Pharmaceutical and Medicinal Organic Chemistry

1st Semester
Introduction to Medicinal Chemistry o Morphine, codeine, heroine
• Squill
History and Evolution of Medical Chemistry
o Urginea maritima (Hyacinthaceae)
DRUGS OF ANTIQUITY o Cardiotonic (heart failure)
• Hyoscyamus “henbane”
• Shen Nung (2735) o Hyoscyamus niger (solanaceae)
− Ch’ang shang, Ma huang o Toothache, asthma, cough
• American Indians
− Chaulmoogra fruit MIDDLE AGES
• Brazil • Basic studies of chemistry and physics shifted
− Ipecacuanha root from the Greco-Roman to the Arabian
• South American Indians alchemist.
− Coca leaves father of
toxicology • Paracelsus glorified Sb as cure-alls in the belief
• Greek Apothecary that chemicals could cure diseases.
− Opium, squill, Hyoscyamus, viper
toxin, Cu, Zn ores, Fe sulfate. Cadmium 19TH CENTURY: AGE OF INNOVATION AND
oxide CHEMISTRY

• From finding new medicaments from vast world

of plants to finding the Al that accounted for
their pharmacologic properties.

1805
Ma huang Chaulmoogra fruit Ipecacuanha root Coca leaves
• Morphine extracted from by Serturner (not
OVERVIEW widely recognized until 1817, when he
reported dose of 100 mg gave symptoms of
• Cháng shang severe opium poisoning to himself and three
o Dichroa febrifuga (Hydrangenaceae) companions)
o Antimalaria
• Ma huang 1810
o Ephedrine
• Organon der rationellen Heilkunde published
o Hypotension, asthma, myasthenia
by Hahneman on his unproven principle
gravis
• Chaulmoogra fruit similia similinus curator (like cures like, _____)
o Hydnocarpus wightianus opposing Gelen’s theory. Therapeutic doses
(Achariaceae) had to be minute as illness renders patient
o For Leprosy highly sensitive to drug.
• Ipecacuanha root Galen’s theory
o Cephaelis ipecacuanha (Rubiaceae)
o Expectorant, emetic • Imbalance four humours
o Emetine- management heavy metal • (blood, phlegm, black bile, yellow bile)
poisoning • “Opposite”- hot remedy → cold
• Cocoa- Erythroxylum coca (erythroxylaceae)
DJFLORIDA

o Cocaine (psychostimulant) 1816

• Opium
• isolation of emetine from ipecacuanha by
o Poppy seed papaver somniferum
Pierre-Pelletier
(papaveraceae)
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1820 • Rise of synthetic chemotherapeutic agents

• purification of caffeine, quinine and colchicine

• Gerhard Domagk
1826 o Prontosil (2,4-diaminoazobenzene-4-
sulfonamide)- g(+) bacteria
• mass production of pharmaceutical natural
product-Pelletier’s factory processed 150,000 1929
kg of cinchona bark annually to products 2600
• discovery of Penicillin by Alexander Fleming
kg of quinine sulfate (an antimalarial
due to negligence
compound)
1940
1845
• bacteriostatic action of sulfonamide-like drugs
• Adolph Kolbe synthesis of Acetic acid
• Prontosil (Sulfonamide) -bacteriostatic
1845 (inhibits the growth of bacteria, does not
totally kill or eliminate)
• Concept of a biological receptor formulated by
British pharmacologist John.

1886

• first alkaloid synthesis, coniine (from

Hemlock)
• Esterases - an enzyme which attacks the
• Coniine
composition of sulfa drugs, decreasing its
o “Hemlock”Conium Maculatum
efficacy and potency.
(Apiaceae)
o First isolated alkaloid PSYCHOPHARMACOLOGIC AGENTS AND ERA OF
BRAIN RESEARCH
1897
Mental illnesses before were associated with
• Ehelich described sidechain theory;
spirituality and not with science.
germicidal capability of a molecule depends on
its structure, particularly its side chains which • Discovery of Chlorpromazine
can bind to disease-causing organisms o single most important breakthrough in
o Sidechain theory psychiatric treatment
o WBC- side chains • Chlorpromazine
o Bacteria, Virus etc. o Antipsychotic, also known as “lytic
o magic bullet cocktail” which induces “Artificial
o Aspenamine “Salvarsan” Hibernation”.
o Arsenic-father of chemotherapy • Artificial Hibernation
• Sedation w/o narcosis
1898
Chlorpromazine + Promethazine + Pethidine
• first mass produced synthetic drug. Aspirin
(Bayer, 1898)
DJFLORIDA

20TH CENTURY AND PHARMACEUTICAL INDUSTRY

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• Discovery of antidepressant effects of
Iproniazid
• Iproniazid
o (Non-selective inhibitors, Monoamine
oxidase Inhibitors) (MAOI’s) was first
used to manage Tuberculosis then it is
used as antidepressants.
o Is now withdrawn in the market
because it causes hepatotoxicity
(hepatotoxic)
• Epinephrine / Adrenaline – first pure
hormone isolated discovered
o “Fight or flight hormones”
o Mostly secreted by adrenal glands and
small amounts are secreted by
Medulla Oblongata
o Are neurotransmitters which are
responsible in the visceral function
(involuntary muscles) such as
breathing
o Drug of choice for Anaphylactic shock
(severe allergic reaction) like rashes,
hypotension, runny nose, and
difficulty in breathing.

1904
• Imipramine
o first dibenzoazepine (tricyclic) • Henry Dale discovered Oxytocin (love
antidepressant hormone/cuddle hormone)
o 2 benzene ring fused with azepine • Oxytocin is secreted in the Posterior portion
group of Pituitary Gland
• Uterotonic (increase uterine contraction)

1914

• Edward Kendall isolated thyroxine from

thyroid gland
• Fluoxetine • Thyroxine is also known as T4 (inactive)
o first commercially successful SSRI which will then be converted to T3
(Selective Serotonin Reuptake o (Active)
Inhibitors o Levo-thyroxine is used in the
o (1 billion dollars) management of Hypothyroidism
• Antidepressant used in Obsessive Compulsive (Goiter)
Disorder (OCD), Panic Disorder, Bulimia
Insulin
Nervosa
• Beta cell of Islet of Langerhans (Pancreas)

Humulin

• (Human Insulin Isophane)

o Recombinant DNA technology by
• Chlordiazepoxide, Diazepam, and
using strain E.coli
meprobamate
• Causes serendipity Pramlintide
DJFLORIDA

ENDOCRINE THERAPY AND STEROIDS • (Symlin)

o Diabetes insipidus

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o insidious imbalance in the body o induces the hardening of the cervix,
decreases vasopressin stimulates the cervix to secrete mucus
• Vasopressin which blocks the entry of sperm.
o Retain in H20 • CPPP Nucleus
o precursor of hormones (similar with
ENDOCRINE THERAPY AND STEROID
progesterone)
1930 • Norethindrone
o similar to progesterone as well but
• Russell Marker was able to convert diosgenin without problems
to progesterone (acid labile)
ANESTHETICS AND ANALGESICS
1950
• First use of synthetic organic chemical
• Carl Djerassi
• Horace Wells
• synthesized Norethindrone (Norminest®)
o dentist who administered nitrous
(first orally active contraceptive steroid)
oxide (N2O/laughing gas) during
1956 tooth extraction
• Crawford Long
• John Rock o used ether as an anesthetic agent
o Progesterone + Norethindrone • William Morton
1980 o gave the first successful public
demonstration of surgical anesthesia
• mifepristone - abortion pill (1846)
1994 • Chloroform
o used as an anesthetic agent at St.
• mifepristone + Misoprostol Bartholomew's Hospital
• “Morning after pill”
o AKA Plan b
o Emergency contraceptive
o Levonorgestrel

NITROUS OXIDE

• Nitrous oxide potency is the lowest but the

most effective. MAC concentration of N2O is
>104%
• Minimum Alveolar Concentration (MAC)
o fraction of volume of anesthetics
Mexican yam Dioscorea floribunda presents in inspired air that provides
sufficient analgesia in 50% of
DJFLORIDA

• (Dioscoreaceae) - Diosgenin - - - >

patients. It defines the effectivity of
Progesterone
anesthetics (mostly inhaled)
• Progesterone
• Low MAC means MORE FAT SOLUBLE
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o Slow induction CHLORAL HYDRATE
o High potency
• Mickey finn
o High lipid/blood solution
o “knockout drop”
o E.g (Halothane)
o “Date rape drug”
• High MAC means MORE WATER SOLUBLE
o Fast induction BARBITURIC ACID
o Low potency
o Low lipid/blood solution • Malonic acid + Urea = Barbituric acid
o E.g (N2O or Nitrous Oxide) o Used in seizures associated with
children
“MAC should always be low” • Benzodiazepine
1921 o used in seizures associated with
adults
• Frederick Banting and Charles Best
LOCAL ANESTHETICS
discovered Insulin
• Humulin (Eli Lilly) 1860
o first genetically engineered drug
approved by US FDA • Albert Niemann isolated cocaine
(Erythroxylon coca)
• Symlin (2005)
o for Type 1 Diabetes • Carl Koller (“Coca Koller”)
o Inhaled Insulin (2006) o Found that cocaine numbs the tongue
o First to use cocaine for topical
HYPNOTICS AND ANTICONVULSANTS anesthesia in ophthalmological
surgery
• Laudanum- induce sleep
• Richard Willstater
o Bromides, chloral hydrate,
o determined the structure of cocaine
paraldehyde, urethane and sulfenal
and atropine
1864 • Benzocaine, procaine, tetracaine and
lidocaine
• Adolph Van Beyer
• Structural analog of cocaine
o Synthesized 5,5-diethylbarbituric acid
• Bayer Pharm’l Company
o Introduced Phenobarbital (Luminal)
o Modification of the barbituric acid
molecule led to the development of
Hydantoins
• Phenytoin (Dilantin)
o Diphenylhydantoin
DRUGS AFFECTING RENAL AND CARDIOVASCULAR
o 5,5- Diphenyl2,4-imidazolidinedione
FUNCTION
LAUDANUM
1775
• Tincture (dissolving a drug in alcohol) of
DJFLORIDA

• William Withering
opium 10% by weight
o Discovered Digitalis pupurea was
• Whole opium
beneficial to those suffering from
o Morphine, Codeine etc.
abnormal fluid buildup
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1841 • Cisplatin
o Inorganic; gold standard against
• E. Humolle and T. Quevenne
which new medicines are compared
o Isolated digitoxin
• Carboplatin - 2nd gen
1929
1963
• Sydney Smith
• Moeroe E. Wall and Masikh C. Wani
o Isolated digoxin (drug of choice for
o Discovered Paclitacel (Taxol)
the management of heart failure)
o Pacific yew Tree (Taxus brevifolia)
1973 o European Yew Tree (Taxus baccata)

• Akira Endo ORGANIC PHARMACEUTICAL CHEMISTRY

o Discovered the first anti cholesterol
• Study of Carbon-based Medicinals
drug
• A scientific discipline at the intersection of
o Compactin (Mevastin) – Penicillium
chemistry and pharmacy involved with
citrinum
designing, synthesizing and developing
1978 pharmaceutical drugs

• Merck Medicinal chemistry

o Discovered a substance nearly
• Identification, synthesis and development of
identical to Endo’s and named
new chemical entities suitable for therapeutic
Lovastatin (Mevacor)
use
• Atorvastatin (Lipitor) (pfizer)
• HMG-COA (3-hydroxy-3-methyl glutarylcoa) Pharmaceutical chemistry
will be converted to mevalonic acid by the
• Focused on quality aspects of medicines and
HMG-COA Reductase
aims to assure fitness for the purpose of
• End product: Cholesterol
medicinal products
• Mevalonic acid
• It also includes the study of existing drugs,
o rate limiting step in the conversion to
their biological properties, and their
cholesterol
Quantitative Structure-Activity Relationship
• Lovastatin, Lovastatin, etc.
(QSAR)
o These medications inhibit the HMG-
COA Reductase. Therefore, HMG-COA QUANTITATIVE STRUCTURE-ACTIVITY
will not be converted into mevalonic RELATIONSHIPS (QSAR)
acid that will form cholesterol
• A strategy of essential importance for
ANTICANCER AGENTS chemistry and pharmacy.
o Based on the idea that when we
• Sulfur mustard (WWI) and nitrogen jstaard
change the structure of a molecule
(WWII)
then also the activity or property of
o leukemia therapy
the substance will be modified.
• Gearge Hitchings and Gertrude Elion
DJFLORIDA

o Developed 6-mercaptopurine
o First effective leukemia drug

1893
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DJFLORIDA

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STEREOCHEMISTRY 2 Types of Isomers

PHARMACEUTICAL CHEMISTRY • Constitutional/Structural

• Sterioisomers
• Focused on quality aspects of medicines and
aims to assure fitness for the purpose of CONSTITUTIONAL ISOMERS (Structural isomers)
medicinal products
• Same molecular formula but different
• The study of drugs, and it involves drug
structure
development
• Same atoms but linked together differently.
• Pharmaceutical chemistry work is usually
• Isomers in which the atoms have differently
done in a lab setting
connectivity
• Involves cures and remedies for disease,
• Compounds that have the same molecular
analytical techniques, pharmacology,
formula but diff. structure/ connectivity
metabolism, quality assurance, and drug
chemistry. Pharmacodynamics and kinetics

STERIOCHEMISTRY

• Branch of chemistry that concerned with 3D

arrangement of atoms and molecules and its
effect on the chemical rx.
• Study of Isomers

Isomers

• (Iso- Same/equal meros- parts) STERIOISOMER

• Same molecular formula
• Compounds that have identical
• Different structural and spatial arrangement
formula/connectivity but different
• Different physical and chemical properties
arrangement of atoms in space.

Sub-type:

• Configurational
o Optical
▪ Enantiomer
▪ Diasteriomer
o Geometric
▪ Cis/trans
▪ e/z
• Conformational
Structural o Boat/chair

• arrangement of atoms w/c gives the SKELETAL ISOMERS

compound a particular structure
DJFLORIDA

• Isomers with different carbon atom

Spatial arrangements and different hydrogen atom
arrangements
• arrangement of atoms in space; 3D geometry
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Chiral example:

POSITIONAL ISOMERS

• Isomers that differ in the location of the

functional group

FUNCTIONAL GROUP ISOMERS

• Isomers that contain different functional

groups
You might think there are 2 hydrocarbons attached to
the carbon but it’s still considered chiral because they
have different arrangement (front and back)

• Wedge- front
• Dash- back
STEREOCHEMISTRY

• Positioning the different functional groups in

their sites of action

3 MAIN GROUPS:

• Optical isomers
o Enantiomer – D and L forms
o Diastereomer – ex Epimers
ACHIRAL EXAMPLE
• Geometric isomers
o Cis and Trans • Symmetrical
• Conformational isomer
o Boat and Chair

OPTICAL ISOMERS

• Chirality/asymmetry
• Contain at least one asymmetric, or chiral,
carbon atom ENANTIOMERS
DJFLORIDA

o Chiral – carbons that have four non-

identical substituents around it. • Non-superimposable mirror image
• Each asymmetric carbon can exist in one of the • Optical isomers that are mirror images of one
two non-superimposable isomeric forms another
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• Have identical physical and chemical DESIGNATING HANDEDNESS USING FISCHER
properties except that one rotates the plane of PROJECTION FORMULAS
polarized light
• D and L system used to designate the
• Dextro/Levo, R/S
handedness of glyceraldehyde enantiomers
• Cahn-ingold-prelog priority
o Atomic number (higher) (utmost
priority)
1. Rank atoms
2. Ensure that #4 is in the back (dash)
3. Cross out #4
4. Trace arc 1-> 2-> 3 PROPERTIES OF ENANTIOMERS
• F - Lowest
• Cl Dextrorotary and Levorotatory Compounds
• Br • Enantiomers are optically active: Compounds
• I – Highest that rotate plane polarized light

2 Types:

Counterclockwise (to right) → S
Clockwise (to left) → R
But if the #4 is in the back (wedge)
• Dextrorotatory
o Chiral compound that rotates light
towards RIGHT (clockwise; +)
• Levorotatory
o Chiral compound that rotates light
towards LEFT (counterclockwise; -)
• There is no correlation between D, L and +, -
• In D and L you need to look at the structure
• + and – are determined by using a polarimeter

▪ Clockwise direction (dextrorotatory,

designated d or +)
▪ Counterclockwise direction (levorotatory,
designated / or -)

• Racemic mixture
o Equal mixture of d and I
DJFLORIDA

• Unpolarized light (Na+ wavelength 589

enantiomers
nanometer)
o Optically inactive
Filter

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• Polarimeter tube o Levorphanol (analgesics)
o contains optically active compounds
plane polarize light rotate when it hits
the compounds
• Analyzer
o Observational rotation number
molecules that are hit by polarize right
DIASTEREOMERS

• Enantiomers can have large differences in • Non-mirror, non-superimposable

potency, receptor fit, biologic activity, • 1 same, 1 different stereocenter
transport and metabolism. These differences • Neither mirror images nor superimposable
result when the drug molecule has an • Drug must have at least two chiral centers in
asymmetric interaction with a receptor, a order to exist in diastereomers
transport protein, or a metabolizing enzyme. • Unlike enantiomers, in which all
stereochemical centers are opposite,
diastereomers have some stereochemical
centers that are identical and some that are
opposite
• Possess different physicochemical properties
and, thus, differ in properties, such as
solubility, volatility, and melting points.

• Levorphanol
o narcotic analgesic, antitussive
• Dextrophanol
o doesn’t possessed narcotic analgesic
• (Morphinan)
o their mother nature char

• Dextrorotatory Isomers
o Dextrorphan (antitussive) EPIMERS

• Special type of diastereomers because all

epimers are also diastereomers
• Compounds that are structurally identical in
all respects except for the stereochemistry
about one chiral center. The process of
• Levorotatory Isomers epimerization (in which the stereochemistry
of one chiral center is inverted) is important in
DJFLORIDA

drug degradation and inactivation.

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o (Z)- alkene on the same side (German;
zusammen = together)
o €-alkene on opposite sides (German;
entgegen = opposite)

GEOMETRIC ISOMER

• Occurs due to restricted rotation of double

bond based on the longest chain
• Not mirror images and have different
physicochemical properties and
pharmacologic activity

• CIS- substituent are on the same side

• TRANS- substituent are on the opposite side

• E- Entgegen (apart)
• Z- Zusammen (same)

(2-Z, 4 E) -1-chloro heptadiene

• E and Z nomenclature
o Cis ≠ Z and trans ≠ E
DJFLORIDA

o Based on a set of priority rules

CONFORMATIONAL ISOMERS
o Relative position of the two higher
priority groups • Boat and “chair” forms
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• Non-superimposable orientations of a
molecule which result from the rotation of
atoms about single bonds
• Provide a more exact representation of the
three-dimensional conformation of sugars in
nature
BIOISOSTERES MOLECULES
• Procaine has ester bond, thus it has shorter
duration
• Esterases- found in blood
• isosteric analog may act antagonisticallyto the
parent molecule
o Alloxanthine is an inhibitor of xanthine
oxidase. It is also an isostere of
xanthine, the normal substrate for the
enzyme

• Phenomenon by which a compound usually fit

in a similar functional groups (isosteres) and
possess the same type of biological activity
• Replacement of functional group
• Containing groups that are spatially and
electronically equivalent and, thus,
interchangeable without significantly altering
the molecules’physicochemical properties.

• Isosteric replacement of functional groups:

o Can increase potency
o Decrease side effects
o Separate biologic activities
o Increase the duration of action by
altering metabolism

BIOSTERES

• Procainamide
o an amide, has a longer duration of
action than procaine, an ester, because
of the isosteric replacement of the
ester oxygen with a nitrogen atom
DJFLORIDA

• Procainamide is more effective because it is

not susceptible to the enzyme esterases

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1st Semester
DRUG DISCOVERY AND DRUG DEVELOPMENT 2. CHOOSING A DRUG TARGET — receptor,
enzymes and nucleic acid
MOLECULAR PHARMACOLOGY
o Receptor
• Programs that focus on scientific study of ▪ OLOL drugs: Propanolol,
biochemical and biophysical characteristics of Atenolol, Metoprolol (Beta 1
drugs at molecular level, interaction with and antagonist)
the effects on biological macromolecules and ▪ Beta 1 Normal Agonist
cellular structures and processes. Vasoconstriction
▪ (HTN) – Antagonist
SOURCES OF NEW DRUGS Vasodilation
• Plant Kingdom o Enzymes
o Digitalis lanata Digoxin (Heart failure) ▪ Allopurinol (Purinase)
o Morphine Papaver somniferum ▪ MOA: Inh. Xanthine oxidase
(Analgesic) enzyme (Responsible for
• Animal Sources converting Hypoxanthine,
o Draculin Saliva of vampire bat - MI Xanthine)
(Heart attack) ▪ Pathway in developing U.A:
o Urine of pregnant mare Hormone Hypoxanthine – (X.O.)
o COD Liver Gadus morhua Sodium Xanthine – (X.O.) Uric acid
morrhuate (Anti-varicouse) *causes gout*
• Microbiological world ▪ Statins (Atorvastatin,
o Anitibiotics – Penicillin Rosuvastatin, Simvastatin)
• Biological Source ▪ MOA: HMG-coA Reductase
o Vaccine, Serum, Biologics, etc. Inhibitor
▪ HMG-coa Mevalonic Acid (rate
DRUG DEVELOPMENT BEFORE limiting step in the conversion
of Cholesterol)
• Even before the synthetic, target-based and
o depend on finding the drug first
selective medicinal agents, remedies were
o discovery of the chemical messenger *
abundantly provided by the various plant
o genome projects — an increasing
sources or more commonly referred to as
number of new receptors and enzymes
herbal remedies. Dating back to the cave men
— potential drug targets
following their instincts to survive or preserve
3. MEDICAL FOLKLORE – used by herbolarios in
their lives, drugs already exist in various
managing disease (EX. 10 herbal medicines)
forms.

NEW DRUG DEVELOPMENT PROCESS 4. EXISTING DRUGS

o (1) Burimamide – for antiallergy; acts
DISCOVERY PHASE
on histamine receptor (poor
• includes synthesis, isolation, fermentation, bioavailability)
screening, and SAR studies o (2) Metiamide – same activity (ADE:
Agranulocytosis)
DJFLORIDA

1. CHOOSING A DISEASE — focus is on the o (3) Cimetidine – same activity; H2

financial return receptor antagonist which manages
ulcer

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o (1) Dichloroisoproterenol – SUMMARY OF DRUG DEVELOPMENT PROCESS
sympathomimetic activity (but
partial)
o (2) Pronethanol (ADE: Light
headedness)
o (3) Propranolol – Non-selective B1/B2
antagonist (X asthama)

5. COMBINATORIAL SYNTHESIS
o OTC drugs
o Antibacterial drugs

DRUG DISCOVERY

• Molecular Modification
• Mechanism-based Design 15 years to 20 years process
o Computer-aided Design • NEW CHEMICAL ENTITY – Information of
o Serendipity and Prepared Mind organic synthesis, molecular modification
• Use of NMR study
AFTER DISCOVERING A DRUG…
• PRECLINICAL – Chemistry of drugs, physical
6. IDENTIFYING A BIOASSAY and chemical property, biological, pre-
o In vivo test formulation, pharmacology, toxicology,
▪ Subsequent bioassay by kinetics and dynamics, bioassay
biological experiment or
technique carried out within a • SUBMIT INVESTIGATIONAL NEW DRUG
living organism (test animals) APPLICATION (INDA) – FDA approximately 1
▪ Drugs activity is tested on year review (to make sure that chemical
isolated tissues, cells or entities are safe for human trial)
enzymes
o In vitro test
✔ special consideration is given on Orphan
▪ Initial bioassay that takes
drugs (treatment IND)
place outside the organism, in
o orphan drug is used to treat orphan
an artificial environment such
disease, or disease that affects fewer
as laboratory where drug
than 200,000 people in the US
activity is tested on isolated
tissues, cells, or enzymes.
▪ Inducing a clinical condition
and treated with the test drug
DJFLORIDA

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CLINICAL TRIAL
✔ Phase I
✔ Phase II
✔ Phase III
NEW DRUG APPLICATION (NDA)
• submitted to FDA to conduct review on data
for approximately 1.5 years (Action for
approval for the availability of the medication
in the market)
✓ Submitted to the FDA for review and
approval after the completion of the
clinical trials and requirements have
been met.
✓ When the preclinical and clinical
studies have proven the IND’s
effectiveness and safety by all
parameters.
POST MARKETING SURVEILLANCE (Phase IV)
• To see any adverse events/effect that a new
drug entity has that wasn’t verified during
Phase I-III
✓ Manufacturing scale up activities take
place.
✓ Scale up – increase in the batch size
from the clinical batch, submission
batch, or to the full-scale production
batch size, using the finished,
marketed product
✓ Then, product development may
continue
Additional applications
ANDA or ABBREVIATED NEW DRUG APPLICATION
• Filed for generic copies by competing
companies following expiration of patent term
protection
✓ Sponsored drug (drug from the
scratch) applies for patent (doesn’t
lasts/expires) other pharmaceutical
company will take inspiration from the
drug and will make a generic
counterpart submit ANDA
✓ Branded medicines – undergo clinical
trials
✓ Generic drugs – copies branded meds
o Biologics License Application (BLA) – for
the manufacture of biologic products,
vaccines and toxins.
o Animal Drug Applications – specific
regulation pertaining to the approval for
the marketing and labeling of drugs
intended for animal use Regulation apply:
INADA’s,
▪ NADA’s – New Animal Drug
Application,
▪ SNADA’S – Supplemental New
Drug Application and abbreviated
NADA’s
SUPPLEMENTAL NEW DRUG APPLICATION (SNDA)
• There are changes in synthesis, formulation,
analytical standards, containers, and labeling
of drug products
✓ A change in the method of synthesis of
the drug substance
DJFLORIDA
✓ Change in the formulation, analytical
standards, method of manufacture, or
in-process control of the drug product
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✓ Change in the container and closure
system for a drug product
✓ Extension of the expiration date for a
drug product based on new stability
data.
PRE-CLINICAL STUDIES
• Phase which includes: Chemical and physical
characterization, pharmacology,
pharmacokinetics, pharmacodynamics,
pharmaceutics, analytical studies, toxicology
• Pharmacology — the science of the properties
of the drugs and its effects in the body
• Pharmacodynamics — the study of the
interaction of drugs with cells (what the drug
does to the body)
• Pharmacokinetics — the handling of a drug
within the body, it includes the ADME
processes (what the body does to the drug)
• Toxicity testing — in vitro and in vivo testing;
determination of LD 50 (dose that cause
fatality in 50% population)
• Pharmaceutics — the general area of study
concerned with the formulation,
manufacturing, stability and effectiveness of a
pharmaceutical dosage form
PRE-CLINICAL OBJECTIVES
• Identify target organs/tissues
• Identify need for specialized, safety
monitoring
• Identify toxicological profile
• Select starting doses/regimens
LEAD COMPOUND
• A compound showing a desired
pharmacological property which can be used
to initiate a medicinal chemistry project
• A prototype chemical compound that has a
fundamental desired biologic or
pharmacologic activity
o Example 1: Development of new
generations of cephalosporin
antibiotics
o Example 2: Additional H2-Antagonists
from the pioneer drug Cimetidine
• Since most drugs have primary and secondary
effects, taking advantage of secondary effects
leads to a drugs secondary indication
o Example: Finasteride
(Proscar/Atepros)
o Finasteride (Proscar) Mgt. Benign
Prostatic Hyperplasia or BPH (affects
older men) difficulty in urination
A/E: Hirsutism (promotes hair
growth) and bronchoconstriction
o Finasteride (Propecia) Mgt. of male
pattern baldness
PRODRUGS
• A compound that requires metabolic
biotransformation after administration to
produce the desired pharmacologically active
compound
o Chemically inactive at first activates
inside the body with the help of certain
enzyme
o EX. Enalapril (ACE Inh.) – (hydrolysis)
Enalaprilat – active metabolite (in the
body)
NEW DRUG
• A combination of 2 or more old drugs or
change in usual proportions of drugs in an
established combination product is
considered new if the change alters safety and
efficacy.
DJFLORIDA
• A change in previously approved formulation
or method of manufacture constitutes
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newness since such change can alter effects population and transmitting that information
and safety of a product. in the physician labeling
• A proposed new use for an established drug, a
PHASE 4
new dosage regimen or schedule, a new route
of administration, or a new dosage form leads • Post-marketing studies and manufacturing
to a drug’s status new and triggers scale-up activities take place
reconsideration for safety and efficacy. • Modification on drug formulation as obtained
from manufacturing scale-up and validation
process may be done
CLINICAL TRIAL
PHASE NO. OF PURPOSE %SUCCESSFULLY
PATIENTS COMPLETING
I 20-80 Health Safety 67
volunteer
II 100-30 Suffer Safety & 45
0 from the effectiveness
target
illness
III 1000-3 With the Safety, 5-10
000 target effectiveness
illness and dosage

PHASE 1

• These studies are designed to determine the

metabolic and pharmacological actions of the
drug in humans, the side effects associated
with increasing doses, and, if possible, to gain
early evidence on effectiveness.
PHYSICOCHEMICAL PROPERTIES
• These studies also evaluate drug metabolism,
structure-activity relationships, and the ACID BASE
mechanism of action in humans. Taste Sour Bitter
Litmus Paper Blue Red Red Blue
PHASE 2
Methyl Orange Red Yellow
• This phase of testing also helps determine the
Phenolphthalein Colorless Pink/Red
common short-term side effects and risks Corrosiveness Highly Corrosive Not all are
associated with the drug. corrosive
• Failure during Phase Il testing is common
o After phase 2, sponsors meet with FDA Corrosive: NaOh
Aqueous solution H+ upon contact OH- upon contact
PHASE 3 reaction with Aq. Sol’n w/Aq. sol

• These studies are intended to gather the

additional information about effectiveness ACID BASE PROPERTIES
and safety that is needed to evaluate the
1. Arrhenius Theory
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overall benefit-risk relationship of the drug.

• Svante Arrhenius
• These studies also provide an adequate basis
• ACID – dissociates of H+ upon contact with
for extrapolating the results to the general
water or aqueous solution
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• BASE – Dissociation of OH- in Aq. Solution • Conjugate acid – base that receives a proton

• Conjugate base – acid that donates a proton

• Limitation:
o H2SO4/HCl + toluene (acid) 3. Lewis Theory
o NaNH2 + NH3 (base) • Gilbert Lewis
• ACID – compound that receives electron pair
• BASE – compound that donates electron pair

• A base which ionizes almost completely in Example:

solution is said to be a strong base,
whereas one which has a small degree of
ionization is a weak base
2. Bronsted-Lowry Theory
• Johannes Nicolaus Bronsted and Martin
Lowry
o ACID – proton (H+) donor
o BASE – proton (H+) acceptor
ACID STRENGTH
Example 1:
• Refers to its ability or tendency to lose a
proton (H+).
STRONG ACID Completely HCl, Hl, HBr,
ionizes HClO4, HNO3,
(dissociates) in a H2SO4
solution
WEAK ACID Partially H2CO2
dissociates CH3COOH

Example 2:
So I Brough No Clean Clothes (STRONG ACIDS)

o Sulfuric
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o Iodic
o Boric
o Nitric
Example 3:
o Hydrochloric
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 Pharmaceutical and Medicinal Organic Chemistry
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o Perchloric acid
• Acid dissociation constant (Ka) – measures
the strength of an acid molecule
• pH – measures the strength of an aqueous
acid solution
• Stronger acid = Larger dissociation constant
(Ka)
• Stronger acid = Smaller logarithmic constant
(pKa)
(1) ACID DISSOCIATION EQUATION
(2) ACID DISSOCIATION CONSTANT expression. (Ka)
Organic acids contain one or more of these
functional groups:
IONIZATION CONSTANT (Ka)
• It indicates the relative strength of the acid or
base
o An acid with Ka of 1 x 10-1 is stronger
(more ionized) than one with a Ka of 1
x 10-3
o where a base with a Ka of 1 x 10-7 is
weaker (less ionized) than one with a
Ka of 1 x 10-9
• Negative log of the ionization constant
o (pKa)
o An acid with a pKa of 5 (Ka = 1 x 10-5)
is weaker (less ionized) than one with
a pKa of 3 (Ka = 1 x10-3)
o whereas a base with a pKa of 9 (Ka = 1
x 10-9) stronger (more ionized) than
one with a pKa of 7 (Ka = 1 x 10-7).
IONIZATION FOR ACIDS AND BASES
• Weakly acidic drugs are less ionized in acid
media than in alkaline media. When the pka of
an acidic drug is greater than the pH of the
medium in which it exists, it will be more than
50% in its nonionized (molecular) form and
thus, more likely to cross lipid cellular
membranes.
• Carboxylic acid group (-COOH)
• (2) Phenolic group
• (3) Sulfonic acid group
• (4) Sulfonamide group
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• (5) Imide group
• (6) beta-carbonyl group
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Strong inorganic bases Very soluble <1mL
Freely soluble 1-10
• sodium hydroxide
Soluble 10-30
• potassium hydroxide,
Sparingly soluble 30-100
• magnesium hydroxide,
Slightly soluble 100-1000
• ¢calcium hydroxide,
Very slightly soluble 1000-10 000
• ¢barium hydroxide
Practically soluble/ > 10 000
• and quaternary ammonium hydroxides are
insoluble
also completely ionized

Organic bases contain the following functional

Valence Shell Electron Pair Repulsion Theory (VSEPR)
group
Model to predict the geometry of individual molecule
1. primary, secondary or tertiary aliphatic or
alicyclic amino group
2. most aromatic or unsaturated heterocyclic
nitrogen’s

A. ACIDS AND BASES

B. SOLUBILITY

• The amount in milliliters of water capable of

dissolving one gram of a given substance.
• Universal solvent: WATER

Some basic properties of water:

C. DRUG POLARITY
• Bond angles
• It is a relative measure of a drug's lipid and
water solubility and is usually expressed in
terms of a partition coefficient.
• Water solubility (or hydrophilicity) depends
primarily on two factors:
• Charge distribution 1. ionic character and
2. hydrogen-bonding capabilities.
• The presence of oxygen and nitrogen
containing functional groups usually enhances
water solubility

Water solubility is required for:

• H-bonding
1. Dissolution in the gastrointestinal (Gl) tract
DJFLORIDA

2. Preparation of parenteral solutions (as

opposed to suspensions)
3. Preparation of ophthalmic solutions

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4. Adequate urine concentrations (pertains
primarily to antibiotics)
• Lipid solubility (or lipophilicity) is enhanced
by nonionizable hydrocarbon chains and ring
systems.
Lipid solubility is required for:
1. Penetration through the lipid bilayer in the GI
tract
2. Penetration through the blood brain barrier
3. Preparation of intramuscular (IM) depot
injectable formulations
has chemical properties and physical
properties that would make it a likely orally
active drug in humans.
• No more than 5 hydrogen bond donors (the
total number of nitrogen— hydrogen and
oxygen—hydrogen bonds)
• No more than 10 hydrogen bond acceptors (all
nitrogen or oxygen atoms)
• A molecular mass less than 500 daltons
• An octanol-water partition coefficient (log P)
that does not exceed 5

PARTITION COEFFICIENT (P)

• defined as the ratio of the solubility of the

compound in an organic solvent to the
solubility of the same compound in an aqueous
environment

P = [Drug] lipid/[Drug]aqueous • Omeprazole is a popular drug that conforms to

DRUGS IN SALT FORM Lipinski’s rule of 5

• A salt is the combination of an acid and a base. PHARMACODYNAMIC

• Two classes based upon the chemical nature of PHARMACODYNAMIC PHASE
the substance
o Inorganic salts are made by combining Drug actions dynamic interactions between drug
drug molecules with inorganic acids molecules and cellular components
and bases
▪ increased water solubility in
comparison with the parent
molecule
o Organic salts are made by combining
two drug molecules, one acidic and
one basic
▪ increased lipid solubility;
generally, is used to make
Types of molecules that a drug may act upon:
depot injections
• lipid — Amphotericin
LIPINSKI’S RULE OF FIVE
• carbohydrate — used as molecular tag
• Pfizer’s rule of five or rule of five (ROS) • protein — receptors
DJFLORIDA

• rule of thumb to evaluate drug likeness or • nucleic acids — DNA and RNA acting as drug
determine if a chemical compound with a target
certain pharmacological or biological activity
RECEPTOR
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• cell or group of cells specialized to detect
changes in the environment and trigger
impulses in the sensory nervous system
• protein in nature and embedded in the cell
membrane
• Ligand - molecule that binds to a receptor
Theories describing the pharmacologic activity of the
drug:
LOCK AND KEY THEORY
• completely complementary relationship
between the drug molecule and a specific area
on the surface of the receptor molecule
TYPES OF RECEPTOR ACTION
DOWN-REGULATION
• caused by continuous prolonged exposure of
receptors to drugs that disrupt the
homeostatic equilibrium and result in altered
levels of the receptors.
• This disruption involves endocytosis of ligand-
bound receptors, resulting in:
o sequestration of receptors from the
cell surface
o accelerated degradation of the
receptors,
o or inactivation of the receptors.

INDUCED FIT THEORY

• complementary relationship between the drug

molecule and its active site

OCCUPATIONAL THEORY OF RESPONSE

• the intensity of pharmacologic activity of a

structurally specific drug is directly
proportional to the number of receptors
occupied by the drug

AFFINITY

• measure of how strongly a drug binds to a

DESENSITIZATION
receptor
• result of down -regulation
EFFICACY
• The target cells become desensitized and the
• maximum biological effect resulting from a effect of subsequent exposure to the same
drug binding to its target concentration of the drug is reduced
• An increased-concentration of the drug is
ENZYME
required to produce an effect of the same
• protein catalysts produced by living cells by magnitude as the initial exposure with a
acting as a surface or focus for the reaction, smaller drug concentration.
bringing the substrate(s) together and holding
them in the best position for the reaction.
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METABOLISM • Other sites include the gut, lungs, skin and
kidneys
• plays a central role in the elimination of drugs
• For orally administered compounds, there is
and other foreign compounds (xenobiotics)
the “First Pass Effect”
from the body
o Intestinal metabolism
• an essential tool for pharmacists in their role
o Liver metabolism
of selecting and monitoring appropriate drug
o Enterohepatic recycling
therapy for their patients
o Gut microorganisms – glucuronidases
BIOTRANSFORMATION
REACTIONS UNDER PHASE I
• PARENT DRUG 1. OXIDATION
METABOLIC PATHWAYS • Most are mediated by microsomes.
• Although oxidation would seem to imply
PHASE I REACTIONS the addition of oxygen, that is not always
• Functional phase the case. Oxidation refers to the change in
• Polar functional groups are introduced into oxidation state of the substrate.
the molecule or unmarked by: Two types of oxidation reactions:
o oxidation
o reduction • Oxygen is incorporated into the drug molecule
o Hydrolysis (e.g. hydroxylation)
• Functional polar groups: • Oxidation causes the loss of part of the drug
o OH molecule (e.g. oxidative deamination,
▪ R ROH dealkylation)
o COOH
Microsomal Mixed Function Oxidases (MFOs)
▪ R RCOOH
o NH2 • “Microsomes” – form in vitro after cell
▪ R RNH2 homogenization and fractionation of ER
o SH o Rough microsomes are primarily
▪ R RSH associated with protein synthesis
o Smooth microsomes contain a class of
Achieved by:
oxidative enzymes called
• by direct introduction of the functional group • “Mixed Function Oxidases” or
o Example: aromatic and aliphatic “Monooxygenases”
hydroxylation o These enzymes require a reducing
• by modifying or "unmasking" existing agent (NADPH) and molecular oxygen
functionalities (one oxygen atom appearing in the
o Examples: product and the other in the form of
▪ reduction of ketones and water)
aldehydes to alcohols
MFO consists of 2 enzymes:
▪ oxidation of alcohols to acids
• hydrolysis of ester and amides to yield COOH, • Flavoprotein, NADPH-cytochrome reductase
NH2 and OH groups; reduction of azo and nitro o One mole of this enzyme contains one
compounds to give NH2 moieties; oxidative N- mole each of flavin mononucleotide
DJFLORIDA

, 0-. And S-dealkylation to give NH2. OH and SH (FMN) and flavin adenine dinucleotide
groups). (FAD)
Liver is principal site of drug metabolism:
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o Enzyme is also called NADPH-
cytochrome P450 reductase
• Cytochrome P450
o named based on its light absorption at
450 nm when complexed with carbon
monoxide
o is a hemoprotein containing an iron
atom which can alternate between the
ferrous (Fe**) and ferric (Fe***)
states
o Electron acceptor
o Serves as terminal oxidase

• NIH Shift leading to the formation of __

• May also acted upon by ___ leading to the

3 ways to stabilize the arene oxide:
OXIDATIVE REACTIONS
• Oxidation of Aromatic Moieties
o Aromatic hydroxylation refers to the
mixed-function oxidation of aromatic
compounds (arenes) to their
corresponding phenolic metabolites
(arenols).
o proceed initially through an epoxide
intermediate called an "arene oxide.”
Which rearranges rapidly and
spontaneously to the arenol
formation of transdihydrodiols
• Or be acted upon by sulfhydryl group in __ to
yield GSH adduct then finally mercapturic acid
derivative
• It is important to prevent the formation of ROS
by arene oxides
a. spontaneous rearrangement (NIH shift)
− ARENOL
b. hydration (epoxide hydrase)
− trans- 1 ,2-dihydrodiol
c. glutathione conjugation
− glutathione metabolite
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• Aromatic hydroxylation
• major route of metabolism for many drugs
containing ___ groups.
• Hydroxylation occurs at the ____ position
Drugs resistant to aromatic hydroxylation
a. Clonidine (Catapres)
− The deactivating groups (Cl. -N H = C)
b. Probenecid (Benemid)
− electron-withdrawing grps: carboxy
and sulfamido grp
Compound with 2 aromatic rigs:
• if there are 2 or more phenyl rings,
hydroxylation proceeds in the electron rich
ring
OXIDATION OF OLEFINS
• The metabolic oxidation of olefinic carbon—
carbon double bonds lead to the
corresponding epoxide OR ____
• Epoxides
o More stable than the arene oxides
formed from aromatic compounds
o Susceptible to enzymatic hydration by
epoxide hydrase to form trans-|,2-
dihydrodiols (also called 1,2-diols or
1,2-dihydroxy compounds
OLEFINIC EPOXIDATION
• The epoxide is cleaved by epoxide hydrases to
form transdiols
• There are inhibitors such as cyclohexene oxide
and trichloropropene
• Eg. Carbamazepine (Tegretol)
• The epoxide is reasonably stable and can be
measured quantitatively in the plasma of
patients receiving the parent drug
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• Protriptyline (Vivactil)

• Cyproheptadine (Periactin)

OXIDATION AT ALLYLIC CARBON ATOMS

• Toxicity of olefinic compounds may result • ALLYL structural formula: H2C=CH-CH2R

from their metabolic conversion to chemically
reactive epoxides. _

• AFLATOXIN
o Other compounds DES, stilbene and
vinyl! Chloride
OXIDATION AT BENZYLIX CARBON ATOMS

• Forms CARBINOL

• Tolmetin (Tolectin)
Other examples see hexobarbital and pentazocine
DJFLORIDA

• Allylic hydroxylation generally does not lead

to the generation of reactive intermediates

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OXIDATION AT CARBON ATOMS ALPHA TO penultimate carbon atom (i.e., next-to-the-last
CARBONYLS AND AMINES carbon) is called w— I oxidation)

• Common to benzodiazepines OXIDATION AT ALIPHATIC CARBON ATOM

o Oxidized to 3-hydroxy metabolites
• Diazepam(Valium)
o 3.hydroxydiazepam (also called N-
methyloxazepam)
• flurazepam (Dalmane) ®
• and nimetazepam are
Take note that the carbon involved is an alpha carbon.
–in forming the 3-hydroxy metabolite

OXIDATION AT ALIPHATIC AND ALICYCLIC CARBON

ATOMS
DJFLORIDA

• Metabolic oxidation at the terminal or the

penultimate methyl group often is referred to
as w oxidation, and oxidation of the

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OXIDATION INVOLVING CARBON-HETEROATOM

SYSTEMS

• Hydroxylation of the alpha-car bon atom

attached directly to the heteroatom (N, O, S).
• Hydroxylation or oxidation of the heteroatom
(N, S only, e.g.. N-hydroxylation. N-oxide
formation. sulfoxide. and sulfone formation).
OXIDATION INVOLVING CARBON-NITROGEN
OXIDATION AT ALICYCLIC CARBON ATOMS
SYSTEMS
• Alicyclic hydroxylation
• Drugs containing nitrogen
• Enzymatic introduction of a hydroxyl group
• natural products
into a monosubstituted cyclohexane ring gen.
o (e.g.. morphine, cocaine, nicotine)
occurs at C-3 and C-4 which leads to cis and
• important drugs
trans isomers
o (e.g., phenothiazines. Antihistamines,
tricyclic antidepressants. beta-
adrenergic agents, phenylethylamines,
benzodiazepines)
• three basic classes of nitrogen-containing
compounds
1. Aliphatic (primary, secondary, and
tertiary) amines 2
2. Aromatic and heterocyclic nitrogen
compounds
3. Amides

• Susceptible to either a-carbon hydroxylation

or N-oxidation
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OXIDATIVE N-DEALKYLATION ✓ oxidative deamination; and
✓ N-oxidation reactions
• N-demethylation
• Dealkylation of secondary amines gives rise to
the corresponding primary amine metabolite
• N-deisopropylation

• Secondary aliphatic amine

SECONDARY ALICYCLIC AMINES

• they are metabolized to their lactam

derivatives.
• Examples: phenmetrazines (anorexic)
ALYCYCLIC AMINES methylphenidate
• Primary aliphatic amines are biotransformed
• Often generate lactam metabolites by alpha by oxidative deamination (through the
carbon hydroxylation reactions. carbinolamine pathway) or by N-oxidation.
o Nicotine
o Cyproheptadine Enzyme: MFO
o Diphenidol • Endogenous primary amines (e.g..
SECONDARY AND PRIMARY AMINES Dopamine,norepinephrine. tryptamine, and
DJFLORIDA

serotonin)
Susceptible to:
Enzyme: MAO
✓ oxidative N-dealkylation
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N-DEMETHYLATION and OXIDATIVE DEAMINATION ● Phenmetrazine

● Nitrone metabolite happens when it is from a

secondary amine

PRIMARY AMINE

• In primary aliphatic amines, such as

phentermine, chlorphentermine and
amantadine, N-oxidation appears to be a
major biotransformation pathway because a-
carbon hydroxylation cannot occur.
• Primary aromatic amines are oxidized to
hydroxylamines then further oxidized to
nitroso (Chlorphentermine, Aniline)

OXIDATION INVOLVING CARBON-OXY GEN SYSTEMS

• Oxidative O-dealkylation
o It involves the oxidation of the alpha
SECONDARY AMINE carbon

• N- hydroxylation of secondary amines

generates the corresponding N-
hydroxylamine metabolites

• Other examples n-benzylamphetamines

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• O-dealkylation Example: Methiural

• Desulfuration [thiono to carbonyl]

C=S C=O

P=SP=O

• S-dealkylation • Sulfoxidation (s- to sulfoxides to sulfone)

o It also involves the alpha carbon • S-Oxidation
hydroxylation
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OXIDATION OF ALCOHOLS AND ALDEHYDES
Primary Alcohol ------ Aldehyde
Secondary Alcohol ------ Ketone
OXIDATIVE AROMATIZATION
[dehydrogenation of the A ring]
• Norgestrel 17-a-Ethinyl- 18-homoestradiol
2. REDUCTION
OXIDATIVE DEHALOGENATION
[hydroxylation 7 of the alpha carbon]
• Trifluoroacetylchloride
o it can acylate tissue nucleophiles
which covalently binds to liver
microsomal proteins.
• can lead to the formation of toxic and reactive
acyl halide intermediates.
• addition of hydrogen or gain of electrons
• play an important role in the metabolism of
many compounds containing carbonyl, nitro,
and azo group
• Hydroxyl and amino groups are susceptible to
conjugation
o Carbonyl reduction ----- alcohol
o nitro, and azo reduction ------ amino
deriv.
o N-oxides ----- tertiary amine
o Sulfoxides----- sulfides
o Disulfide ---- -SH + -SH
REDUCTION OF ALDEHYDE AND KETONE
CARBONYLS
• Ketones are resistant to oxidation are reduced
to secondary alcohol
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• Aldehydes are reduced to form primary Acetohexamide
alcohol

• Enzyme: aldo-keto reductases

WARFARIN

● The (R) (+) enantiomer of the oral anticoagulant

ALDEHYDE warfarin undergoes extensive reduction of its side
chain keto group to generate the (R, S) (+) alcohol as
Chloral Hydrate Reduction
the major plasma metabolite

Chlorpheniramine

REDUCTION OF NITRO AND AZO COMPOUNDS

• Leads to primary amine metabolites

Examples:
Acetophenone
o Clonazepam
o Nirazepam
o Dantrolene (dantrium)
o Metronidazole
o 7-nitro benzodiazepine derivatives

• clonazepam and nitrazepam

• are metabolized to 7-amino metabolites
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● Azo reduction will proceed via a hydrazo
intermediate (-NH-NH.-) that is cleaved reductively to
yield the corresponding aromatic amines:

Dantrolene (Dantrium)

Prontosil

Metronidazole
Tartrazine

Chloramphenicol

Amaranth
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MISCELLANEOUS REDUCTIONS
• Reduction of N-oxides to tertiary amine
• Reduction of sulfur-containing functional
groups, such as the disulfide and sulfoxide
• Disulfiram (Antabuse) yields N, N-
diethyldithiocarbamic acid (free
glucuronidated) as a major metabolite
• Although sulfoxide functionalities are oxidized
mainly to sulfones (-SO2-), they sometimes
undergo reduction to sulfides.
• Reduction of DMSO to dimethyl sulfide
3. HYDROLYSIS
• (reaction of water with substrate resulting in
breaking scissile carbon-heteroatom bonds)
• ester or amide − The reaction is frequently
enzyme - mediated although serum pH may
cause reaction.
• ester hydrolysis is mediated by nonspecific
esterases found in the Liver, kidney, and
intestine and Pseudocholinesterases present
in plasma
• Amide hydrolysis appears to be mediated by
liver microsomal amidases. Esterases and
deacylases
or • major biotransformation pathway for drugs
containing an ester functionality
Cocaine
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o This water-soluble derivative is
metabolized to the parent steroid by
plasma and tissue esterases.

ESTER DERIVATIVES

Carbenicillin Indanyl Ester (Geocillin)

• To improve the poor oral absorption

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• Prednisolone hemisuccinate sodium salt.

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PHASE II METABOLISM or CONJUGATION substrates, greatly increases the water
REACTIONS solubility of the conjugated product

• Attachment of small, polar and ionizable Two steps in the formation of B – glucuronides
endogenous molecules, such as:
o glucuronic acid • involves synthesis of an activated coenzyme,
o sulfate uridine-5'-diphospho-a-D-glucuronic acid
o glycine (UDPGA)
o glutamine • subsequent transfer of the glucuronyl group
from UDPGA to an appropriate substrate
CONJUGATED PRODUCTS o catalyzed by microsomal enzymes
called UDP-glucuronyltransferases
• relatively water soluble and readily excretable
found primarily in the liver but also
• biologically inactive and nontoxic
occur in kidneys, intestine, skin, lungs,
• methylation and acetylation
and brain.
o do not generally increase water
solubility but mainly serve to
terminate or attenuate
pharmacological activity
• phase II reactions can be regarded as
detoxifying pathways
• The role of GSH is to combine with chemically
reactive compounds to prevent damage to
important biomacromolecules

PHASE 2

• endogenous compounds that undergo

conjugation reactions
o Bilirubin
o Steroids
o Catecholamines
o Histamine
• mediated by more specific transferase
enzymes.
GLUCURONIC ACID CONJUGATION
The most common conjugative pathway in drug
metabolism for several reasons:
a. a readily available supply of D-glucuronic acid
b. numerous functional groups that can combine
enzymatically with glucuronic acid
Types of Compounds Forming Oxygen. Nitrogen,
Sulfur, and Carbon Glucuronide
Hydroxyl compounds
• Phenols: morphine, acetaminophen. p-
hydroxyphenytoin
• Alcohols: Tricholoroethanol.
chloramphenicol. propranolol
• Enols: 4-hydroxycoumarin
• N-Hydroxyamines: N-Hydroxydapson
• N-Hydroxyamides; N-Hydroxy-2-
acetylaminofluorene
Carboxyl compounds
DJFLORIDA

c. the glucuronyl moiety (with its ionized • Aryl acids: benzoic acid, salicylic acid
carboxylate (pKa 3.2) and polar hydroxyl • Arylalkyl acids: naproxen. Fenoprofen
groups) which, when attached to xenobiotic

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GLUCURONIC ACID CONJUGATION Propranolol

• functional groups undergoing

glucuronidation: Phenolic hydroxyls
• Morphine Acetaminophen, hydroxyphenytoin

Enols:

o Eg. 4-hydroxycoumarin

N-Hydroxyamines:

o Eg. N-Hydroxydapsone

O-GLUCORONIDE

ALCOHOLIC HYDROXYLS

Trichloroethanol

N-Hydroxyamides

o Eg. N-Hydroxy-2-acetylaminofluorene

Chloramphenicol
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CARBOXYL COMPOUNDS S-GLUCURONIDE

Aryl acids: benzoic acid, salicylic acid Sulfur Glucuronide

• Sulfhydryl groups: methimazole,

propylthiouracil, diethyithiocarbamic

Arylalkyl acids: Naproxen, fenoprofen Carbon Glucuronides

● 3,5-Pyrazolidinedione: phenylbutazone
(Butazolidin)

● sulfinpyrazone (Anturane)

N-GLUCURONIDES

Nitrogen Glucuronides

• Arylamines: 7-amino-5-nitroimidazole
• Alkylamines: desipramine
• Amides: meprobamate
• Sulfonamides: Sulfisoxazole
GLUCORINIDATION
• Tertiary amines: Cyproheptadine,
tripelennamine • In neonates and children, glucuronidating
processes are often not developed fully
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• neonatal hyperbilirubinemia

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o inability of newborns to conjugate
bilirubin with glucuronic acid
• Gray baby syndrome
o inability to metabolize
chloramphenicol

SULFATE CONJUGATION

• endogenous compounds that undergo sulfate

conjugation:
o steroids, heparin. chondroitin,
catecholamines, and thyroxine S
• For many phenols, sulfoconjugation may
SULFATE CONJUGATION PROCESS represent only a minor pathway.
o Competes with Glucuronidation of
• involves activation of inorganic sulfate to the
phenols
coenzyme 3’-phosphoadenosine-
▪ Eg. Acetaminophen
5'.phosphosulfate (PAPS).
• Subsequent transfer of the sulfate group from
PAPS to the accepting substrate is catalyzed by
various soluble sulfotransferases present in
the liver and other tissues (e.g. kidneys,
intestine).
• leads to water-soluble and inactive metabolite • In adults:
o Major metabolite: O-glucuronide
conjugate
o O-sulfate conjugate formed in small
amounts
• In infants and young children (ages 3 to 9
years)
o 0-sulfate conjugate is the main urinary
product

• alcohols
o (e.g. aliphatic C1 to C5 alcohols,
diethylene glycol)
• aromatic amines
DRUGS SUSCEPTIBLE TO SULFATE FORMATION o (e.g. aniline, 2-naphthylamine)
o
• Drugs containing phenolic moieties
• 0-sulfate conjugates of some N-hydroxy
compounds give rise to toxic metabolites
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• Aromatic acids and arylalkyl acids are the
major substrates undergoing glycine
conjugation

GLYCINE CONJUGATION

• hepatotoxic and nephrotoxic

• Sulfate conjugation of N hydroxy metab
(ultimate carcinogenic agent) 0-sulfate esters

CONJUGATION WITH GLYCINE, GLUTAMINE AND

OTHER AMINO ACIDS

• glycine and glutamine are used by

mammalian systems to conjugate carboxylic
acids, particularly aromatic acids and
arylalkyl acids
o glycine - mammals
o Glutamine — human
• not converted to activated co-enzymes GLUTAMINE CONJUGATION
• Instead, the carboxylic acid substrate is
activated with adenosine triphosphate (ATP)
and co-enzymeA (CoA) to form an acylCoA
complex

• Acylation of glycine or glutamine by N-

acyltransferase (mitochondria of liver and
kidney cells)

GSH or MERCAPTURIC ACID CONJUGATES

• important pathway for detoxifying chemically

reactive electrophilic compounds
• GSH protects vital cellular constituents
against chemically reactive species by virtue
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of its nucleophilic sulfhydryl (SH) group.

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• The SH group reacts with electron-deficient
compounds to form S-substituted GSH
adducts
• GSH — tripeptide (y-glutamyl-
cysteinylglycine)
GLUTHATHIONE CONJUGATION
• GSH Conjugation
o catalyzed by a family of cytoplasmic
enzymes known as glutathione S-
transferases (liver and kidney)
• Many industrial chemicals, such as benzyl
chloride, allyl chloride (CH2 = CHCH2CI). and
methyl iodide are known to be toxic and
carcinogenic
• The reactivity of these three halides toward
GSH conjugation in mammalian systems is
demonstrated by the formation of the
corresponding mercapturic acid derivatives.
• Arene oxides and aliphatic epoxides (or
oxiranes) represent a very important class of
substrates that are conjugated and detoxified
by GSH.
o primary aliphatic amines
• The amide derivatives formed from
acetylation of these amino
• Primary function of acetylation:
o is to terminate pharmacological
activity and detoxification
• few reports indicate that acetylated
metabolites may be as active (N-
procainamide) or more toxic (N-
acetylisoniazid) than parent compounds
• The acetyl group used in N-acetylation of
xenobiotics is supplied by acetyl-CoA.
• Transfer of the acetyl group from this cofactor
to the accepting amino substrate is carried out
by soluble N-acetyltransferases present in
hepatic reticuloendothelial cells.
• Aromatic compounds with a primary amino
group such as:
o aniline
o p-aminobenzoic acid
o p-aminosalicylic acid
o procainamide(Pronestyl)
o dapsone (Avlosulfon)
especially susceptible to N-acetylation.

ACETYLATION

• constitutes an important metabolic route for

drugs containing primary amino groups
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o primary aromatic amines (ArNH2)

o Sulfonamides (H2NC6H4SO2NHR).
o hydrazines (—NHNH2)
o Hydrazides (—CONHNH2); and
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Sulfonamides o more likely to show an inadequate
therapeutic response to standard drug
• Metabolites are less water soluble (can cause
doses
crystalluria, older)
• Egyptians and some Western European
groups
o mainly slow acetylators
o more likely to develop adverse
reactions

ACETYLATION ISONIAZID

• plasma half-life
o (rapid acetylators) = ranges from 45 to
80 minutes ®
o (slow acetylators) is about 140 t0 200
minutes
Hydrazines and Hydrazides • slow acetylators
o Greater Adverse effects: eg. peripheral
neuritis and drug-induced systemic
lupus erythematosus syndrome)
• rapid acetylators
o more likely to develop isoniazid-
associated hepatitis (acetylhydrazine)

Aliphatic Amines

• Slow acetylators
• Increase tendency to cause lupus
erythematosus syndrome to patients taking:
• hydralazine and procainamide

ACETYLATION POLYMORPHISM

• The proportion of rapid and slow acetylators

varies widely among different ethnic groups
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throughout the world.

• Eskimos and Asians
o rapid acetylators

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METHYLATION

• Play an important role in the biosynthesis of

many endogenous compounds
o epinephrine and melatonin
• and in the inactivation of numerous
physiologically active biogenic amines
o norepinephrine, dopamine, serotonin,
and histamine
• coenzyme involved: S-adenosylmethionine
(SAM)
• catalyzed by various cytoplasmic and
microsomal

• Methyltrasferases
o catechol-O-methyltransferase (COMT)
o phenol-O-methyltransferase
o nonspecific N-methyltransferases; and
o S-methyltransferases.

N- METHYLATION

• antiviral & antiparkinsonism = amantadine

(Symmetrel)
• norephedrine

O-METHYLATION

• Examples of drugs that undergo significant 0-

methylation by COMT in humans include:
o (S)(—)a-methyldopa (Aldomet)
o (S)(—)-dopa (levodopa)
o isoproterenol (Isuprel)
o dobutamine (Dobutrex) S- METHYLATION
• COMT selectively 0-methylates only the
• Thiol-containing drugs such as:
phenolic OH at C-3.
o propylthiouracil
• Substrates undergoing 0-methylation by
o 3-dimercapto- I -propanol (BAL)
COMT must contain an aromatic 1,2-
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o 6-mercaptopurine
dihydroxy group

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• Vitamins, minerals, starvation, and
malnutrition
• Cancer, cirrhosis
• Pathologic state
o Liver diseases
o pregnancy
▪ Hormonal disturbances (e.g.,
thyroxine, steroids), and
circadian rhythm.
FACTORS AFFECTING METABOLISM
STEREOCHEMICAL ASPECTS OF DRUG
• Age differences METABOLISM
• Deficiency in enzymes like Potency
glucuronyltransferase
o Leading to gray-baby syndrome • (S) (—) enantiomer of warfarin
o Neonatal hyperbilirubinemia • is 5 times more potent as an oral anticoagulant
• Species and strain differences than the (R) ( +) warfarin
o metabolism of amphetamine occurs by
Different pharmacological activities
two main pathways:
▪ oxidative deamination or • (+)-a-propoxyphene (Darvon) = analgesic ®
aromatic hydroxylation. • (—)-a-propoxyphene (Novrad) = antitussive
▪ human, rabbit,and guinea • P-hydroxylation is referred
pig = oxidative deamination • In humans, Pentazocine forms trans
appears to be the predominant metabolite
▪ Rat=aromatic hydroxylation
o Cats lack glucuronyltransferase Regioselectivity
enzymes therefore through • denotes the selective metabolism of two or
sulfoconjugation more similar functional groups (e.g.. OCH3,
o Pigs lack sulfoconjugation OH,NO2) or two or more similar atoms that are
o P-hydroxylation positioned in different regions ofa molecule.
o Pigs-no sulfotransferase • Papaverine o demethylation at the 4 th
o Instead of glycine, ornithine is used in position
conjugation of phenols • Trimethoprim n-oxide formation at the 3 rd
position
• Hereditary or genetic factors genetic • Dobutamine o-methylation at the 3 rd
polymorphism position.
• Sex differences
o Adult male rats metabolize faster e
• Enzyme induction (phen rbital ind l
ronyltransfer lifl rand charcoal broiled foods
• Exposure to insecticides and pesticides
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• Enzyme inhibition (chloramphenicol,

isoniazid, disulfiram and GRAPEFRUIT)

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