See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/324476579

Pharmacological activity of Alkaloids: A Review

Article · April 2018

DOI: 10.63019/ajb.v1i2.467

CITATIONS READS

42 21,797

1 author:

Noureddine Bribi
Université de Béjaïa
22 PUBLICATIONS   134 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Intestinal anti-inflammatory activity of alkaloids in DNBS, DSS and Acetic Acid Models View project

All content following this page was uploaded by Noureddine Bribi on 12 April 2018.

The user has requested enhancement of the downloaded file.

Asian Journal of Botany (2018) Volume 1
doi:10.63019/ajb.v1i2.467

Pharmacological activity of Alkaloids: A Review

Noureddine Bribi 1,2
1
Laboratory of Biological Engineering of Cancer. Faculty of Medicine. University of Bejaia, 06000 Bejaia, Algeria
2
Laboratory of Plant Biotechnology and Ethnobotany, University of Bejaia. Bejaia 06000, Algeria

ABSTRACT
Plant alkaloids, one of the largest groups of natural products, represent a highly diverse group of chemical entities.
Historically, although plants containing alkaloids have been used by man for at least 3000 years as medicines, teas, and
potions, the compounds responsible for activity were not isolated and characterized until the 19th century. The basic
character of alkaloids allows the formation of salts with mineral acids or organic acids, alkaloids salts are generally
soluble in water and in dilute alcohols, and they are, except in rare cases, not soluble in organic solvents. They are
classified using various signatures such as natural sources or chemical nature. The most correct and common
classification of alkaloids is their distribution according to principal structure, the principal C-N skeleton.
Keywords: Alkaloid; natural products; plants; secondary metabolites

1. Introduction
A characteristic feature of plants and other organisms, which cannot run away in case of danger or which do not
have an immune system to combat pathogens, is their capacity to synthesize an enormous variety of low molecular
weight compounds, the so-called secondary metabolites[1]. The Secondary metabolites can closely interact with
molecular targets in cells and tissues or other physiological features in animals or microorganisms. Quite often
structures of SM resemble endogenous substrates, hormones or neurotransmitters and can thus mimic a response at the
corresponding molecular targets. There is hardly a target in animals or microorganisms for which a natural product does
not exist. Thus, plants provide a wide array of bioactive substances. This is the reason so many natural products can be
used in so many ways in biotechnology, pharmacy, agriculture and medicine. The diversity of the biosynthetic pathways
in plants has provided a variety of lead structures that have been used in drug development and which have been
estimated to account for more than 50% of current drugs. The plant kingdom still remains a treasure trove of new
molecules with therapeutic potential[2,3].
Plant alkaloids, one of the largest groups of natural products, represent a highly diverse group of chemical entities.
Alkaloids encompass an enormous class of approximately 12 000 natural products. The principal requirement for
classification as an alkaloid is the presence of a basic nitrogen atom at any position in the molecule, which does not
include nitrogen in an amide or peptide bond. As implied by this exceptionally broad definition, the alkaloids form a
group of structurally diverse and biogenically unrelated molecules. Many of these compounds possess potent
pharmacological effects. For example, the well known plant alkaloids include the narcotic analgesics, morphine and
codeine, apomorphine (a derivative of morphine) used in Parkinson’s disease, the muscle relaxant papaverine, and the
antimicrobial agents sanguinarine and berberine. Also several potent anti-cancer drugs have been developed from plant
compounds[3,4].
The term alkaloid was introduced by W. Meisner at the beginning of the nineteenth century to designate natural
substances reacting like bases, in other words like alkalis (from the Arabic alkaly, soda, and from the Greek eidos,
appearance). There is no simple and precise definition of alkaloids, and it is sometimes difficult to distinguish the thin
line between alkaloids and other natural nitrogen-containing metabolites[5].
Copyright © 2018 Noureddine Bribi.
doi: 10.63019/ajb.v1i2.467
EnPress Publisher LLC.This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
http://creativecommons.org/licenses/ by/4.0/

1
 Although plants containing alkaloids have been used by man for at least 3000 years as medicines, teas, and potions,
the compounds responsible for activity were not isolated and characterized until the 19th century. Many proved to be
challenging chemical problems and the structures were resolved only in recent years[6]. The first isolations of alkaloids
in the nineteenth century followed their introduction into medicine of a number of alkaloid-containing drugs and were
coincidental with the advent of the percolation process for the extraction of drugs. Although the concept of alkaloid is
relatively recent, but it is relatively recently (early 19th century) that therapeutically active substances have been isolated.
The first crude drug to be investigated chemically was opium, a drug that had been used for centuries for both its
analgesic and narcotic properties[7]. It was probably Derosne, who, while extracting a mixture of narcotine and
morphine from opium in 1803, was the first to isolate a vegetable alkali. In 1806, Serturner recognized the alkaline
nature of the somniferous principle of opium, which he named morphine about ten years later. Shortly
afterwards, between 1817 and 1820, two French pharmacists, Pelletier and Caventou, “discovered” an impressive series
of active compounds: caffeine, emetine from ipecac, strychnine from nuxvomica, quinine and cinchonine from
cinchona bark, followed a little later by coniine (Fig.1). Today advanced NMR techniques and X-ray diffraction
spectrometry allow the elucidation of the most complex structures. Because of their importance, many attempts
have been made to produce alkaloids in plants tissue culture. About 30 alkaloids account for most commercial interest,
primarily as medicines, flavorings, or poisons[5,6,8,9].

Figure 1. Some alkaloids isolated by pharmaceutists Pierre Joseph Pelletier and Joseph beinamé Caventou during 1817-1821.
Modern methods and instrumentation have greatly facilitated these investigations, and it is interesting to note that
the yields of ‘minor’ alkaloids, too small for further investigation, isolated by chemists during the first quarter of the last
century would now be sufficient, several thousand times over, for a complete structure analysis. In the second half of
the twentieth century alkaloids featured strongly in the search for plant drugs with anticancer activity (Fig. 2). A notable
success was the introduction of Catharanthus alkaloids and paclitaxel into medicine and there is much current interest in
other alkaloids having anticancer properties as well as those exhibiting antiaging and antiviral possibilities[9].

2
 Figure 2. Schemes of taxol, vinblastine, vincristine and vincamine used as anticancer drugs.
2. Distribution and localization of alkaloids
Initially defined as nitrogen-containing, basic substances of natural origin and of limited distribution, alkaloids
have a complex structure. Their nitrogen atom is part of a heterocyclic system and they possess a significant
pharmacological activity; according to some authors, they occur only in the vegetable kingdom. They are found as salts,
and we may add that they are formed biosynthetically from an amino acid. These elements characterize what may be
referred to as true alkaloids. Many authors distinguish, in addition, proto-alkaloids and pseudo-alkaloids[5]. Only rarely
do alkaloid-containing plants contain only one alkaloid: sometimes they do contain virtually only one constituent
(hyoscyamine from the leaves of belladonna), but, most often, they yield a complex mixture, which may be
dominated by one major constituent. It is not uncommon to find several dozen alkaloids in one drug. As a general rule,
all of the alkaloids of a given plant have a common biogenetic origin, even if their structures may at first seem quite
different. In a given plant, the concentration of alkaloids can vary widely from part to part, and some parts may contain
none[5].
3. Properties of alkaloids
Probably the only single character that distinguishes all alkaloids is that they have nitrogen. In general, this
nitrogen comes from amino acid, is incorporated into a heterocyclic ring, and is basic. Pelletier (1983) defined an
alkaloid as a cyclic compound containing nitrogen in a negative oxidation state, which is of limited distribution among
living organisms. Alkaloids almost always have physiological activity in animals, although some have limited effects[6].
Most alkaloids are well-defined crystalline substances which unite with acids to form salts. In the plant they may exist
in the free state, as salts or as N-oxides. In addition to the elements carbon, hydrogen and nitrogen, most alkaloids
contain oxygen. A few, such as coniine from hemlock and nicotine from tobacco, are oxygen-free and are liquids.
Although colored alkaloids are relatively rare, they are not unknown; berberine, for example, is yellow and the salts of
sanguinarine are copper-red[9].
The basic character of alkaloids allows the formation of salts with mineral acids (hydrochlorides, sulfates, nitrates)
or organic acids (tartrates, sulfamates, and maleates). Alkaloids salts are generally soluble in water and in dilute
3
alcohols, and they are, except in rare cases, not soluble in organic solvents. The crystallized salts can be conserved
fairly well and are the common commercial form of these compounds[5]. Acknowledge of the solubility of alkaloids and
their salts are of considerable pharmaceutical importance. Not only are alkaloidal substances often administered in
solution, but also the differences insolubility between alkaloids and their salts provide methods for the isolation of
alkaloids from the plant and their separation from the non-alkaloidal substances also present[9].
4. Classes of alkaloids
The chemistry of alkaloids is one of the most interesting and important topics of bioorganic chemistry. The term
“alkaloid” was initially applied to N-containing compounds of plant origin that had a distinctly basic nature. Now this
term is used much more broadly. Alkaloids form an expansive group of natural N-containing organic compounds
produced by plants, micro- and marine organisms, and fungi. In contrast with other classes of natural compounds,
alkaloids have practically unlimited structural frameworks and contain an N atom in their molecules, for this reason, the
alkaloids are highly variable[10]. They are classified using various signatures such as natural sources or chemical nature.
The most correct and common classification of alkaloids is their distribution according to principal structure, the
principal C-N skeleton. According to the last signature, alkaloids are divided into the following large groups, (Fig. 3),
including; pyrrolidine, pyridine, quinoline, isoquinoline, indole, quinazoline, steroidal, diterpenoid, and other alkaloids.
Each of these groups is subdivided into several subgroups depending on the structural features of its representatives[11].

Figure 3. Heterocyclic structure of skeleton constituting the group of alkaloids.

5. Pharmacological activities of alkaloids
The activity of alkaloids against herbivores, toxicity in vertebrates, cytotoxicity activity, the molecular targets of
alkaloids, mutagenic or carcinogenic activity, antibacterial, antifungal, and antiviral properties, and their possible roles
as phytoalexins have been tabulated. Many alkaloids are sufficiently toxic to animals to cause death if eaten. Several
alkaloids such as nicotine and anabasine are used as insecticides. Many alkaloids act on the nervous system, one of two
important information systems in animals[6]. Plants that contain protoberberine alkaloids are reported to be used as
analgesics, antiseptics, sedatives, and stomatics in Chinese folk medicine. In Indian and Islamic folk medicine, such
plants are used for bleeding disorders and eye diseases, and antiseptics, sedatives, stomatics, and uterine muscle
depressants. Both quaternary alkaloids and their tetrahydro derivatives possess many substantiated biological and
therapeutic effects, e.g., palmatine, jatrorrihizine, and tetrahydropalmatine have been reported to show in vitro
antimalarial activity. In china, tetrahydropalmatine is used as an analgesic, and has been reported to exhibit bradycardial,
hypotensive, and sedative activities[12].
Among many thousands of modern drugs, about 40% are of natural origin. The widest spectrum of

4
pharmacological action is exhibited by alkaloids, especially, isoquinoline ones[13]. In previous studies, it was reported
that the isoquinoleine alkaloid extract from Fumaria capreolata, in addition to exert antioxidant, analgesic, and intestinal
anti-inflammatory activities in DNBS model of experimental colitis in mice, was devoid of significant toxicity when
administered orally to mice[14-18]. The alkaloids zephyrantine and narcyclasine-glucoside exhibit antitumor activity.
Even in low doses, these alkaloids inhibit the growth of the epithelium carcinoma Hela, epidermic carcinoma KB, and
carcinoma P388. Besides cytostatic activity, the aglyconenarcyclasine, dihydronarcyclasine, and the alkaloid
secocepharantine exhibit a marked antiviral effect. Detailed studies revealed a marked antivral activity in the drugs
earlier known protozoacide; the alkaloid norberbamine-2 turned out to be a strong inhibitor of reverse transcriptase,
while the alkaloid noscapine, an anti-cough remedy[13]. Berberine, an isoquinoline alkaloid isolated from C. chinensis,
inhibits the proliferation and migration of breast cancer ZR-75-30 cells by targeting Ephrin-B2. Furthermore, berberine
downregulates the phosphorylation of VEGFR2 and downstream signaling members (AKT and Erk1/2), which in turn
downregulates the expression of MMP2 and MMP9[19]. Berberine also possesses anti-HIV, anti-fungal, cardioprotective,
immunoregulative, anti-malarial, anti-inflammatory, antioxidant, cerebro-protective, anti-mutagenic, vaso-relaxing,
anxiolytic and analgesic activities[20].
Actions on the immunologic system are also described for these alkaloids; induction and inhibition of gene
expression, anti-inflammatory, anti-proliferative, anti-system complement, and apoptosis induction. At the level of the
digestive system, some relevant actions were reported such as anti-diarrhetic, electrolyte transport inhibition, and
antiulcer activities[12]. The prodrug codeine is extensively metabolized by CYP2D6, and the clinical analgesic effect of
codeine is mainly attributed to its conversion to morphine. Like apomorphine, also buprenorphine (a semi synthetic
opioid derived from the baine, naturally occurring alkaloid of Papaver somniferum, and used as substitution therapy in
the treatment of opioid dependence), undergoes extensive first-pass metabolism and therefore has very low
oral bioavailability[3].
References
1. Michael Wink. Functions and biotechnology of plant secontary metabolites. Introduction, Chapter 1. Ann Plant Rev
2010; a(39): 1-20.
2. Michael Wink. Biochemistry, physiology and ecological function of secondary metabolites. Chapter 1, Introduction.
Wiley-Blackwell Ann Plant Rev 2010; b(40): 1-19.
3. Kaisa A Salminen, Achim Meyer, Lenka Jerabkova, et al. Inhibition of human drug metabolizing cytochrome P450
enzymes by plant isoquinoline alkaloids. Phytomedecine 2011; (18): 533-538.
4. Sarah O’Connor. Alkaloids in comprehensive natural products IIL. Mander, H-W. Lui, Eds. Elsevier. Oxford 2010;
(1): 977-1007.
5. Jean Bruneton. Pharmacognosy, phytochemistry, medicinal plants. Lavoisier, 2nd Edition 1999; 1136.
6. David Seigler. Plant secondary metabolism. Springer Science Business Media New York. 1st Edition 1998;
506-507.
7. Roberts MF, Michael Wink. Alkaloids: Biochemistry, ecology, and medicinal applications. Plenum Press, New York,
USA, 1998: 1-7.
8. Verpoorte R, van der Heijden R, van Gulik WM, et al. Plant biotechnology for the production of alkaloid: Present
status and prospects. In A. Brossi (ed). The alkaloid. 40. Academic Press, San Diego 1991: 1-187.
9. Evans William. Pharmacopoeial and related drugs of biological origin. In: Trease and Evan’s Pharmacognosy.
London: WB Saunders Co. Ltd 2009: 353-416.
10. Shakhnoz Azimova, Yunusov Marat. Natural Compounds-Alkaloids. Springer Science Business Media New York
2013.
11. Ahmed Shakil. Isolation and structural elucidation of chemical constituents from fumaria indica, ferula oopoda
and withania somnifer. Doctorate Thesis. International center for chemical researche, university of Karachi 1998:
10-25.
12. Leitao Da-Cunha EV, Fechine IM, Guides DN, et al. Protoberberine alkaloids, in: The alkaloids; Chemistry and
Biology, 1st edition, ISBN: 0-12-469562-0. Elsevier Academic Press, London 2005; 62.
13. VG Kartsev. Natural compounds in drug discovery. Biological activity and new trends in the chemistry of
isoquinoline alkaloids. Med Chem Res 2004; (13): 325-336.
14. Noureddine Bribi, Yacine Bouguezza, Fadila Maiza. Evaluation of erythrocytes toxicity and antioxidant activity of

5
View publication stats

alkaloids of fumaria capreolata. Inter J of Pharma and Bio Scien 2013; (4): 770-776.
15. Noureddine Bribi, Francisca Algieri, Alba Rodriguez-Nogales, et al. Anti-nociceptive and anti-inflammatory effects
of total alkaloid extract from fumaria capreolata. Evidence-Based Complementary and Alternative Medicine
2015; 736895(7): 1-8.
16. Noureddine Bribi, Francisca Algieri, Alba Rodriguez-Nogales, et al. Intestinal anti-inflammatory effects of total
alkaloid extract from fumaria capreolata in the DNBS model of mice colitis and intestinal epithelial CMT 93 cells.
Phytomedicine 2016; (23): 901–913.
17. Noureddine Bribi, Messaoud Belmouhoub, Fadila Maiza. Analgesic and anti-inflammatory activities of ethanolic
extract of fumaria capreolata. Phytothérapie 2017; 15(4): 211-216.
18. Maria Contreras, Noureddine Bribi, Anna Gomez-Caravaca, et al. Alkaloids profiling of fumaria capreolata by
analytical platforms based on the hyphenation of gas chromatography and liquid chromatography with
quadrupole-time-of-flight mass spectrometry. International Journal of Analytical Chemistry. 2017; 5178729: 1-16.
19. Ma Weina, Zhu Man, Zhang Dongdong, et al. Berberine inhibits the proliferation and migration of breast cancer
ZR-75-30 cells by targeting Ephrin-B2. Phytomedicine 2017； 25: 45-51.
20. Feng Zuo, Norio Nakamura, Teruaki Akao, et al. Pharmacokinetics of berberine and its main metabolites in
conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry. Drug
Metab Dispos 2006; (34): 2064–2072.