residue. The alcoholic solution is left overnight, where upon yellow needles of
mp 125‐126°C are deposited; yield, 0.3 g.
(*) Dilute ethanol KOH solution is added to the concentrated extract to keep acidic
material in solution and/or as solid gummy material that is precipitated in the
vessel.
Piperine is extremely low solubility in water. Outline of the traditional separation of the Cinchona alkaloids
Raphael Ikan. 1991 227 Przemysław J. Boratynski. 2019 228

Alkaloid isolation Alkaloid isolation Reversed‐phase chromatography (RPC) is a particular
form of bonded‐phase chromatography in which the
– Chromatography – Chromatography mobile phase is an aqueous–organic solvent mixture
and the stationary phase a relatively low‐polarity
sorbent
Colin F Poole. 2019 229 Colin F Poole. 2019 230
– Chromatography
– Chromatography
stationary phase • Adsorption column chromatography
 Stationary phase: Al2O3, Silica gel (Si‐OH (silanol) và Si‐O‐
Si (siloxane)),.
 Mobile phase: Chloroform, ethyl acetate or mixture of solvents.
• Reversed‐Phase Chromatography
 HPLC is commonly used
column  Stationary phase: C18, C8, phenyl
 Mobile phase: mixture (H2O, MeOH, Acetonitrile, THF
Sample solvent (tetrahydrofuran))
(eluent)
(Mobile phase)
231 JI Yubin. 2014 232

– Separation by HPLC
– Chromatography
• Reversed‐Phase Chromatography
3 2 5
18 37 8 17 6 5
A Soliven. 2013 233 Ronald E Majors. 2018 234
– Ion‐exchange (ionit):
– Separation by ion exchange chromatography
• B + HCl ‐> [BH]+ Cl‐
1. Strongly acidic: sulfonic
• Cationit
acid groups
 Cat‐H+ + [BH]+Cl‐ ‐> Cat‐[BH]+ + H+ + Cl‐ 2. Strongly basic:
 Elute by alkaline solution (NaOH, NH4OH…) quaternary amino groups
 Cat‐[BH]+ + NH4OH ‐> Cat‐H+ + B + H2O 3. Weakly acidic: carboxylic
acid groups
• Anionit
4. Weakly basic: primary,
 Ani+OH‐ + [BH]+ Cl‐ ‐> Ani+Cl‐ + B + H2O secondary, and/or
• Alkaloids change to free bases which do not dissolve in water and eluted by organic tertiary amino groups
solvents.
Phạm Thanh Kỳ . 2015 235 Pratima Bajpai. 2018

236
Alkaloid isolation ISOLATION OF COLCHICINE
– Separation by preparative TLC – Colchicum corms or seeds are exhaustively extracted with ethanol. Alcoholic
• Up to 100 mg of compound is deposited in a extract is concentrated and dried to syrupy residue. The residue is dissolved in
O
water to precipitate the insoluble fats and resins. The filtered aqueous extract O
horizontal thin line at the bottom of the plate, and
is then repeatedly extracted with chloroform or digested with lead carbonate. O
the plate is run in the appropriate solvent system
It is re‐filtered, evaporated to a small volume and further extracted with
as usual.
chloroform. Colchicine is recovered as a crystalline complex with chloroform. O
• The product is (ideally) located by UV visualization, The chloroform is distilled off and the amorphous colchicine is recovered after
and marked with a pencil. the evaporations of the residual solvent. Amorphous colchicine may be O HN
• A razor blade is used to scrape the silica containing crystallized from ethyl acetate as pale yellow needles. Melting point: 142– O
the product off the plate. 150°C
– Colchicine used in the management of gout, a condition associated with the
• The silica is placed in a fritted funnel and flushed
painful deposition of urate crystals in the joints. Other than its use in gout,
with a polar solvent (like EtOAc). The pure product
colchicine has been approved for managing exacerbations of Familial
can be isolated from the filtrate.
Mediterranean Fever (FMF), a hereditary autoinflammatory condition
[drugbank.ca]
Phạm Thanh Kỳ . 2015 Rabel, Fred. 2017
237 [Biren Shah. 2010] 238
http://chem.chem.rochester.edu
Isolation of emetine Isolation of emetine
– Emetine is the major active constituent of the rhizomes and roots – The powdered ipecacuanha is extracted with about 70% ethanol or methanol. The extract
of Cephaells ipecacuanha and C. acuminata; family Rubiaceae. O obtained is concentrated and dissolved in water and the solution is made strongly basic with
ammonia and extracted with di‐isopropyl ether. Di‐isopropyl ether extract is then treated with
Emetine was first isolated in a crude form by Pelletier in 1817, N
O 10–15% aqueous potassium hydroxide to remove cephaeline. The extract is further evaporated
and recognized as an alkaloid in 1823. Ipecacuanha also consists to yield emetine. It is purified via HBr or HI salt. These halide salts are converted to the HCl by
of some other related isoqunoline alkaloids which includes H neutralizing the regenerated free base.
N
cephaeline, psychotrine and emetamine [Biren Shah. 2010] – In another process, ipecac powder is treated with ammonia and ether. The ether extracts is
– Emetine has amoebicidal components. It may be useful for subjected to dilute sulphuric acid treatment to yield alkaloids. Dilute acid extract is then nearly
neutralized and washed with ether and then made strongly alkaline and treated with ether.
amoebic abscesses and hepatitis. Emetine injected O
O
Emetine goes into ether while cephaeline remains in the aqueous phase. The ether extract is
intramuscularly is distributed systemically. Emetine has been concentrated and redissolved in methanol and converted to emetine hydrobromide with a
Emetine
used for more than a century to treat dysentery. [drugs.com] methanolic solution of hydrobromic acid.
– Melting point: 70°C
[Biren Shah. 2010]
[Biren Shah. 2010] 239 240
ISOLATION OF ERGOMETRINE ISOLATION OF ERGOMETRINE
H
– Ergometrine or ergonovine is a naturally occurring indol alkaloid O N – In the laboratory scale isolation technique, ergot powder is completely defatted with
OH
found in the sclerotia of Claviceps purpurea; Clavicipitaceae petroleum ether (60–80°) in Soxhlet extractor. The petroleum ether extract removes
developed on plants of rye, Secale cereale; Gramineae. It is classified
about 30% fat and colouring matter.
as one of the water‐soluble, amine ergot alkaloids. It was discovered N
almost simultaneously in 1935 by five independent research groups. – The residual marc dried below 40°C is transferred to a porcelain dish, made to semi‐
H
Ergot also contains ergotamine and ergotoxine groups of alkaloids solid mass by adding sufficient solvent ether and dilute ammonia with stirring. The
which are water‐insoluble groups [Biren Shah. 2010] material is stirred to dryness and then packed in a Soxhlet and extracted with solvent
HN
– Used to treat postpartum haemorrhage and post‐abortion ether for about 5 h. The ether extract filtered and to it little acetone added and shaken
haemorrhage in patients with uterine atony. Ergonovine
in separating funnel with three volumes of 1% of tartaric acid. The total acidic extract is
(ergometrine) belongs to the group of medicines known as ergot
alkaloids. These medicines are usually given to stop excessive combined and dried under reduced pressure to yield total ergot alkaloid.
bleeding that sometimes occurs after abortion or a baby is delivered.
They work by causing the muscle of the uterus to contract.
[drugbank.ca]
241 242
ISOLATION OF ERGOMETRINE ISOLATION OF LEVODOPA
– The total alkaloid is further dissolved in dilute ammonia and extracted with four volumes of ether. The
– Levodopa or L‐Dopa is a dihydroxyphenyl alanine obtained from
combined total ether extract is washed thoroughly with five successive quantities of water. Water‐insoluble 2
the dried mature seeds of Mucuna pruriens; Fabaceae. Two types
ergotamine and ergotoxine alkaloids stay with ether while the water‐soluble ergometrine tartrate remains
of seeds, i.e., black or spotted variety are generally found in the
with aqueous extract. The aqueous extract is made faintly alkaline with dilute ammonia and further
market which consists of about 2.0% of L‐Dopa content. [Biren Madopar® [Levodopa +
saturated with ether. Ergometrine free base is shifted to ethereal solution. It is again washed with water to Benserazide]
Shah. 2010]
remove impurities of other alkaloinBds. The ether extract is again treated with three volumes of 1% w/w
– Levodopa on its own is formulated as an oral inhalation powder Duodopa® [Levodopa +
tartaric acid in water. The combined acid extract is concentrated under reduced pressure to yield water Carbidopa]
soluble alkaloid. It is further purified by the column chromatographic fractionation. indicated for intermittent treatment of off episodes in Parkinson's
Dazonay® [Levodopa +
patients who are already being treated with carbidopa and Entacapone, +
– Melting point: 162°C
levodopa Levodopa is most commonly formulated as an oral Carbidopa]
– Thin Layer Chromatography of Ergometrine tablet with a peripheral dopa decarboxylase inhibitor indicated for
• Dissolve about 1 mg/ml of alkaloid in methanol and apply on silica gel‐G plates. Solvent system treatment of Parkinson's disease, post‐encephalitic parkinsonism,
toluene‐butanol NH4Cl (saturated) (6:4) and spray the dried TLC plates with Dragendorff ’s and symptomatic parkinsonism following carbon monoxide
reagent. Ergometrine maleate shows the Rf 0.30. The elution of the silica gel‐G TLC plate in other intoxication or manganese intoxication [drugs.com]
solvent system chloroform–ethanol– acetone (6:4:4), shows the Rf value 0.23.
Biren Shah. 2010. 243 244
HO
ISOLATION OF LEVODOPA ISOLATION OF OPIUM ALKALOIDS
O H
– Coarsely powdered Mucuna seeds are extracted with demineralized water containing – The powdered drug is extracted with boiling water and to the N
HO
1% v/v of acetic acid at 50°C. Acetic acid extract is filtered. The filtered extract is aqueous phase, calcium chloride is added and concentrated Morphine
concentrated by reverse osmosis and the liquid concentrate so obtained is kept at a to get salts of morphine and codeine as crystals. It is treated O
low temperature (6–8°C) for about 24 h for crystallization of L‐dopa. The crystals are with chloroform. The soluble portion consists of codeine and
O H
filtered through a centrifuge, washed with cold water and dried under vacuum at the insoluble portion consists of morphine
N
50°C. The filtrate and water washings still contain the compound of interest, i.e., L‐ HO
Codeine
dopa. It is mixed, concentrated and processed for second crop. The crystalline O
O
product obtained in I and II crops combiningly yield about 2.0–2.5% of L‐dopa which
still consists of some impurities of amino acids. It is further purified either by re‐
O
crystallization or by using liquid ion exchangers. N
Papaverine
[Biren Shah. 2010] 245 [Biren Shah. 2010] 246
O
ISOLATION OF OPIUM ALKALOIDS ISOLATION OF PIPERINE
N
– The powered drug is shaken with calcium chloride and filtered. To the filtrate add 10% of sodium
Piperine O
hydroxide solution. It is filtered. The marc consists of narcotine, papaverine, thebain and the filtrate
O
consists of morphine, codeine. The filtrate is extracted with chloroform. The chloroform layer is
separated. It consists of codeine while the aqueous layer consists of morphine and narceine. The – Piperine is isolated from unripe fruit (black pepper) and the kernel of the ripe fruit
aqueous layer is first acidified and later on slightly alkalized with ammonia. Morphine is precipitated (white pepper) of Piper nigrum, from the fruit of aschanti (Piper clusii), from long
on the addition of ammonia and the aqueous layer consists of narceine. The marc consisting of pepper (Piper longum), seeds of Cubeba censii, Piper fainechotti and Piper chaba. The
narcotine, papaverine and thebain is dissolved in alcohol and then acidified with acetic acid. To the piperine content of black pepper varies from 6 to 9%.
acidified solution, add three volumes of boiling water. Precipitates of narcotine and papaverine are
formed and thebain still remains in the aqueous solution. Papaverine is separated from narcotine by – Finely powdered 20 g of black pepper is extracted with 300 ml 95% ethanol in a
the addition of 0.3% oxalic acid solution and allowed to cool. On cooling the papaverine crystals are Soxhlet extractor for 2 h. The solution is filtered and concentrated in vacuum on a
obtained. The aqueous solution is made alkaline with ammonia for the precipitation of narcapine water bath at 60°C. 20 ml of alcoholic potassium hydroxide is added to the filtrate
which is re‐crystalized using water. residue and after it while decanted from the insoluble residue. The alcoholic solution
– Melting point: Morphine 254°C, Thebaine 193°C, Codeine 154–156°C is left overnight, whereupon yellow coloured needle shaped crystals are deposited.
The yield of piperine is 0.3 g. Melting point: 125–126°C
ISOLATION OF QUININE AND QUINIDINE ISOLATION OF QUININE AND QUINIDINE
N N – The powdered Chinchona bark is mixed with about 30%, of its weight of Ca(OH)2 or CaO and sufficient
– Cinchona is the dried bark of the stem or of quantity of 5% sodium hydroxide solution. The moistened mass is then transferred into Soxhlet and
OH OH
the root of Cinchona calisaya Wedd, Cinchona extracted with benzene. To the benzene extract, add 5% sulphuric acid. The benzene layer is separated
from that of the aqueous layer, the benzene layer is discarded and to the aqueous layer sodium
ledgeriana Moens, Cinchona officinalis Linn O
hydroxide is added to adjust the pH to 6.5. Cool and on cooling precipitates of quinine sulphate is
and Cinchona sucirubra Pavon or hybrids of formed. The separated precipitate is then re‐crystalized from hot water to free the salts from
N N cinchonine and cinchonidine. The colouring matter is removed by treating it with activated charcoal.
any of the first two species with any of the
Quinine Cinchonine The mother liquor consisting of quinidine, cinchonine and cinchonidine are slightly made alkaline with
last two species (Rubiaceae). Quinine is ammonia, and the precipitate formed is again subjected to extraction with ether. Two portions are
N N obtained: the first is ether insoluble fraction consisting of cinchonine crystals and the other is the
laevorotatory while quinidine is
OH ether extract with quinidine and cinchonidine. The ether soluble fraction consisting of quinine and
dextrorotatory stereoisomer OH
cinchonidine is first stirred with dilute hydrochloric acid followed by the addition of 25% of solution of
sodium potassium tartrate. Precipitates from resulting solution of cinchonidine tartrate is formed. The
O
cinchonidine is re‐crystalized from alcohol. To the liquor obtained after the separation of cinchonidine
tartrate add potassium iodide solution. Addition of potassium iodide results in the precipitation of
N N quinidine hydro‐iodide. This on treatment with an alkali (ammonia) liberates a base, which is dissolved
Quinidine Cinchonidine in acetic acid. The quinidine obtained is finally re‐crystallized from alcohol. Melting point: Quinine
177°C, Quinidine 174–l75°C
ISOLATION OF RESERPINE ISOLATION OF RESERPINE
– Reserpine is an indole alkaloid obtained from the roots of – Rauwolfia root powder is exhaustively extracted with 90% alcohol by suitable method of
Rauwolfia serpentina, family Apocyanaeae and also from extraction such as percolation. The alcoholic extract is concentrated and dried under
reduced pressure below 60°C to yield rauwolfia dry extract containing about 4% of total
other different species of Rauwolfia, such as R.
alkaloids. Rauwolfia dry extract is extracted further with proportions of ether–
micrantha, R. vomiforia and R. tetraphylla. The material chloroform–90% alcohol (20:8:2.5). To the extract obtained, add little dilute ammonia with
obtained from natural sources may contain closely intermittent shaking. Alkaloid is converted to water‐insoluble base. Add water and allow
related alkaloids, which includes ajmaline, ajmalicine, the drug to settle after few vigorous shakings. Fitter off the solution and extract the
ajmalinine, rescinnamine, reserpinine, serpentine and residue with 4 volumes of 0.5 N H2SO4 in separating funnel. Combine the total acid extract
which contains the alkaloidal salt. The extract is filtered, made alkaline with dilute
yohimbine. In R. serpentina, reserpine and rescinnamine
ammonia to liberate alkaloid. Finally, it is extracted with chloroform. The total chloroform
both respond to the extraction procedures and extracted extract is filtered; chloroform is removed by distillation and the total alkaloidal extract is
as a mixture of both while in R. tetraphylla, reserpine and dried under vacuum to yield total rauwolfia alkaloids. Total rauwolfia alkaloid consists of
deserpidine are extracted together. the mixture of over 30 different components. It is subjected to column chromatographic
fractionation for the seperation of reserpine. Melting point: 270°C
Isolation of solasodine Isolation of solasodine
– Solasodine is an aglycone of steroidal glycoalkaloid found in – The dried berries are first powdered and subjected to defat with petroleum ether to
many species of Solanaceae family. The various sources yield greenish yellow oil which is rejected as it is devoid of the glycoalkaloid The
commonly used for the preparation of solasodine include the defatted material is extracted thrice with ethyl alcohol; the extracts are combined and
berries of Solanum incanum (1.8–2%), S. khasianum (1– concentrated to 1/10th of its volume. Concentrated hydrochloric acid is then added to
1.75%) and S. xanthocarpum. Solasonine is a steroidal it until the final concentration reaches 5–6%. The whole mass is refluxed for about 6 h
glycoalkaloid which yields an aglycone solasodine and the to attain complete hydrolysis of glycoalkoloid. The reaction mixture is then basified
sugar such as mannose, glucose and galactose on hydrolysis. HN with ammonia and again refluxed for 1 h. The cooled reaction mixture is filtered and
H
the residue obtained is thoroughly washed with water till neutral pH and dried. The
H O
H dried material is then dissolved in chloroform. Solasodine goes into chloroform. The
H H
HO
solution is filtered and the solvent is evaporated to yield the residue containing
H
Solasodine
solasodine. It is further purified by crystallizing it from methanol or by sublimation in
high vacuum.
Test for alkaloid – specific reagent
Test for alkaloid
Alkaloid Reagent Reagent composition color
– Material (50mg) + dilute acid (HCl, H2SO4), filter, filtrate + precipitating reagent Purine murexide potassium chlorate (KClO3)+ HCl+NH4OH purple
(Dragendorff). False positive: purines, proteins, betaines, ammonium salts. Colchicine mineral acids mineral acids yellow
– Material + MeOH (EtOH), filtre  filtrate  residue (solvent removed); Residue + Indole alkaloids Van Urk (Erlich) + p‐dimethylaminobenzaldehyde+ FeCl3+Sulphuric purple
Morphine Marquis Formaldehyde/H2SO4 Purple red ‐> purple
dilute acid; filter; filtrate + precipitating reagent. [1]
Fröhde Molybdate/sulfuric Violet ‐>purplish red ‐> brown
– Material + NH4OH + Organic solvent (CHCl3, DCM)  filtre; filtrate + dilute acid (HCl, Mecke (Lafon) Selenious acid/sulfuric Green ‐>greenish blue ‐>blue ‐>bluish green
H2SO4), acid water + reagent. Tropane Vitali‐Morin HNO3+ KOH bright purple or reddish
Schaer H2O2 + sulfuric acid green
– Precipitating reagent:
Ipecacuanha Fröhde Molybdate/sulfuric greenish
• Reagent: Dragendorff (KBiI4)(reddish‐brown), Mayer (K2HgI4)(cream), Hager (yellow), Bouchardat
Cinchona Thalleoquin bromine water + NH4OH Emerald (Lục tươi)
(Wagner) (KI3); Marmé (cadmium iodide + potassium iodide + water), Scheibler, Reineckate, Red (+sulfuric acid )
Bertrand (Silicotungstic). Erythroquinine Br2water + K ferrocyanide (K4[Fe(CN)6] + NH4OH Red
Nuxvomica Mandelin NH4OH + ammonium vanadate violet blue ‐> Orange
(Strychnine)
Malaquin HCl+Znc+t0+sodium nitrate red
[1]. PP NC DL Subhash Mandal. 2015 Sunil Kumar. 2014 W. C. Evans.2009 255 Subhash Mandal. 2015 256

Test for alkaloid TLC analysis for alkaloids
• Numerous reactions have been described for the detection of alkaloids
in aqueous solutions. The most common are precipitation reactions Tan k lid
Development
such as Dragendorff’s reagent (bismuth iodide), Mayer’s reagent, picric Rf = a/b
TLC tan k
acid, and Reinecke’s salt. All these reagents are more or less specific for
protonated tertiary nitrogens (and quaternary nitrogens). Dragendorff’s Sol ve n t fr o n t
TLC Plate Com p o u n d
reagent is also used for the detection of alkaloids on thin‐layer
dista n ce fr o m
origi n (2. 8c m ) b dista n ce
from origi n a
(2. 3 cm )
chromatography (TLC) plates. It may cause false‐positive reactions with,
Pen c i l line
for example, compounds containing conjugated carbonyl or lactone 1-2 cm abo ve
botto m of
Sol ve n t level
TLC plate
functions. Extr ac t or mixt u r e spo tte d
as a sing l e spo t or line
Before developm ent After developm ent

A. Conqueiro. 2015
257 Satyajit D. Sarker (2012). 258
TLC analysis for alkaloids TLC analysis for alkaloids
https://chem.libretexts.org
https://chem.libretexts.org 259 260
– Highly nonpolar compounds , such as fatty acids, glycerides, alkanes, and some lower
– Acidic compounds can “tail” and “streak” with nonband flow on silica due to interactions
(smaller) terpenoids such as monoand sesquiterpenes require simple nonpolar solvents
systems (e.g., cyclohexane, hexane, pentane, diethyl ether:hexane mixtures) and may be diffi
between acidic groups (e.g., –COOH, –OH) and silanols. This may be reduced by the addition
cult to detect by UV light (as they have no chromophore) or by spray detection (use charring
of a small amount of acid (e.g., 1% trifluroacetic acid, HCOOH or acetic acid) to the mobile reagents, e.g., vanillin–sulfuric acid).
– Highly polar metabolites , such as sugars, glycosides, tannins, polyphenolics, and certain
phase and this will maintain any acidic groups in a nonionized form. alkaloids require the development of polar mobile phases and in some cases such
compounds may be irreversibly adsorbed onto the silica. Choice of mobile phase should
– Basic compounds also may behave poorly on silica and the addition of weak bases (e.g., 1% evolve through the use of a mono or binary system, i.e., 100% CHCl3 or hexane:EtOAc (1:1) as
a starting point and if this does not give a good result then the addition of acids or bases to
diethylamine; NH4OH; or triethylamine) should also eradicate any tailing and improve improve chromatography, i.e., toluene:EtOAc:acetic acid (60:38:2) should be tried and as a
last resort the use of tertiary or quaternary systems, e.g., butanol:acetic acid:water (4:1:5) or
chromatography.
hexane:EtOAc:formic acid:water (4:4:1:1) should be employed.
Satyajit D. Sarker (2012).
261 Satyajit D. Sarker (2012). 262
– Sample preparation (1‐2 g) – Stationary phase: Silica gel (for most alkaloids). Aluminium oxide‐pre coated
• Extracted by MeOH TLC plates (for berberine; columbamine and jatrorrhizine)
• Sample + NH4OH + organic solvent (CHCl3) – Mobile phase: NH4OH, diethylamin (DEA), triethylamine (TEA) added into
• Sample + H2SO4 0.1N  extract; extract + NH4OH + Organic solvent (CHCl3) mobile phase to improve separation
• Defatted by n‐hexane (Strychni semen, Colchici semen) before extracted by suitable • Methanol – ammonium hydroxide (9 : 1): TLC analysis of strychnine and brucine
solvent
• Hexane‐chloroform‐diethylamine (50 : 30 : 7): Analysis of morphine alkaloids
• Extract concentrated and applied on TLC plate (ca. 50‐100 g of total alkaloids).
• Cyclohexane‐CHCl3‐Glacial acetic acid (45:45:10): Berberine and protoberberine
– Standard preparation (1% in alcohol (MeOH, EtOH))
– Applied volume: 10‐20 L
Harbone. 1996. 263 M. Muzquiz. 2000 Harbone. 1996. 264

– Detection
• UV 254 nm: Pronounced quenching of some alkaloid types such as indolcs, quinolines,
isoquinolines, purines; weak quenching of e.g. tropine alkaloids.
• UV 365 nm: Blue, blue‐green or violet fluorescence of alkaloids, e.g. Rauvolfiae radix, Chinae
cortex (Cinchonae cortex), Ipecacuanhae radix, Boldo folium. Yellow fluorescence, e.g. colchicine,
sanguinarine, berberine
• Spray reagents
 Dragendorff: Appear as brown or orange‐brown (vis.) zones immediately on spraying. The colour is
fairly stable. Some types such as purines or ephedrine need special detection. The colour of alkaloid
zones can be intensified or stabilized by spraying first with Dragendorff reagent and then with 10%
sodium nitrite solution or 10% ethanolic sulphuric acid.
 Iodoplatinate: Directly after spraying, alkaloids appear as brown, blue or whitish zones (vis.) on the
blue‐grey background of the TLC plate
Wagner. 2001
Verpoorte. 2000 265 M. Muzquiz. 2000 266
– Special detection
• Iodine‐potassium iodide‐HCl reagent  purines
• Iodine CHCl3 reagent  emetine, cephaeline
• Marquis reagent  opium alkaloids
• Van Urk reagent  secale alkaloids
• Ninhydrine reagent  ephedrine
• 10% ethanolic H2SO4  chinae alkaloids (Cinchonae
alkaloids)
Wagner. 2001
M. Muzquiz. 2000 267 Wagner. 2001 268
QUANTITATIVE ANALYSIS OF ALKALOID
QUANTITATIVE ANALYSIS OF ALKALOID
– Gravimetry
– Gravimetry • Apply for weak base alkaloids or non‐elucidated structure, or difference of molecular weight
– Acid‐base titration • Total alkaloids extracted, dried and weighed
• Low amount of alkaloids: precipitating with silicowolframic acid, phosphowolframic acid, picrolonic
– Spectrophotometry acid. E.g.: Nicotine, caffeine với silicowolframic.
– HPLC – Acid – base titration
• Apply usually for alkaloid in Solanaceae
– GC (GAS CHROMATOGRAPHY)
• Free base of alkaloids extracted, remove NH4OH by evaporation.
– Capillary Electrophoresis (CE) • Decolor by liquid‐liquid extraction or adsorbed substances (charcoal)
• Back titration with an excess of acid.
• HCl, H2SO4 0.01‐0.1 N for titration. Indicator: red methyl (4.2‐6.3), orange methyl (4.0) or mixture of red
methyl + blue methylene (Cinchona) to observe easily
• Non‐aquaeous titration: HClO4, Crystal violet (0.5 per cent in glacial acetic acid) as indicator
• Application: Datura alkaloids, Holarrhena alkaloids DĐVN V), Belladon (BP 2015).
269 Phạm Thanh Kỳ. 2015 270
QUANTITATIVE ANALYSIS OF ALKALOID QUANTITATIVE ANALYSIS OF ALKALOID
– Colorimetric and spectrophotometric determination – High performance
• Color reagent:
liquid
chromatography
 Ergot alk + p‐dinotroaminobenzaldehyde + H2SO4 + H2O2 (FeCl3).
(HPLC)
 Cinchona bark + Renecke reagnet ‐> acetone
 Morphine ‐> Nitrosomorphine
 Physostigmine + alkaline solution ‐> Erosoline + methylamin. Methylamin. Methylamin + Ninhydrin ‐>
màu. [Phạm Thanh Kỳ. 2015]
• Spectrophotometry
 Sstrychnine in Stru=ychnos in max of 262 nm and 300 nm.
 Total alkaloid in Solanum by reaction with Bromothymol [DĐVN V. 2017]
• The sum of quinolizidine alkaloids in the seeds of lupine (Lupinus) has been determined using the
method of extraction photometry, based upon the formation of complexes between alkaloids and
picric acid and measured at 345 nm. [M. V. Gavrilin. 2006]
https://www.analyticaltoxicology.com/en/high‐performance‐
271 liquid‐chromatography‐hplc/ 272
QUANTITATIVE ANALYSIS OF ALKALOIDS QUANTITATIVE ANALYSIS OF ALKALOIDS
– HPLC – PLC
• HPLC is a major tool for the analysis of alkaloids.
• Stationary phase: reversed‐phase (RP) materials (C8‐, C18‐ and phenyl‐bonded phases on silica).
• Mobile phase: alkylamines (e.g. hexylamine), triethylamine or tetramethylammonium in low
concentrations is added to the mobile phase to reduce the tailing
• The pH of the mobile phase must be strictly controlled.
• Detection:
 UV is most widely used. Diode array detection
• Indole and isoquinoline alkaloids: strong and speciRc UV chromophores.
• Poor UV absorption properties, e.g. tropane, pyrrolizidine and steroidal alkaloids: 200‐220 nm.
 Mass spectrometry is a major tool in the identiRcation and structure elucidation of alkaloids
Verpoorte. 2000 273 Verpoorte. 2000 274
QUANTITATIVE ANALYSIS OF ALKALOIDS
%
100
%
100
100
QUANTITATIVE ANALYSIS OF ALKALOIDS
100
– HPLC GC (Gas chromatography) 250-3200C
SKĐ Thử
Chromatogram of sample
Recorder
N2
SKĐ chuẩn berberine He
Chromatogram of berberine Ar FID, NPD, MSD
H2 40-3200C
15-60 m
NGUYỄN NGỌC KHÁNH VY. 2016. Unpublished data 275 276

QUANTITATIVE ANALYSIS OF ALKALOIDS‐GC (Gas chromatography) QUANTITATIVE ANALYSIS OF ALKALOIDS‐GC (Gas chromatography)
Flame Ionization Detector (FID) Separation of an alkaloid extract from L. angustifolius (A) and L. mutabilis (B) bitter seeds by capillary GC Injector, 2400C; detector 3000C; oven
Nitrogen–phosphorus detector (NPD) Mass Selective Detector (MSD) 150‐2350C, 50C/ min1; carrier gas, helium; detection of alkaloids by nitrogen-specific detector (NPD) and massselective detector.
M. Muzquiz. 2000 277 278
M. Muzquiz. 2000
QUANTITATIVE ANALYSIS OF ALKALOIDS ‐Capillary Electrophoresis‐CE Ecological Role of Alkaloids
– Because of their ionic nature alkaloids can be analyzed by capillary zone – Alkaloids being toxic help the plants, herbivores, and insects to ward off their enemies
electrophoresis.
– Low pH‐buffers can be used for the analysis of alkaloids (e.g., a pH 2.5 phosphate or competitors and facilitate their own survival in the ecosystem.
buffer).
– Natural weedicide (herbicide)
R Verpoorte. 2005 279 Shaily Goyal. 2013 280

Uses of alkaaloids Uses of alkaaloids
No Type Alkaloid Activity
1 Poison Pyrrolizidine alkaloids (from Conversion to DNA‐ and protein‐alkylating agent in the liver; No Type Alkaloid Activity
Senecio, Heliotropium, Crotalaria) causing liver cirrhosis, mutations, cancer
5 Constriction of Ergot alkaloids (Claviceps purpurea) Used in obstetrics
Ergot alkaloids (from Claviceps Cause vasoconstrictions, hallucinogenic effects, gangrenous limps blood vessels Ephedrine (Ephedra spec.) bronchial asthma, cold, sinusitis
purpurea) (hoại tử chân tay); disease named ‘ergotism’ ( convulsive
and gangrenous symptoms). No specific antidote Scopolamine (Hyoscyamus, Atropa, Inhibitor of smooth muscles, for example, dilatator in
and Datura) vessels
2 Analgesics Aconitine (Aconitum), Local anesthetic, general paralytic effect.
Morphine (Papaver somniferum). Very effective pain killer (used since ancient times); with 6 Muscle relaxant Tubocurarine (Chondrodendron Block nicotinic acetylcholine receptor.; used in surgery
addictive properties tomentosum)
Codeine (Papaver), Pain and cough depression Hyoscyamine (atropine), Hyoscyamus, Antispasmodic at smooth muscles (gastrointestinal
Cocaine (Erythroxylum coca) Local anesthetic Atropa, and Datura) tract and bladder)
3 Cardiac Quinidine (Cinchona spec.) Antiarrhythmic properties at the heart ventricle Papaverine (Papaver somniferum) Smooth‐muscle relaxant
stimulant Sparteine (Cytisus scoparius) Antiarrhythmic properties
7 Antiparasitic and Berberine (Berberis, Mahonia, and Intercalates DNA and inhibits parasites and
Ajmalicine (Rauvolfia serpentina) Antiarrhythmic properties at the heart ventricle
antimicrobial Coptis) microorganisms (*)
4 Respiratory Nicotine (Nicotina), cytisine Stimulation of respiration is followed by respiratory depression,
Emetine (Psychotria ipecacuanha) Intestinal amebiasis, emetic drug (*)
stimulant (Laburnum) asphyxia, or even respiratory failure
Boldine (Peumus boldo) Anthelmintic activity (*)
Lobeline (Lobelia spec.) Stimulant; used to treat bronchial asthma
Quinine (Cinchona succirubra) Antimalarial
Coniine (Conium maculatum) Used as a potent poison in antiquity (Socrates)
Wink. 2016
281 (*): Not in Drugbank.ca Wink. 2016 282
No Type Alkaloid Activity Alkaloid Natural source Therapeutic property
8 Anti‐inflammatory Colchicine (Colchicum autumnale) Treatment of acute gout, recurrent gout Antipyretic and analgesic (limited application
Aconitum napellus
activity Aconitine because of narrow therapeutic index) [Chan TY.
Ranuculaceae
9 Anti‐Alzheimer’s Physostigmine (Physostigma Inhibitor of acetylcholinesterase. 2009)
disease venenosum) Used in atropine overdose and other anticholinergic drug Catharanthus roseus
Ajmaline Antiarrhythmic agent (Phase 4)
overdoses. Apocynaceae
Galantamine (Galanthus nivalis) Inhibitor of acetylcholinesterase. For the treatment of poisoning by susceptible
Atropa belladonna
Atropine organophosphorous nerve agents having anti-
10 Eye treatments Pilocarpine (Pilocarpus jaborandi) Miotic used in the treatment of open‐angle glaucoma Solanaceae
cholinesterase activity or carbamate insecticides
11 Cancer Taxol (Taxus brevifolia) Treatment of breast and ovary carcinoma; other Berberis vulgaris
chemotherapy malignancies. Berberine Parasitic, fungal infections and antidiarrhea
Berberidaceae
Vinblastine, vincristine Treatment of lymphomas and other tumors For management of fatigue, orthostatic
Coffea spp., Cola spp.
(Catharanthus roseus) Caffeine hypotension, and for the short term treatment of
Rubiaceae
Camptothecin (Camptotheca Cancer chemotherapy apnea of prematurity in infants.
acuminata) Cathine (d- Catha edulis Celastraceae
Used to decrease appetite.
norpseudoephedrine) (Khat, qat)
Drugbank.ca Wink. 2016
283 Tadeusz A. 2015 Drug.com, drugbank.ca 284
Alkaloid Natural source Therapeutic property
For the introduction of local (topical) anesthesia of accessible mucous Alkaloid Natural source Therapeutic property
Erythroxylum coca
Cocaine membranes of the oral, laryngeal and nasal cavities. (Inj. 40 mg/mL, 100
Erythroxylaceae Claviceps purpurea postpartum haemorrhage and postabortion haemorrhage in patients
mg/mL, Topical: 10%, 100mg) Ergometrine
Clavicipitaceae with uterine atony. IM, IV 0.25 mg/mL.
Papaver somniferum relief of mild to moderately severe pain. cough suppressant in adults aged 18
Codeine For use as therapy to abort or prevent vascular headache, e.g.,
Papaveraceae and above Claviceps purpurea
prophylaxis and treatment of gout flares. Familial Mediterranean Fever Ergotamine migraine, migraine variants, or so called "histaminic cephalalgia".
Colchicum autumnale Clavicipitaceae
Colchicine (hereditary inflammatory disorder) in children and adults of 4 years of age and Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist
Colchicaceae
older. For the treatment of glaucoma, and in the treatment of severe
Camptotheca acuminata. Investigated for the treatment of cancer. Topoisomerase inhibitor Physostigma anticholinergic toxicity. Physostigmine is a parasympathomimetic,
Camptothecin Physostigmine
Nyssaceae Irinotecan topotecan, rubitecan (synthetic) [G. Samuelsson (2004)] venenosum ‐ specifically, a reversible cholinesterase inhibitor which effectively
(Eserine)
Fabaceae increases the concentration of acetylcholine at the sites of
Cephaelis acuminata
Emetine (Carapichea ipecacuanha) Anti‐amoebic (interfere with muscle contractions, leading to cardiac failure) cholinergic transmission. IV 1 mg/mL
Rubiaceae mild to moderate dementia of the Alzheimer's type. Has also been
An alpha‐ and beta‐adrenergic agonist. treatment of asthma, heart failure, investigated in patients with mild cognitive impairment who did not
Galanthus nivale
Ephedra sinica rhinitis, and urinary incontinence, and for its central nervous system Galanthamine meet the diagnostic criteria for Alzheimer's disease. Galantamine is a
Ephedrine
Ephedraceae
Amaryllidaceae
stimulatory effects in the treatment of narcolepsy and depression. IV 50 parasympathomimetic, specifically, a reversible cholinesterase
mg/1mL. inhibitor. 4; 8; 12;16; 24 mg/tab. Reminyl®
Tadeusz A. 2015 Drug.com, drugbank.ca 285 Tadeusz A. 2015 Drug.com, drugbank.ca 286
Alkaloid Natural source Therapeutic property Alkaloid Natural source Therapeutic property
Hydrastis canadiensis Lycorine has been seen to have promising biological and
Hydrastine Haemostatic drug during the 1910s [Römpp CD,, 2006]
Ranunculaceae
Lycoris pharmacological activities such as antibacterial, antiviral, or anti‐
Duboisia, Datura, For the treatment of excessive salivation, colicky abdominal pain, Lycorine
Hyoscine Amaryllidaceae inflammatory effects and may have anticancer properties [Jahn,
Hyoscyamus bradycardia, sialorrhoea, diverticulitis, irritable bowel syndrome
(scopolamine) Sandra. 2012]
Solanaceae and motion sickness. muscarinic antagonist. Anticholinergic.
For treatment of bladder spasms, peptic ulcer disease, Papaver chronic moderate‐to‐severe pain. Epidural; Intramuscular;
Hyoscyamine diverticulitis, colic, irritable bowel syndrome, cystitis, and Morphine somniferum Intrathecal; Intravenous 1; 4; 8; 10; 15; 20; 40 mg/mL. Capsule,
Atropa belladonna Papaveraceae extended release: 15; 30; 45; 60; 90; 120 mg
(levo‐isomer to pancreatitis. Also used to treat certain heart conditions, to control
Solanaceae Mitragyna
atropine) the symptoms of Parkinson's disease and rhinitis. Oral; Sublingual, Mitragynine is an indole‐based opioid‐receptor agonist [Jansen KL,
0.125; 0.375 mg mg/tab. Mitragynine speciosa
Prast CJ (1988).]
An alkaloid that has actions similar to nicotine on nicotinic Rubiaceae
cholinergic receptors but is less potent. It has been proposed for a Papaver Papaverine is used to treat many conditions that cause spasm of
Lobelia inflata Papaverine somniferum smooth muscle. This includes chest pain, circulation problems, heart
Lobeline variety of therapeutic uses including in respiratory disorders,
Campanulaceae Papaveraceae attack, or disorders of the stomach or gallbladder. IM, IV. 30 mg/mL
peripheral vascular disorders, insomnia, and smoking cessation.
Investigational. Noscapine ((−)‐ P. Somniferum
Cough suppressant
narcotine) Papaveraceae
Tadeusz A. 2015 Drug.com, drugbank.ca 287 Tadeusz A. 2015

Drug.com, drugbank.ca 288
Alkaloid Natural source Therapeutic property Alkaloid Natural source Therapeutic property
For the treatment of radiation‐induced dry mouth (xerostomia) and Alternative medicine for cancer; however, the U.S. FDA
Sanguinaria canadiensis ‐ warns that products containing bloodroot, or other
symptoms of dry mouth in patients with Sjögrens syndrome. For Sanguinarine
Papaveraceae sanguinarine‐based plants, have no proven anti‐cancer
miotic and in the treatment of glaucoma.
effects
Pilocarpine Pilocarpus spp Cholinergic parasympathomimetic agent. It increase secretion by
Cytisus scoparius antiarrhythmic agents. Sparteine is not currently FDA
the exocrine glands, and produces contraction of the iris sphincter Sparteine
Fabaceae approved for human use.
muscle and ciliary muscle by mainly stimulating muscarinic Strychnos nux‐vomica highly toxic, used as a pesticide, particularly for killing mall
receptors. Strychnine
Loganiaceae vertebrates such as birds and rodents [Sharma, R. K.2008]
For the treatment of ventricular pre‐excitation and cardiac Taxol Taxus brevifolia
Quinidine Cinchona spp Chemotherapeutic agent
dysrhythmias (Paclitaxel) Taxaceae
Treat hypertension. Rescinnamine inhibits angiotensin‐converting Stephania tetrandra Anti‐inflammatory, immunologic and antiallergenic effects.
Rescinnamine Rauvolfia spp Tetrandrine
enzyme. (ACE). Tsuruselpi S®. Menispermaceae [Zhang L 2009]. No medicine approved.
Antihypertensive and an antipsychotic as well as a research tool, Theobroma cacao It was formerly used as a diuretic and in the treatment of
Reserpine Rauvolfia spp Theobromine
but its adverse effects limit its clinical use Sterculaceae angina pectoris and hypertension.
Theobroma cacao
Theophylline Chronic asthma and other chronic lung diseases
Sterculaceae
Tadeusz A. 2015
Drug.com, drugbank.ca 289 Tadeusz A. 2015 Drug.com, drugbank.ca 290
Uses of alkaaloids Important alkaloid groups
Alkaloid Natural source Therapeutic property – Tropane alkaloids
Used as a diagnosis agent for myasthenia gravis, and also to
– Cinchona Alkaloids
Chondodendron facilitate the intubation after induction of anesthesia in surgical
Tubocurarine tomentosum procedure. IM 3mg/mL. It is now rarely used as an adjunct for – Purine alkaloid
Menispermaceae clinical anesthesia because safer alternatives, such as – Ergot alkaloid
cisatracurium and rocuronium, are available
Vinblastine, Catharanthus roseus
Antitumor
Vincristine Apocynaceae
Vinca minor
Vincamine Cerebral vasodilator. Oxybral SR (vincamine 30 mg ) 20 capsules
Apocynaceae
Indicated as a sympatholytic and mydriatic. Impotence has been
Rauvolfia spp successfully treated with yohimbine in male patients with
Yohimbine
Apocynaceae vascular or diabetic origins and psychogenic origins. Yohimbine
blocks presynaptic alpha‐2 adrenergic receptors.
Tadeusz A. 2015
Drug.com, drugbank.ca 291 292
Tropane alkaloid (TAs) Tropane alkaloid (TAs)
A. Scopolamine, Hyoscyamine and Anisodamine and Their Derived Drugs:
– TAs: • Anticholinergic drugs: central and peripheral nervous system as competitive, non‐selective
• 3‐tropanole (tropine) muscarinic acetylcholine receptor (mAChR) antagonists.
• 3‐tropanole (pseudotropine) • Two acetylcholine: Muscarinic (M1–M5), and Nicotinic receptors [Kathrin Laura Kohnen. 2019]
– Solanaceae: hyoscyamine and scopolamine • Side effects: drowsiness or sedation, blurred vision, mydriasis, dizziness, urinary retention, confusion
or delirium, hallucinations, increased heart rate, dry mouth, constipation, reduced sweating and
– Erythoxylum coca: cocaine elevated body temperature, falls and risk for fracture. [drug.com]
– Convolvulaceae, Solanaceae, Moraceae, Erythrocylaceae and Brassicaceae:
Calystegine (polyhydroxylated nortropane alkaloids)
– ~200 different TAs have been described
Kathrin Laura Kohnen. 2019 293 Kathrin Laura Kohnen. 2019 294
A. Scopolamine, Hyoscyamine and Anisodamine and Their Derived Drugs: A. Scopolamine, Hyoscyamine and Anisodamine and Their Derived Drugs:
• Quaternary ammonium compounds are antimuscarinic compounds that are less lipid soluble than • Hyoscyamine, atropine: antidote against organothiophosphate (pesticide parathion) intoxication
atropine, and thus may be less likely to cross the blood‐brain barrier. They are less well absorbed • Physostigmine: Antidote against atropine, hyoscyamine, scopolamine intoxication.
than atropine. The central side effects are reduced with respect to atropine, but the peripheral
1. Scopolamine: motion sickness (Kimite, Ariel, Scopoderm TTS)
effects remain common at therapeutic doses. Quaternary ammonium compounds include:
2. L‐Hyoscyamine and () Atropine: for poisoning by susceptible organophosphorous nerve agents.
 Ipratropium bromide (Atrovent®)
3. Anisodamine: from Anisodus tanguticus (Tibet). For gastric disorders.
 Hyoscine butylbromide (Buscopan®)
 Mepenzolate bromide 4. Homatropine, Cyclopentolate and Tropicamide (synthetic): ophthalmology, for mydriatic
Br‐
 Pipenzolate bromide 5. Trospium Chloride: (synthetic) (quaternary ammonium). Not able to cross blood‐brain barrier. For
 Boldine methylsulphate
the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and
urinary frequency, detrusor instability and frequency of micturition.
 Propantheline bromide Ipratropium bromide
Hyoscine butylbromide
https://www.gpnotebook.co.uk
295 Kathrin Laura Kohnen. 2019 296
A. Scopolamine, Hyoscyamine and Anisodamine and Their Derived Drugs: B. Cocaine Derived Drugs
• Tropisetron: tropane skeleton , serotonin receptor antagonist, antiemetic in chemotherapy, and • Cocaine inhibits the reuptake of dopamine, noradrenaline and serotonin, thus increasing their
additionally as analgesic in fibromyalgia concentration in the synaptic cleft of the limbic system.
• N‐butylscopolamine (hyoscine N‐butyl bromide) (Buscopan®): cannot longer pass the blood‐brain • The intake of cocaine has an influence on the brain which is detectible in an electroencephalogram
barrier. Treat abdominal pain from cramping, renal colic and bladder spasms. Tablet and (EEG). However, the effects are inconsistent and may appear as increased or lowered signals in EEGs
Suppository: with or without paracetamol. • Procaine
• Tiotropium Bromide (Spiriva®), Ipratropium Bromide (Atrovent®) and Oxitropium Bromide: • Tetracaine: for minor face surgeries and in ophthalmology
inhalation. For treatment of asthma and COPD.
• Lidocaine
• Benzatropine (selective M1): treatment of early stages of Parkinson’s disease
• Oxybuprocaine
• Ropivacaine
C. Calystegine Derived Drugs: Until now, no drug products derived from calystegines
Kathrin Laura Kohnen. 2019 297 Kathrin Laura Kohnen. 2019 298
Cinchona Alkaloids Purine alkaloid
– Quinine: antimalaria and leg cramps. 200mg, 300 mg, 324 mg (capsule or tablet).
Quinine was frequently prescribed as an off‐label treatment for leg cramps at night, – These structures are based on xanthine or uric acid skeletons.
but this has become less common due to a FDA warning that this practice is associated – purine alkaloids, including caffeine, had been detected in at least 80 species in 13 orders of
with life‐threatening side effects. [FDA. 07‐08‐2010] plant kingdom O
O
– Qunidine: For the treatment of ventricular pre‐excitation and cardiac dysrhythmias N H
N
HN
(80 mg/1mL, IV, 200 mg, 300 mg, Tab.) [drugbank.ca] N
N
N O N
O N
theophylline
theobromine
Przemysław J.Boratyński. 2019 299 Hiroshi Ashihara. 2013 300

Purine alkaloid Purine alkaloid
– Caffeine: Central nervous system stimulant, increasing alertness and producing agitation. It
also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis. For management of
fatigue, orthostatic hypotension, and for the short‐term treatment of apnoea of prematurity in
infants.
– Theophylline: A methylxanthine derivative from tea with diuretic, smooth muscle relaxant,
bronchial dilation, cardiac and central nervous system stimulant activities. Stronger and shorter
diuretic than caffeine. For the treatment of the symptoms and reversible airflow obstruction
associated with chronic asthma and other chronic lung diseases, such as emphysema and
chronic bronchitis. Tablet, extended release, 100, 200, 300, 400, 600mg. Liquid: 80 mg/15ml.
Intravenous: 0.8; 1.6; 4 mg.
– Theobromine (3,7‐dimethylxanthine) is the principle alkaloid in Theobroma cacao (bean) and
other plants. Bronchodilator and vasodilator. Strong diuretic than caffeine. It has a weaker
diuretic activity than theophylline and is also a less powerful stimulant of smooth muscle. It has
practically no stimulant effect on the central nervous system. It was formerly used as a diuretic
and in the treatment of angina pectoris and hypertension.
Cf, caffeine; Mu, methyluric acid; Px, paraxanthine; Tb, theobromine; Tp, theophylline
Hiroshi Ashihara. 2013
301 Kukula‐Koch. 2017 Drugbank.ca 302
Purine alkaloid
Purine alkaloid: Synthetic xanthine derivatives
No Composition Indication
1 Caffeine citrate (IV) the short‐term treatment of apnea of prematurity in – Aminophylline: combination of theophylline and ethylenediamine in 2:1 ratio, is a
infants
2 Caffeine Capsules and Tablets (200 mg) It is used to make you more alert bronchodilatating and antiasthmatic compound.
3 Acetaminophen and Caffeine (Exedrin®) pain
4 Aspirin and Caffeine Tablets Pain, arthritis
– Propentofylline: is a unique xanthine derivative which exhibits various biochemical and
5 Ergotamine and Caffeine (1 mg +100 mg/Tab.), migraine headaches. pharmacological activities due to its neuroprotective, antioxidant and anti‐
(2+100/supp.)
6 Aspirin/ caffeine/ propoxyphene mild to moderate pain
inflammatory effects.
7 Acetaminophen / caffeine / salicylamide pain, swelling (sưng), fever, arthritis Investigated for use/treatment in alzheimer's disease.
8 Butalbital, Aspirin, and Caffeine tension headaches – Pentoxifylline: For the treatment of patients with intermittent lameness or immobility
9 Acetaminophen, Caffeine, and Dihydrocodeine Pain
10 Acetaminophen, Caffeine, and Pyrilamine (antihistamin) painful period (menstrual) cycles
arising from chronic occlusive arterial disease of the limbs. (Torental® 400 mg)
11 Orphenadrine (antihistamin), Aspirin, and Caffeine It is used to calm muscles
12 Acetaminophen/ caffeine/ magnesium salicylate/ mild to moderate aches, colds and flu, sinusitis,
phenyltoloxamine toothache, and minor pain from arthritis.
13 Acetaminophen / salicylamide /phenyltoloxamine minor aches and pains, colds, arthritis, muscle spasm,
(antihistamin)/ caffeine sinusitis
Drugs.com 303 Drugbank.ca Nivedita Singh. 2018 304

Ergot alkaloid Ergot alkaloid
– Ergot or ergot fungi refers to a group of fungi of the genus Claviceps [Schardl CL. 2006]. 1. Metylergometrine (Methylergonovine, methergine)
– The genus Claviceps = approximately 36 species. These species are known to 2. Ergotamine
parasitize over 600 monocotyledonous plants of the families Poaceae, Juncaceae 3. Didydroergotamine
(Bấc) and Cyperaceae, including forage grasses, corn (Zea mays), wheat (Triticum), 4. Methysergide
barley (Hordeum), oats (Avena, Yến mạch), millet (Panicum miliaceum, Eleusine 5. Dihydro‐alpha‐ergocryptine
coracana, Setaria italica …), sorghum (Sorghum, cao lương), rice (Oryza), and rye 6. Nicergoline
(Secale cereal, lúa mạch đen). The most prominent member of this group is Claviceps 7. Cabergoline
purpurea ("rye ergot fungus") [Paul L. 2006] 8. Quinagolide
9. Metergoline
10. Bromocriptine
11. Lisuride
12. Lysergic acid diethylamide
305 306
(LSD)
(Tamik®) (Parlodel®)
Paul L. 2006 307 Paul L. 2006 308
– Metylergometrine (Methylergonovine, methergine): For the prevention and control of
excessive bleeding following vaginal childbirth. Methylergometrine acts directly on the
smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic
contractions through binding and the resultant antagonism of the dopamine D1
receptor. Tablet 0.2 mg as maleate.
– Ergometrine (Ergobasine, Ergonovine): Used to treat postpartum haemorrhage and
postabortion haemorrhage in patients with uterine atony. Ergonovine directly
stimulates the uterine muscle to increase force and frequency of contractions. Tab.; IM,
0.2 mg/1 as maleate.
Paul L. 2006 309 Drugbank.ca; drug.com 310
– Ergotamine: A vasoconstrictor. It is an alpha‐1 selective adrenergic agonist and is – Methysergide: An ergot derivative that is a congener of lysergic acid diethylamide. It
commonly used in the treatment of migraine disorders. Tablet, orally disintegrating. antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth
2mg. Ergotamine tartrate (2 mg) + Caffeine (100 mg) (Cafergot® Supp.) muscle, but has few of the properties of other ergot alkaloids. Methysergide is used
– Didydroergotamine: For the acute treatment of migraine headaches with or without prophylactically in migraine and other vascular headaches and to antagonize serotonin
aura (sợ sáng) and the acute treatment of cluster headache episodes. in the carcinoid syndrome. Tab. 2mg as maeate.
Dihydroergotamine binds with high affinity to 5‐HT1Da and 5‐HT1Db receptors. Tamik® – Dihydro‐alpha‐ergocryptine: studied for the early treatment of Parkinson disease as
3mg. well as for its use in migraine prophylaxis; treatment of low blood pressure and
peripheral vascular disorder.
Drugbank.ca; drug.com 311 Drugbank.ca; drug.com 312

– Nicergoline: For the treatment of senile dementia, migraines of vascular origin, – Quinagolide: Indicated for the treatment of hyperprolactinemia (idiopathic or
transient ischemia, platelet hyper‐aggregability, and macular degeneration (Thoái hóa originating from a prolactin‐secreting pituitary microadenoma or macroadenoma).
hoàng điểm). Tab. 10mg. 30 mg (Sermion®). – Metergoline: Its use has been studied in various clinical settings such as a treatment for
– Cabergoline: For the treatment of hyperprolactinemic disorders, either idiopathic or seasonal affective disorder, prolactin hormone regulation due to its inhibitory effect on
due to prolactinoma (prolactin‐secreting adenomas). May also be used to manage prolactin release, premenstrual dysphoric disorder in women and antianxiety
symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic treatment.
management or as an adjunct to levodopa therapy during advanced stages of disease.
Dostinex® (Pfizer) Tab. 0.5 mg
– Bromocriptine (semisynthetic): For the treatment of galactorrhea due to – Lisuride: For the management of Parkinson's Disease. Lisuride is an anti‐Parkinson drug
hyperprolactinemia, prolactin‐dependent menstrual disorders and infertility, prolactin‐ chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride binds to the
secreting adenomas, prolactin‐dependent male hypogonadism, as adjunct therapy to 5‐HT(1A) and 5‐HT(2A/2C) receptors. Dipergon®; Dopergin® (Bayer) tab. 0.2 mg.
surgery or radiotherapy for acromegaly or as monotherapy is special cases, as – Lysergic acid diethylamide (LSD) (synthetic): It's effects, often called a "trip" can be
monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in stimulating, pleasurable, and mind‐altering or it can lead to n unpleasant, sometimes
advanced cases with motor complications. Bromocriptine has also been used off‐label terrifying experience called a "bad trip.“. Effect: hallucinations; distorted visual
to treat restless legs syndrome (hội chứng chân không yên) and neuroleptic malignant perception of shapes, colors; altered sounds; anxiety and depression; flashbacks (a
syndrome. Bromocriptine stimulates centrally‐located dopaminergic receptors resulting return of the "trip" experience) days or months later; rapid heart rate, increased body
in a number of pharmacologic effects. Tab. 2.5 mg, 5mg. Parlodel® temperature and high blood pressure; dilated pupils
–

Hallucinogens Hallucinogens
1. Tryptamines 3. Others:
• Simple tryptamines: DMT (N,N‐dimethyltryptamine), 5‐methoxy‐DMT (5‐MeO‐DMT), and • NMDA = N‐methyl‐D‐aspartate.
psilocybin • COCAINE
• Ergolines: analogues including LSD and a few very closely related compounds • OPIATES and Opioid: morphine, codeine, dextromethorphan, …
• Ibogaine: Tabernanthe iboga Apocynaceae • DESIGNER STIMULANTS: phenylethylamine, benzylpiperazine, phenylpiperazine,
pyrrolidinophenone, and cathinone derivatives
2. Phenethylamines • BENZODIAZEPINES: diazepam
• Mescaline (peyote cactus Lophophora williamsii)
• Ketamine (synthetic): Anesthesia.
• Amphetamine
• Nitrous Oxide
• MDMA = 3,4‐methylenedioxy‐methamphetamine.
• Phencyclidine (Synthetic)
• MDA = 3,4‐methylenedioxyamphetamine.
• Salvia (Salvia divinorum): salvinorin A (non‐alkaloid)
• Cathinone (Khat or qat (Catha edulis) [Al‐Mugahed, Leen (2008)]
• Cannabinoids: CB1 = cannabinoid 1; THC = Δ9‐tetrahydrocannabinol.
Albert Garcia-Romeu. 2016 https://www.drugabuse.gov David E. Nichols. 2004 317 Albert Garcia-Romeu. 2016 https://www.drugabuse.gov David E. Nichols. 2004 Loralie J. L. 2019 318
Hallucinogens Hallucinogens
Ibogaine
Tabernanthe iboga
Voacanga africana Cathinone
Bufotenin = 5-OH-DMT
Tabernaemontana undulata
Apocynaceae
DMT (N,N‐dimethyltryptamine)
319 320
Hallucinogens Alkaloid‐bearing plants
Non-heterocyclic alkaloid
Plants Part used Main compounds Uses
Treatment of common cold, asthma,

pseudoephedrine, ephedrine,
hay fever, bronchitis, edema, arthritis,
Sympathomimetics that either
1. Ma hoàng – fever, and hypotension urticaria. Treat
MDMA: methylenedioxy‐methamphetamine methylenedioxyamphetamine Herba directly or indirectly stimulate α-
Dextromethorphan Ephedra sinica bronchoconstriction for centuries,
Ephedrae and β-adrenergic receptors.
Ephedraceae because of its activity at β2-
Less extensively used with the
adrenergic receptors. [V.S. Vaidya.
advent of more selective
2014]
2. Tỏi độc –
Colchicum Semen Gout, Familial Mediterranean Fever
Colchicin
autumnale Colchici (FMF)
Colchicaceae
THC Ketamine
salvinorin A
321 Phạm Thanh Kỳ. 2015
Alkaloid‐bearing plants Alkaloid‐bearing plants
Non-heterocyclic alkaloid Pyridin, piperidine Alkaloid N N
H
Plants Part used Main compounds Uses Plants Part used Main compounds Uses
In 2018, Vietnam was the world's
treatment of gynecologic disorders such as
3. Ích mẫu – Herba largest producer and exporter of
menorrhagia, menostasia, and other irregular
Leonurus and Leonurine, black peppercorns, producing
menstruation. It is also used as a diuretic in the 1. Hồ tiêu – Piper nigrum
heterophyllus Fructus stachydrine Fructus Piperis Piperine, piperyline 262,658 tonnes or 36% of the
treatment of edema and acute nephritis. [Tang W., Piperaceae
Lamiaceae Leonuri world total (Wikipedia)
Eisenbrand G. (1992) ]
Toothaches, stomach ache,
Capsaicin is used internally for various diarrhea, common cold
conditions, including colic and for improving
4. Ớt – 2. Lựu – Punica granatum
peripheral circulation, and externally for unbroken Pelletierine,
Capsicum Fructus Capsaicin, Punicaceae Cortex Granati Expel tapeworms, toothache
chilblains. A cream for topical application has Isopelletierine
annuum Capsici capsicoside (pomme granate)
been used to relieve the pain of postherpetic
Solanaceae
neuralgia and other pain syndromes.[J.K.
Aronson. 2016]
Phạm Thanh Kỳ. 2015 Phạm Thanh Kỳ. 2015

Alkaloid‐bearing plants Alkaloid‐bearing plants N
Tropane Alkaloids
Pyridin, piperidine alkaloids N N
H tropan
Main
Plants Part used Uses
Plants Part used Main compounds Uses compounds
pain reliever, muscle relaxer, and
Taenifuge;; Intestinal worms; treat
L-hyoscyamine; anti-inflammatory, and to treat
diarrhoea, and dysentery; malaria 1. Belladon – Atropa Folium
Semen et d,l-atropine, menstrual problems, peptic ulcer
3. Cau – Areca catechu Arecoline, (Fresh nut; kernel). Pericarp is belladonna Solanaceae Belladonnae
Pericarpus cuscohygrine disease, histaminic reaction, and
Arecaceae arecaidine, guvacine effective in the treatment of
Arecae motion sickness
flatulence, oedema, dysuria and
hyperaemesis of pregnancy asthma, cough, convulsion and
Folium, flos, L-scopolamine insanity (mất trí)
entheogenic, emetic, and a 2. Cà độc dược – Datura
semen Daturae (hyoscine), Scopolamine: Prevent nausea and
4. Lobelia inflata Lobeliaceae Herba Lobeliae Lobeline, Lobenine dermatological and respiratory aid metel Solanaceae
metelis atropine vomiting caused by motion sickness
Smoking cessation aid (Lobeline) or medications used during surgery.
Nocotine,
5. Thuốc lá – Nicotiana Folium nornicotine, Insecticide; hemostasis; synthesis 3. Loa kèn độc – Brugmansia
tabacum Solanaceae Nicotianae anabasine, of nicotinic acid aurea Solanaceae
nicotyrine 4. Cô ca – Erythroxylum Cocaine, hygrine,
Folium Anesthetic (cocaine)
coca Erythroxylaceae cuscohygrine
Alkaloid‐bearing plants N
Alkaloid‐bearing plants
N
N
Quinoline Isoquinoline Alkaloid
Quinolizidine Alkaloids
1. Ipeca (Cephaelis anti-protozoal and to induce
Radix Emetine
1. Sarothamnus scoparus ipecacuanha) Rubiaceae vomiting (Emetine)
Herba antiarrhythmic agent
(Cytisus scoparus) Sparteine Nhựa (opium)
Sarothamni (sparteine) Opium: treating dysentary,
Fabaceae Quả (fructus Morphinan: Morphine, codeine,
2. Thuốc phiện Papaver thebaine; Benzyl isoquinoline: diarrohea, spasms, pain.
Papaveris)
Quinoline alkaloids somniferum Papaveraceae Papaverine, Laudnine, Seed: important food item and the
Hạt (semen) laudanosine source of poppyseed oil
Plants Part used Main compounds Uses Lá (folium)
1. Cinchona succirubra Fever, intestinal complaints, sleep
3. Bình vôi Stephania glabra Tuber
(Canh ki na đỏ); Rotundine, palmatine disturbances; asthma,
Menispermaceae Stephaniae
tuberculosis, dysentery
2. C. calisaya (Canh ki na
vàng); treat malaria and babesiosis gastrointestinal disorders;
4. Hoàng liên – Coptis Rhizoma Berberine, palmatine,
Cortex Quinine, quinidine, (quinine) chinensis Ranunculaceae Coptidis jatrorrhizine
antidiarrheal; antimicrobial,
3. Cinchona officinalis (Canh Chinconae cinchonine, cinchonidine antipyretic
ki na xám); antiarrhythmic (quinidine)
tonic, antiperiodic, diuretic,
4. Cinchona ledgeriana Radix and
5. Thổ Hoàng liên –Thalictrum Berberine, palmatine, febrifuge, purgative and stomachic
Rhizoma
(Canh ki na lá thon) foliolosum Ranunculaceae jatrorrhizine and for the treatment of snakebite,
Thalictrii
Rubiaceae jaundice, and rheumatism.
N N
Alkaloid isoquinoline Alkaloid isoquinoline
Main Main
Plants Part used Uses Plants Part used Uses
compounds compounds
fever, abdominal pain, 9. Hoàng đằng Fibraurea ophthalmia, furunculosis, prurigo,
6. Vàng đắng Coscinium Berberine, inflammation; malaria; diarrhoea, tinctorial; F. recisa Radix et rhizome Palmatine enteritis, gastritis, cystitis,
Caulis et Radix
fenestratum palmatine, bacillary dysentery, enteritis, Menispermaceae dysentery and fever.
Coscinii
Menispermaceae jatrorrhizine jaundice, pyrexia and dyspepsia; Erysopine,
ophthalmia 10. Vông nem Erythrina Folium et cortex erysonine,
insomnia and anxiety
diarrhoea, dysentery, orientalis Fabaceae Erythrinae erysodine,
7. Hoàng liên gai Berberis Radix et Caulis
Berberine ophthalmia;dyspepsia;headache, erysovine,
wallichiana Berberidaceae Berberidis
vertigo and photopsia Nuciferine, N-
neurasthenia, spermatorrhoea;
jaundice following cholecystitis, 11. Sen Nelumbo nucifera Folium, fructus, nornuciferine, O-
metrorrhoea, insomnia,
urinary duct inflammation, chyluria, Nelumbonaceae rhizome nornuciferine,
haemorrhage and haematemesis.
8. Hoàng bá Phellodendron Berberine, dysentery, diarrhoea, dyspepsia, roemerine
Cortex Phellodendri
amurense Rutaceae phellodendrine haemorrhoids, ophthalmia, otitis,
spermatorrhoea, leucorrhoea, fever
and night sweats
Phạm Thanh Kỳ. 2015
Alkaloid nhân indole Alkaloid indole
1. Mã tiền Strychnos nux-vomica
3. Lá ngón Gelsemium elegans Gelsemine, gelsevirine, Succide (xem film “Ma
Loganiaceae
Strychnine, Gelsemiaceae sempervirine ngón”) (THNA)
rheumatism, pain in the extremities,
brucine, vomicine,
 Mã tiền cành vuông S. neuralgia, paralysis, myasthenia, Clavin: agroclavine powerful vasoconstrictor,
vanprukii Semen novacine,
enteric hypotonia, enuresis and 4. Nấm cựa gà Claviceps Lysergic: simple amine migraine headaches;
Strychni colubrine Fruiting body
 Đậu gió S. ignatia anaemia. purpurea Clavicipitaceae (ergometrine) and peptide treatment of uterine atonia,
 Mã tiền hoa nách S. axillaris (⾺錢⼦) (alkaloid >1.2% postpartum bleeding
an antidote to barbiturate (ergotamine)
 Mã tiền hoa tán S. umbellata tính theo
derivatives (strychnine) 5. Ba gạc Rauvolfia verticillata; treatment of hypertension
strychnine, pp UV)
 Mã tiền Cát hải S. cathayensis
R. serpentina, R. vomitoria Radix Yohimbine. Reserpine, and psychoses (reserpine),
treating rheumatism, ostealgia, (BG bốn lá); R. cambodiana; Rauvolfiae Serpentine, Ajmaline erectile dysfunction
Strychnine paralytic cramp of the extremities, R. indochinesis. Apocynaceae (Yohimbine)
(2.81%), brucine lumbago, sciatica, colic and treating oliguria,
2. Hoàng nàn Strychnos Lá: 0.37-1.15% alk. Rễ 0.8-
Cortex (2.37-2.43%) diarrhoea (hoàng nàn chế); treating 6. Dừa cạn Catharanthus roseus Folium et Radix haematuria, diabetes
wallichiana Loganiaceae 1.2%. Vinblastine,
scabies, leprosy and certain Apocynaceae Catharanthi mellitus and menstrual
Alkaloid > 5.23%, persistent dermatoses (external vincristine
disorders; leukaemia
uses)
H
N
Alkaloid indole N Alkaloid quinazoline N

N
H purine

species name “febrifuga” means
7. Lạc tiên Passiflora foetida Herba Harman, harmol, harmine, neurasthenia, insomnia, -Dichroine
“medicine used to reduce fever”
Passifloraceae Passifloraceae harmalol, harmaline nightmares and anxiety 1. Thường sơn Dichroa febrifuga (Febrifugine); -
Folium Pilocarpi and refers to the use of it to
Hydrangeaceae (họ Tú cầu) dichroine
treat high fever, particularly
8. Dạ cẩm Hydyotis capitellata capitellin, cyclocapitellin, (Isofebrigugine)
Herba et Radix gastrointestinal diseases related to malaria
Rbiaceae isocyclocapitellín,
Alkaloid Purine
Alkaloid Imidazole Plants Part used Main compounds Uses
Main Caffeine (2.5-4.5%); cancer prevention, to lower
Plants Part used Uses 1. Chè Camellia sinensis Folium et Theophylline (0.02- cholesterol. diuretic, an astringent and
compounds
Theaceae Bud 0.04%); Theobromine to improve heart's health. Caffeine
lower intraocular pressure in primary open- (0.05%) used to increase alertness
angle glaucoma; treat dry mouth caused by
1. Pilocarpus jaborandi; P. stimulant, nervine, and diuretic.
radiotherapy in people with head and neck
microphyllus; P. Folium Pilocarpine, Caffeine used to improve mental
cancer and to treat dry mouth in people with 0,3 - 2,5% caffein và có
pennatifolius; P. Pilocarpi pilosine 2. Café Coffea arabica (Chè); C. Semen et
ít theobromin, alertness, in combination with
Sjogren's syndrome (a condition that affects the exselsa (Mít); C. robusta (Vối) folium painkillers (aspirin and
racemus. Rutaceae theophylline
immune system and causes dryness of certain acetaminophen) and with ergotamine
parts of the body such as the eyes and mouth). for treating migraine headaches
Phạm Thanh Kỳ. 2015 DDVN V. 2017. Phạm Thanh Kỳ. 2015
Alkaloid Steroid Alkaloid diterpene
0,22 - 4,2% alk (vỏ).
1. MỨC HOA TRẮNG Holarrhena against amoebiasis; anti-
Cortex et semen Conessin (>1,0 %. DDVN treating rheumatism,
antidysenterica Apocynaceae diarrheal 1. Ô đầu Aconitum fortunei; Ô củ mẹ: 0,36 - 0,80%, củ con:
V, PP acid-base) paresis, arthralgia,
đầu châu Âu A. napellus; Ô 0,78 - 1,17%.; aconitine,
Chemical structures of Radix luxation (sai khớp),
đầu TQ: A. carmichaeli - hypaconitine. DDVN V: alk
solamargine and solasonine are sprains (bong gân) and
Ranunculaceae. >0.6% aconitine (PP acid-base)
Solasonine,
very similar to steroidal contusions(giập).
2. CÀ LÁ XẺ Solanum laciniatum Herba Solani hormones and used as an Other Alkaloid
solamargine; solasodine
Solanaceae laciniati important source for
(aglycone) Plants Part used Main compounds Uses
manufacture of contraceptives
and steroidal anti-inflammatory
Alkloid > 0,50 % (tính
drugs (progesterone; cortisone) 1. Bách bộ Stemona tuberosa Cough, ascariasis and
Radix theo tuberostemonin LG)
Alk > 0,1 % tính theo Stemonaceae. oxyuriasis.
3. Cà gai leo Solanum Herba Solani treatment of hepatitis, (DDVN V, PP Acid – base)
solasodine (DDVN V)
procumbens Solanaceae procumbensỉs cirrhosis; rheumatism, pain
(PP UV-Vis)
HN
H
H
O
DDVN V. 2017. Phạm Thanh Kỳ. 2015
H H
N
conessine HO
H solasodine
DDVN V. 2017. Phạm Thanh Kỳ. 2015
References References
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Zhong. NXB BLUE POPPY PRESS. 1998. 2. Walter Sneader (2005). Drug Discovery – A history. John Wiley & Sons.
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Science.
7. Hannu Hotti and Heiko Rischer (2017). ”The killer of Socrates: Coniine and Related Alkaloids in the 5. W.A. Kukula‐Koch et al. (2017). Chapter 9. Alkaloid in Pharmacognosy. Elserver.
Plant Kingdom”. Molecules, 22, 1962. 6. S. W. Pelletier. 1999. Alkaloid: Chemical and biological perspectives. V.14 Pergamon.
8. Sneader Walter (2005) ‐ Drug Discovery (A History) Chapter 9: Alkaloids
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339 340

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Mục tiêu bài giảng Glossary

Chỉ tính từ đầu năm 2019, quân y Đồn biên phòng

Cuscohygrine Atropine Senecionine CYTOTOXICITY

Treatment of dry mouth

Pyridine/pyrrolidine Hordenine; L-Tyrosine

Hordenine stachydrine Piperidine Sesquiterpene Phenyl alkyl Phenyl terpenoid Purine

Cassinine Cathine Capsaicin Conessine

Pyrrolo-indole (C10N2) – ca. 27000 alkaloid were known. (William Charles Evans. 2009)

Magic mushrooms are sold in bags. Photo: Tuoi Tre

Spores of magic mushrooms are kept in a fluid

(Tadeusz Aniszewski . 2015). Evans.2009 75 HEGNAUER. 1988 76

Amaryllidaceae tyrosine Isoquinoline Lycorus, Galanthus Lycorine, galanthamine

Friday, October 12, 2012 10:45 Friday, March 09, 2018, 11:58 GMT+7

Five farmers were rushed to a hospital in Vietnam after enjoying a pufferfish hotpot on

Mạng xã hội rộ lên thông tin một

• Tuber: Aconitum, Stephania rotunda, Stemona tuberosa

[1] D.K.Holdsworth. 1998. [2]. G. Biswas. 2012. [3]. D. M. Culbreth ‐ 1996 W.A. Kukula‐Koch. 2017 95 Mazen A. El‐Sakka.2010 W.A. Kukula‐Koch. 2017 96

Mazen A. El‐Sakka.2010 W.A. Kukula‐Koch. 2017 97 Joaquín Isac‐García. 2016 98

PHYSICAL PROPERTIES PHYSICAL PROPERTIES pKa of some alkaloids

A.N.M. Alamgir. 2018 105 [M. A. El‐Sakka. 2010] A.N.M. Alamgir. 2018 106

W. C. Evans.2009 Phạm Thanh Kỳ. 2015 111 Subhash C. Mandal. 2015 112

Subhash C. Mandal. 2015 113 W. C. Evans.2009 Abdel‐Azim M. Habib. 1980 114

Abdel‐Azim M. Habib. 1980 115 Phạm Thanh Kỳ. 2008 116

Subhash C. Mandal. 2015 117 Subhash C. Mandal. 2015 118

Subhash C. Mandal. 2015 119 120

Timothy Soderberg. 2016 123 Richard Koplík. https://web.vscht.cz 124

Richard Koplík. https://web.vscht.cz 125 Richard Koplík. https://web.vscht.cz 126

λ (nm) Colour of light Colour of absorbing body –Lambert‐Beer law

Richard Koplík. https://web.vscht.cz 129 L.D.S. Yadav. 2005 130

Argyrolobine: C=C-N-C=O grouping with a maximum at 240 nm

concentrations) Atropine 258, 262 Hygrine No chromophore

145 https://www2.chemistry.msu.edu 146

Sue Clarke. 2008 147 Timothy Soderberg. 2016 148

Malgorzata Baranska. 2009 G. W . GRIBBLE. 1973

codein base heroin.HCl

SOMOGYI, Á. (2008). 159 Timothy Soderberg. 2016 160

SOMOGYI, Á. (2008). 163 SOMOGYI, Á. (2008). 164

–MS Magnetic field B

G. Gauglitz. 2014 169 Magnetic Sector Mass Analyzers G. Gauglitz. 2014 170

robust. Ideally suited to isotope analysis and Isotope-ratio mass spectrometry.

• Photomultiplier (or Scintillation Counter)

http://www.chm.bris.ac.uk/ms/detectors.xhtml 175 http://www.chm.bris.ac.uk/ms/detectors.xhtml 176

most common detectors

http://www.chm.bris.ac.uk/ms/detectors.xhtml 177 Timothy Soderberg. 2016 178

O.D. Sparkman et al. (2011) 179 Arpana Vaniya et al. 2015 180

183 the degree of unsaturation 184

187 Hee Jung Shim. 2013 188 Hee Jung Shim. 2013

Timothy Soderberg. 2016 189 http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 190

http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 191 http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch13/ch13‐hnmr.html 192

– The identification of an alkaloid is first of all a matter of classification.

• Complete isolation is not necessary.

R. VERPOORTE. 1994 195 R. VERPOORTE. 1994 196

R. VERPOORTE. 1994 197 JI Yubin. 2014 198

JI Yubin. 2014 203 JI Yubin. 2014 204

hòa tan trong HCl loãng

Atropin.HCl Hyoscyamin.HCl Hyoscin.HCl

+ dd. NaHCO3 đến pH 7.5 Lắc phân bố với Et2O

Atropin.HCl Hyoscin base

JI Yubin. 2014 207 JI Yubin. 2014 208

- chỉnh về pH 6-7, dd. sẽ hơi đục, chiết (lần 1) = CHCl3

- chỉnh về pH 8-9, dd. nước lại đục, chiết (lần 2) = CHCl3

- chỉnh về pH 12-13, dd. nước lại đục, chiết (lần 3) = CHCl3