Chapter 1

Introduction to Medicinal Chemistry

BY URAEL G.
October, 2023
Adama, Ethiopia

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Chapter outlines
 Definition of medicinal chemistry
 Sources of drugs
 Drug targets and drug-target interactions
 Introduction to drug design and discovery
 Stereochemistry and drug action
 Receptors and drug action
 Drug metabolism

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 Introduction
 Medicinal chemistry is the science deals with the discovery and
design of new and better therapeutic chemicals and development of
these chemicals into new medicines and drugs.

 IUPAC definition:
 Medicinal Chemistry- explains the design and production of compounds
that can be used for the prevention, treatment or cure of human and animal
diseases

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 Cont’d…
➢ Concerned with intervention, discovery, design, identification and
preparation of biologically active compounds.
✓ Study their metabolism
✓ Interprets their mode of action at molecular level and
✓ Constructs their structure-ativity relationship.

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 Common Terms
 Drug – chemical substance, which when consumed, causes change in
organism’s physiology or psychology
 Drug Discovery – Process by which a new compound is identified as a drug
candidate, holding promise for further development into a drug.
 Hit, Lead (or lead compound)
 Drug Development – Process of taking a drug candidate to final product
(medicine) available for public use
 Research and Development (R & D)
 Preclinical studies; Clinical trials; Regulatory approvals
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 Scope of Study
 The overall aim is to produce and develop drugs which benefit humanity.

 synthesis of new compounds

 isolation from natural sources

 structure-activity relationships (SAR & QSAR)

 Pharmacokinetic characters of drugs

 elucidating the mode of interaction ligands with targets & their outcomes

(receptors/enzymes/DNA, etc…)

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 Relationship to other disciplines

➢ It is an interdisciplinary science
▪ A central science positioned to provide a molecular bridge between the basic
science of biology and chemistry and the clinical sciences of pharmacy and
medicine

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 Source and classification of drugs

Natural sources
 Plant source: Majority of natural products are plant origin.
e.g Quinine. Ephedrine, Digoxin, Vincristine, Vinblastine, Marinol,Warfarin
 Animal source: e.g, Insulin, thyroxin, vaccines
 Microbiological Sources: penicillin (from Penicillium notatum), Aminoglycosides (from
streptomycis and micromonosporas)
 Venoms and Toxins: e.g. Teprotide, Captopril (anti-hypertensive), Tubocurarine (from
curare)
 Mineral source: Simple inorganic substances such as; Zinc, Iodine, Calcium, Sodium,
Magnesium, Iron, etc
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 Lead Compounds from the Natural World
O
VENOMS AND TOXINS C OH
O
C N
Teprotide O O O
H
C N CH C N CH C N
O H
O CH2 CH CH3
C N CH C N CH2 CH2
O O H
CH2 C O CH3
H2N CH C N CH C N
H CH2 NH2
CH2 CH2 O
CH2
C OH
CH2
NH O
C O
HN C NH C N
MeO
OH
NH2
CH3 CH3
N HS
HO CH3
O H

Captopril
(anti-hypertensive)
H O
H3C
N OH
H 3C
OMe
Tubocurarine
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 Cont’d…
Synthetic sources
 When the nucleus of the drug from natural source as well as its
chemical structure is altered, we call it synthetic.
 Development of a synthetic drug offers a challenge and intelectual
satisfaction
 Design and synthesis regarded as an art
 Synthetic drugs replace natural compounds
 By providing improved and simplified analogues
 Can make the suply reliable
 Examples include Emetine, Bismuth Iodide, Aspirin, Paracetamol
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 Cont’d…
Semi Synthetic Source:

 When the nucleus of drug obtained from natural source is retained but the

chemical structure is altered, we call it semi-synthetic.

 Examples include Apomorphine, Ethinyl Estradiol, Homatropine,

Ampicillin and Methyl testosterone.

 Most of the drugs used nowadays are synthetic forms.

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 Cont’d…
Existing drugs

 Observing side effects (Sildenafil)

 Studying metabolism (Phenacetin to paracetamol)

 Me too strategies (biological and structural copies)

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 Classification of Drugs
Drugs can be classified according to various criteria:

 1. By origin—sources of drugs
Drugs may be obtained from
◼ Natural

◼ Semi synthetic.

◼ Synthetic compounds.

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 Cont’d…
 2. By Pharmacological action
These drugs mainly affect the normal dynamic processes of the body.
◼ Analagesics
◼ Diuretics
◼ Bronchodilators
◼ Antivirals
◼ Antimalarials
◼ Anti-hypertensives
◼ Hypocholesteric agents
◼ Drugs acting on GIT etc…

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 Cont’d…
 3. By Chemical structure
Drugs are classified according to the chemical moiety or functional group.
◼ Steroids
◼ Alkaloids

◼ Quinolones

◼ Glycosides

◼ Betalactams

◼ Halogenated compounds

◼ Alcohols

◼ Carboxylic acids,etc

 4. By their target (site) of action

 e.g. Adrenergics, Dopaminergics, Cholinergics…..

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 Nomenclature of drugs
Drugs may have different names

 Code number: used for a drug (chemical) under investigation.

❖ Formed with the initial(s) name of a laboratory, the chemist or research team that prepared or
tested the drug the first time and followed by a No. to represent drug.

❖ It does not identify the chemical nature or structure of the drug.

❖ It is discontinued as soon as an adequate name is chosen

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 Cont’d…
➢ Chemical name: describes the chemical structure of the drug
❖ It is given according to the rules of nomenclature of chemical compounds.
❖ Not suitable for routine use.
 E.g 2-acetoxy benzoic acid

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 Cont’d…
 Proprietary: brand or trade name
❖ Is the individual name selected and used by the manufacturer.
❖ If a drug is manufactured by more than one company, as frequently
happen, each firm assigns its own proprietary name.
❖ It should be written with capitalization of the first letter of each word of the
name
 e.g. Panadol® /Tylenol®, Vermox ® /Quemox®

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 Cont’d…
➢ Non-proprietary name: generic, official name
❖ Refers to the common established name, which a drug is known as an
isolated substance, irrespective of its manufacturer.
❖ It should be simple, concise, and meaningful but often it is not.
❖ The first letter is not capitalized.
❖ WHO is the official agency to select, approve and disseminate names of
drugs.
Eg. paracetamol, aspirin

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 Drug targets and drug-target interactions
What is a Drug Receptor?
 It is a specific binding site present on the cell surface made up of protein or nucleic
acid where a ligand can bind and initiates a characteristic response
 Contain specific regions (receptor sites) that react with complementary functional
groups on their endogenous substance or a drug molecule (drug–receptor affinity).
 Drug–receptor interactions are often generally referred to as ligand– receptor
interactions.
 Allow for physiological messages to be communicated from the drug and/or
endogenous substances.

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 Targets for Drug

Receptors agonists
antagonists
partial agonists
inverse agonists

Enzymes inhibitors
activators

Ion Channels openers

blockers
Protein-Protein activators
inhibitors

Nucleic acids intercalator

Urael G. 21 alkylating agent
 Receptors and Drug Action
 Drugs are active chemicals the interact ➢ Proteins
with the living cell ▪ Receptors
 Different drugs act ▪ Enzymes
o at different locations of the cell ▪ Carrier proteins
o At different molecular target ▪ Structural proteins (tubulin)
➢ The main molecular targets are ➢ Carbohydrates
➢ Lipids: Cell membrane lipids ➢ Cell surface carbohydrate
➢ Nucleic acids: DNA, RNA ➢ Antigens

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Drug-target interaction
Binding
regions

Drug Binding
groups

Intermolecular
bonds

Binding site

Binding Drug
site

Drug

Macromolecular target Macromolecular target

Unbound drug Bound drug

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 The Role of Chemical Bonding
 When a drug or endogenous substance interacts with a receptor
 the initial attraction (affinity) is based on interactive chemical bonding forces
 which are either covalent or noncovalent (i.e., ionic, hydrogen bonding, or
hydrophobic bonding).
 Most drugs bind via non-covalent bonding which is reversible, relatively weak,
and mainly ionic or ion–dipole.
 H-bonding is not very significant for affinity but plays an important role in
stabilizing the drug–receptor interaction.

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 Cont’d…

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 Examples of various types of drug–receptor bonds

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 Cont’d…
hydrophobic, van der Waals,
charge-transfer
hydrophobic, van der Waals,
dipole-dipole, charge-transfer H-bond
H-bond acceptor donor

H
H-bond donor H-bond acceptor,
O O O dipole-dipole
H
S
N O
N

H-bond acceptor, H H-bond acceptor,

H dipole-dipole
dipole-dipole Cl
H-bond
H-bond donor donor
dipole-dipole

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treatment of edema associate with congestive heart failure
 Types of drug-receptor interactions
1. Irreversible covalent bonding with the receptor active site.
▪ Active-site-directed irreversible inhibition
▪ Anticancer agents such as the alkylating agents
▪ Antibacterial agents such as the beta-lactamase inhibitors

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 Cont’d…
2. Reversible drug-receptor complex
✓Most common and desirable. why?
✓ Requires rather weak receptor-drug interactions
✓ When two or more of the following weak forces added together afford a stable
interaction
✓ Hydrogen bonds: 1 to 7 kcal (proteins and DNA )
✓ Ionic bonding: 5 to 10 kcal
✓ Ion-dipoles bonds:1 to 7 kcal
✓ Dipole-dipole bonds: 1 to 7 kcal
✓ Van der walls: 0.5 to 1 kcal
✓ Hydrophobic bonding:1 kcal
✓ Covalent bonds can range from 40-140 kcal

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 Assignment-I

Discuss all theories that describe the interaction of drugs

(ligands) with receptors.

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 Introduction to drug design and discovery
➢ Some Terminologies
➢ A hit compound is a molecule that shows the desired type of activity in a screening assay,
such as binding to a target protein or inhibiting an enzyme.
➢ Lead compound is a compound that has a desirable biological activity with therapeutic
relevance, selected from a collection of hits, they are modified to improve efficacy,
bioavailability and toxicity.
 Pharmacophore is the section of structure of lead compound that binds to a receptor and
responsible for the biological activity of the drug
 Structure-activity relationship (SAR) is the relationship between chemical structure and
pharmacological activity for a series of compounds.
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 Cont’d…
➢ Drug Design-Is the inventive process of finding new medications based on
the knowledge of a biological target.
➢ Affinity – strength at which compounds bind to a receptor.
➢ Efficacy - measure of the maximum biochemical effect resulting from binding
of a compound to a receptor.
➢ Potency - concentration of an agonist required to produce 50% of the
maximum possible effect.
➢ Prodrug: Inactive compounds which are converted to active compounds in
the body.

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 The process of drug discovery
Drug Discovery Drug Development

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 Cont’d…
1) Identify target disease 6) Identify a pharmacophore
2) Identify drug target
7) Preclinical Trials
3) Establish testing procedures
8) Patenting and regulatory affairs
4) Find a lead compound
9) Clinical trials
5) Structure Activity Relationships

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1. TARGET DISEASE 2. DRUG TARGETS
 Questions to be addressed from Target selectivity
pharmaceutical point of view is  Between species
 Can the profits from marketing a new drug  Antibacterial, antifungal and antiviral agents
outweigh the cost of developing and testing that
drug?  Identify targets which are unique to the invading

 Is the disease widespread? (e.g. cardiovascular pathogen

disease, ulcers, malaria)  Identify targets which are shared but which are
 Does the disease affect the developed significantly different in structure
world?(e.g. cardiovascular disease, ulcers)  Within the body
 Are there drugs already on the market?  Selectivity between different enzymes, receptors
 If so, what are their advantages and etc.
disadvantages (e.g. side effects)
 Selectivity between receptor types and subtypes
 Can one identify a market advantage for a new
therapy?  Selectivity between isozymes
 Organ and tissue selectivity
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 3. TESTING DRUGS
• Tests are required in order to find lead ❑ in vitro Tests: not carried out on
compounds and for drug optimisation
animals/humans
• Tests can be in vivo or in vitro
• A combination of tests is often used in
• Target molecules (e.g. isolated
research programmes enzymes or receptors) Cells (e.g.
❑ in vivo Tests: Carried out on live animals or cloned cells), Tissues (e.g. muscle
humans tissue), Organs, Micro-organisms (for
• Measure an observed physiological effect antibacterial agents)
• Can identify possible side effects • More suitable for routine testing
• Drug potency- concentration of drug
required to produce 50% of the maximum • Does not demonstrate a physiological
possible effect or clinical effect
• Therapeutic ratio/index - compares the ED50 • Does not identify possible side effect
versus LD50 of the sample.
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 4) Find a lead compound
 LD is the one that has basic structural Lead optimization
requirements for exhibiting the  As soon as lead structure is generated
desired action. the next step is optimize its
 Used as the starting point for drug pharmacological and
design and development. physicochemical properties
 Optimization gives a molecule high
 lead compound can be identified from efficacy and low side effects in an
• Existing drugs animal disease model.
• screening collection of compounds
(“compound library”)
• compound from published literature
• Screening of Natural Products
• structure-based design
(“rational drug design”)
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 Design of Lead Compounds

Protein

Optimise Optimise
38 epitope epitope
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 Design of Lead Compounds

Link

Protein

Optimise Optimise
39 epitope epitope
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 4. Design of Lead Compounds

LEAD COMPOUND

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 4. Design of Lead Compounds
Design of a lead compound as an immunosuppressant

OH
O

OMe N
H
N O HO
O
O Epitope B

MeO OMe
OMe

Epitope A

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 4. Design of Lead Compounds
Design of a lead compound as an immunosuppressant

OH
O

OMe N
H
N O HO
O
O

MeO OMe
OMe

Lead compound

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5. Structure Activity Relationships (SAR)
 Identify which functional groups are important for binding and/or activity
• Alter, remove or mask a functional group
• Conclusions depend on the method of testing
 in vitro - tests for binding interactions with target
 in vivo - tests for target binding interactions and/or pharmacokinetics.
• If in vitro activity drops, it implies group is important for binding
• If in vivo activity is unaffected, it implies group is not important

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5. Structure Activity Relationships (SAR)
IMPORTANT GROUPS FOR ACTIVITY

HO

O MORPHINE
NMe

HO

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 6) Identify a pharmacophore
• Defines the important groups involved in binding

• Defines the relative positions of the binding groups

• Need to know the active conformation

• Important to drug design and discovery.

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 HO

O MORPHINE
NMe

HO

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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

HO

O MORPHINE
NMe

HO

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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

HO

O MORPHINE
NMe

HO

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 ANALGESIC PHARMACOPHORE FOR OPIOIDS

HO

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 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
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 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
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 8. Patenting and
7. Preclinical Trials regulatory affairs
Pharmacodynamics Patenting carried out before preclinical
 What the drug does to body and clinical trials
 Properties of drug metabolites  Patent a group of compounds rather
Pharmacokinatics than an individual structure
 Drug must be approved by regulatory
 What the body does to drugs
bodies
Toxicology  Food and Drugs Administration
 In vivo and in vitro tests for acute,
(FDA)
sub-acute and chronic toxicity.  European Agency for the Evaluation
 Side effect caused by drug to the of Medicinal Products (EMEA)
body  IND (“investigational new
Formulation drug”)application for clinical trials
 Stability tests  NDA (New Drugs Application)
 Methods of delivery

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12. CLINICAL TRIALS
Phase 1 Phase 3
 Carried out on healthy volunteers  Carried out on a larger number of
 Useful in establishing dose levels patients
 Useful for studying PK, safety and
 Establishes statistical proof for
predictable toxicity
efficacy and safety
 Carried out as double-blind cross-
over designs
Phase 2
 Carried out on patients Phase 4: Post market surveillance
 Carried out as double blind studies  Observing long term effects of the
 Demonstrates whether a drug is drug on the general population after
therapeutically useful approval
 Establishes a dosing regime  Identifies unusual side effects
 Dose–response studies are a critical part  Report from professional
of phase II studies  Renewal or cancellation of licenses.
 Identifies side effects

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 How new drug or lead structure are discovered?
Serendipity (24.1% of drugs)
 Accidental discovery of drugs in the laboratories or clinics by pharmacists, physicians or other
investigators.

 Cisplatin (chemotherapy for bladder cancer, discovered while studying E.coli bacteria),

 Vinblastine (first discovered while studying a plant’s anti-diabetic effect)

Random screening
 All available chemical substances are submitted to a variety of biological tests in the hope that some may
show useful activity. Not very rewarding.

 E.g. It is estimated that for a new anticonvulsant discovery through this process it might be necessary to
screen 500,000 chemical compounds.

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 Cont’d…
Rationally directed random screening
 E.g. the search for new antibiotics from microorganisms after the discovery of
penicillin result in the recognition of more than 600 antibiotics, more than 100 of
which are used in medicine.
Natural Products as Leads for Drug Discovery
 Morphine, atropine, ephedrine, curare and many others have binding affinities to
certain receptors, enzymes, etc., and are thus useful as lead structures for drug
discovery.
Drug Metabolites as Leads for Drug Discovery
 For example the acetanilide and acetophenetidin are metabolized to
acetaminophen, which exerts the main analgesic actions.

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 Cont’d…
Clinical observation of side effects of drugs

➢ e.g. Sulphanilamide cause alkaline diuresis in patients. The lead was used
by chemists and led to the identification and development of diuretics,
such as chlorothiazide

Rational design
 Designing appropriate molecular structure of a drug on the basis of
information about its biologic receptor.
 Very effective approach
 Have now become the major route to lead discovery
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 Analogue design
➢ The term analogue (from the Greek analogos) means proportionate, but in
everyday activity we use it to indicate similarities between things.
➢ In medicinal chemistry, an analogue drug has a chemical and/or pharmacological
relationship with another drug.
❖ Structural analogues are drugs that have a similar chemical structure but quite different
pharmacological properties.
❖ pharmacological analogues are drugs that have a similar pharmacological activity without any
discernible chemical or structural relationship
➢ There are only a few drugs for which no successful analogues have been
discovered, these we have termed standalone drugs.
➢The first drug in the class (often termed as first in class) used as a lead for the development of
analogues can be considered a pioneer drug
➢ After the discovery of a pioneer drug, there are almost always efforts to improve upon it with
analogues in order to obtain new drugs with better therapeutic properties (Pharmacological
properties) .

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 Cont’d…

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General Process
Two general processes may be used in the method of variation

1. Disjunction or molecular simplification

➢ It is the systematic synthesis and evaluation of the simpler and simpler

analogs of the lead compound.

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 Cont’d…
2. Conjunction or Molecular Association
➢ It is the synthesis and evaluation of more and more complex analogs of prototype.
➢ These analogs incorporate certain or all features of the lead compound.
Three main types of association can be distinguished:
i. Molecular addition:
➢ Association of different moieties through weak forces such as electrostatic
attraction and hydrogen bonding, example is methenamine mandelate.

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 Cont’d…
ii. Molecular Replication:
 Association of identical moieties through covalent bond formation (Identical
twin drug) e.g., salicyl salicylate.
 This is also can be found among several natural products e.g., dicumarol.

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 Cont’d…
iii. Molecular Hybridization:
➢ Association of different or mixed moieties through covalent bond
formation (non-identical twin drug) e.g., acetaminosalol (aspirin with
acetaminophen).

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Special Process
Several special processes for molecular modifications were grouped in two classes
1. Alterations which increase or decrease the dimensions and flexibility of a molecule,
this can be achieved through the following:
i. Ring closer or opening:
 Several examples are found of new drugs designed by either closure of a chain
(e.g. nefopam from diphenhydramine) or opening of a ring (diethylstilbsterol from
estradiol)

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 Cont’d…
ii. Formation of Lower or Higher Homologues:
 A homologous series is analogs that differ in their structure by simple increment of in molecular
formula.
 These may be produced by sequential chemical changes, which include increasing or decreasing the
length of a carbon chain.
 For example, alkyl trimethyl ammonium analogs possess different types of activity depending on the
length of alkyl groups:

 If alkyl group is up to 6 carbons (n = 5) the compounds are muscarinic agonists. With 7 to 8 carbons (n
= 6 or 7), these compounds are partial agonists. However, when the length is greater than 9 carbons (n
= 8) these compounds are muscarinic antagonists

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 Cont’d…
iii. Introduction of Double Bonds:
The introduction of double bonds may cause two main effects:
1. The possibility of the existence of geometrical isomers with different
activity
➢ The synthetic estrogen diethylstilbestrol (DES) is a tetra substituted
ethane and exists in cis-trans forms
➢ The trans isomer is much more active than the cis isomer. The reason is
that the trans geometric isomer resembles the estrogen (estradiol)
structure and better fits the estrogen receptor (designed by nature to fit
estrogens) to bring about estrogen-like response.

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 Cont’d…
➢ Here the shape of trans-DES positions the two hydroxyl groups for
hydrogen bonding to the receptor.

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 Cont’d…
2. Altering physicochemical properties
 Another example is the conversion of morphinic receptor agonists into the
corresponding antagonists in case of morphine.

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 Cont’d…
iv. Introduction of Chiral centers
 Receptors are chiral entities and the interactions of many drugs at specific
sites exhibit chirality of interaction.
 They clearly prefer synthetic compounds with absolute configuration
corresponding to the natural mediator.
 Thus changing the stereochemistry of the drug molecule may significantly
alter its pharmacological activity.

For example, the R(-)-isomer of epinephrine is more potent on both -

and -adrenergic receptors than the S(+)-isomer.

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 Cont’d…
➢ The binding of epinephrine isomers and epinine (the deoxy analog of
epinephrine) is illustrated below.
➢ Only R isomer can bind to all three sites, while both the S isomer and the
deoxy isomer, which show similar activity, can bind to only two of these sites.

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 Cont’d…
v- Introduction, Removal, or Replacement of Bulky groups:
➢ This approach is used mainly to convert agonists into antagonists and
vice versa as illustrated by the following examples:

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 Cont’d…
Other Possible Modifications
Isosteric Replacements:
➢ Isosteres are molecules or groups of atoms that have the same number and arrangements of
electrons.
For example, N2 and CO, N3- and NCO-. These substances have similar physical properties.
➢ Bioisosterism is the procedure of the synthesis of structural analogues of a lead compound by
substitution of an atom or a group of atoms in the parent compound for another with similar
electronic and steric characteristics.
➢ Bioisosetres are substituents or functional groups which have similar spatial and electronic
character, and as a result they produce similar/better biological properties with the parent
compound.

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 Cont’d…
 Aminopyrine Marketed as an analgesic and anti-inflammatory drug in 1896.
 In 1922, It was revealed that aminopyrine was a carcinogen!
 Propylphenazone: Developed by Roche in 1951.
 Bioisosteric modification of aminopyrine into a isopropyl group removed its
carcinogenic action.

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 Cont’d…
Change of Position or Orientation of certain groups:
➢ The position of certain groups is sometimes essential for a given biological activity.
Eg. from the three isomers of hydroxybenzoic acid only the o-hydroxy is active,
because it can form an intramolecular hydrogen bond and in this way, it can act as a
chelating.

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 Structure Activity Relationship (SAR)
➢ Basically, activity of a drug either increases or decreases as a result of some structural change
(relative to the prototype).
➢ SAR is a statement of the effect of structure change on biological activity within a family of
compounds.
➢ With the structure change known and the biological activity that accompanies this change, the
medicinal chemist can use the information to discover the optimum drug.
How SAR is caried out?
➢ Developing a large number of analogues in a particular chemical category (Ex. Quinoline,
Pyrazole, etc.) by changing different substituents at different positions.
➢ Testing them for a particular biological activity, Ex. Anti-diabetic, Anti-hypertensive, etc
➢ Analyzing which groups are
Essential / non-essential

75
Increase / decrease / abolish the activity Urael G. 10/22/2023
 Pro-drug design
Prodrugs
➢ Prodrugs are compounds that are biologically inactive but are metabolized to an
active metabolite, which is responsible for the drug’s action.

76 Urael G. 10/22/2023
 Cont’d…
Bioprecursor prodrugs
➢ Bioprecursor prodrugs are compounds that already contain the embryo of the
active species within their structure.
➢ This active species is liberated by metabolism of the prodrug.

77 Urael G. 10/22/2023
 Cont’d…
Carrier prodrugs
➢ Carrier prodrugs are formed by combining an active drug with a carrier species to form a
compound with the desired chemical and biological characteristics, for example, a lipophilic
moiety to improve transport through membranes.
➢ The link between carrier and active species must be a group, such as an ester or amide,
that can be easily metabolized once absorption has occurred or the drug has been delivered
to the required body compartment.
➢ The overall process may be summarized by:

78 Urael G. 10/22/2023
 Cont’d…
➢ Carrier prodrugs that consist of the drug linked by a functional group to the carrier
are known as bipartate prodrugs.
➢ Tripartate prodrugs are those in which the carrier is linked to the drug by a link
consisting of a separate structure.

79 Urael G. 10/22/2023
 Cont’d…
The application of prodrugs
 Prodrugs are converted into the active drug within the body through enzymatic or
non-enzymatic reactions. The various applications of prodrugs are
A. Improving absorption and transport through membranes
➢ The transport of a drug through a membrane depends largely on its relative
solubility in water and lipids.
➢ Good absorption requires that a drug’s hydrophilic–lipophilic nature is in
balance.
➢ The lipophilic nature of a drug may be improved by combining a lipophilic carrier
with a polar group (s) on the drug.

80 Urael G. 10/22/2023
 Cont’d…
➢ However, it is difficult to select a lipophilic carrier that will provide the degree of
lipophilic character required. If the carrier is too lipophilic, the prodrug will tend to
remain in the membrane.
➢ Similarly, improving the water solubility of a drug may be carried out by
introducing a carrier with a water solubilizing group or groups.

81 Urael G. 10/22/2023
 Cont’d…
B. Improving patient acceptance
➢ Odour and taste are important aspects of drug administration.
➢ A drug with a poor odour or too bitter a taste will be rejected by patients, especially
children.
➢ Furthermore, a drug that causes pain when administered by injection can have a
detrimental effect on a patient.
➢ The formation of a carrier prodrug can sometimes alleviate some of these problems.
➢ For example, palmitic acid and other long chain fatty acids are often used as carriers,
since they usually form prodrugs with a bland taste.

82 Urael G. 10/22/2023
 Cont’d…
 Chloramphenicol palmitate is the sparingly soluble of prodrug of
chloramphenicol, which is practically tasteless due to its low aqueous
solubility, as well as it is hydrolyzed to active chloramphenicol by the action
of pancreatic lipase.

83 Urael G. 10/22/2023
 Cont’d…
C. Slow release/increase duration
➢ Prodrugs may be used to prolong the duration of action by providing a slow release
mechanism for the drug.
➢ Slow release and subsequent extension of action is often provided by the slow hydrolysis
of amide and ester linked fatty acid carriers.
➢ Hydrolysis of these groups can release the drug over a period of time that can vary from
several hours to weeks.
➢ For example, the use of glycine as a carrier for the anti-inflammatory tolmetin sodium
results in the duration of its peak concentration being increased from about 1-10 Hrs.

84 Urael G. 10/22/2023
 Cont’d…
D. Site specificity
➢ In theory, it should be possible to design a carrier prodrug that would only release the drug
in the vicinity of its site of action.
➢ Furthermore, once released, the drug should remain mainly in the target area and only
slowly migrate to other areas.
➢ In addition the carrier should be metabolized to nontoxic metabolites.
➢ Unfortunately, these requirements have only been achieved in a few cases.
➢ One area where the site specific carrier prodrug approach has been used with some degree
of success is to design drugs capable of crossing the blood–brain barrier.
➢ This barrier will only allow the passage of very lipophilic molecules unless there is an
active transport mechanism available for the compound.

85 Urael G. 10/22/2023
 Cont’d…
➢ A method developed by Bodor and other workers involved the combination of a
hydrophilic drug with a suitable lipophilic carrier, which after crossing the blood–brain
barrier would be rapidly metabolized to the drug and carrier.
➢ Once released, the hydrophilic drug is unable to recross the blood–brain barrier.
➢ The selected carrier must also be metabolized to yield nontoxic metabolites.

86 Urael G. 10/22/2023
 Cont’d…
E. Minimizing side effects
➢ Prodrug formation may be used to minimize toxic side effects.
➢ For example, salicylic acid is one of the oldest analgesics known. However, its use can
cause gastric irritation and bleeding.
➢ The conversion of salicylic acid to its prodrug aspirin by acetylation of the phenolic
hydroxy group of salicylic acid improves absorption and also reduces the degree of stomach
irritation, since aspirin is mainly converted to salicylic acid by esterases after absorption
from the GI tract.
➢ This reduces the amount of salicylic acid in contact with the gut wall lining.

87 Urael G. 10/22/2023
 Introduction to CADD
Modern Drug Discovery & Development
 Drug discovery & development in the modern era is complex, involving
many processes, time and money
 Delivering a successful drug requires
 Immense resources
 Excellent scientific & logical minds
 Highly sophisticated labs
 Multifaceted project management team
 Persistence, Luck (good fortune)

88 Urael G. 10/22/2023
 Cont’d…
Role of Computers
 Computers have changed many things in our world today
 Every aspect of life has been affected by the use of computers
 Education
 Business
 Industry
 Entertainment etc
 And so is drug discovery …

89 Urael G. 10/22/2023
 Cont’d…
Computer Aided Drug Design
 (Rational) Drug Design – process of finding new chemical substances based on knowledge
of a biological target, a biomolecule such as protein.
 Drugs can bind to and modify the function of biological target, resulting in therapeutic
effect.
 When computer modelling techniques & other computer-based software are employed, the
process is referred to as Computer-Aided Drug Design (CADD).
 CADD uses computing resources, algorithms, and 3D-visualization.
❖ to help generate rational ideas about how to create or modify molecules
❖ to make decisions in the execution of the drug design process.

90 Urael G. 10/22/2023
 Cont’d…
 Recall that drug discovery/ development
 takes 12-15 years;
 costs up to $ 2 billion; and
 only one compound succeeds out of about 10,000 that enter the process
 CADD aims to rationalize the process; serving to reduce
 Duration
 Cost
 Attrition rate

91 Urael G. 10/22/2023
 Cont’d…
Current roles of computers in CADD
 Storing and retrieving information
 Structures of proteins (determined by X-ray crystallography)
 Molecules and their biological activities
 ADMET information
 Visualizing molecules
 Drug-receptor interactions
 Comparisons of drugs acting in the same way or on similar targets
 Calculations
 Interaction strengths
 Motion (dynamics)

92 Urael G. 10/22/2023
Types of CADD
I. Ligand (compound) based drug II. Structure (target) based drug
design design
 Indirect CADD  Direct CADD

93 Urael G. 10/22/2023
General Representation of workflow for CADD

94 Urael G. 10/22/2023
Ligand based drug design (Indirect) CADD
 Utilizes knowledge of compounds that bind to the biological target.
 Defines the pharmacophore (i.e. minimum structural requirements for binding to
the target).
 Uses the information to project for new chemical entities that would act on the
target.
 example – from SAR studies, quinoline antimalarials were believed to interact
with a target such that they needed to have: a flat surface; chiral carbon; basic N
centre; quaternary N; 5-carbon chain separation.

→→→→

quinine chloroquine

95 Urael G. 10/22/2023
 Cont’d…
 Generally ligand-based techniques are pharmacophore based approach and
quantitative-structure activity relationships (QSARs).
 QSAR can also be used to achieve this;
 Properties of active molecules are calculated. These include- partition
coefficient (hydrophobicity), electronic effects (electron
withdrawing/releasing properties) and steric effects (bulkiness).
 Expressed in a relationship (such as Hansch equation)
 Correlate calculated properties with experimentally determined biological
activity
 Predict activity of new analogues.

96 Urael G. 10/22/2023
 Cont’d…
Methods
Virtual screening :
 The first method is identification of new ligands for a given receptor by searching
large databases of 3D structures of small molecules to find those fitting the binding
pocket of the receptor using fast approximate docking programs.
de novo design of new ligands:
 Ligand molecules are built up within the constraints of the binding pocket by
assembling small pieces in a stepwise manner.
 These pieces can be either individual atoms or molecular fragments.
 The key advantage of such a method is that novel structures can be suggested.
Optimization of known ligands
 By evaluating proposed analogs within the binding cavity.

97 Urael G. 10/22/2023
Structure Based drug design (Direct) CADD
 Utilizes knowledge of 3D structure of biological target (usually obtained
from X-ray crystallographic studies, NMR spectroscopy).
 If structure of target is not available, that of a similar protein can be used
(Homology modelling)
 From structure of target and using appropriate graphics, binding of
compounds can be predicted (docking).
 New drug candidates can be obtained.
 This avoids the need to synthesize and screen large numbers of compounds
in automated HTS programs.
 Reduces cost significantly.

98 Urael G. 10/22/2023
 Cont’d…
Steps involved in SBDD
1. Target Identification & validation.
2. Analyze structure for potential ligand binding sites.
3. Lead Identification & Molecular Docking.
4. Lead Validation & Optimization.
5. Preclinical and Clinical Trials.

99 Urael G. 10/22/2023
 Cont’d…
Binding site identification
 It is the first step in structure based design.
 Relies on identification of concave surfaces on the protein that can
accommodate drug sized molecules that also possess appropriate "hot spots"
(hydrophobic surfaces, hydrogen bonding sites, etc.) that drive ligand
binding.

100 Urael G. 10/22/2023

 Cont’d…
Molecular Docking & Scoring
 Docking attempts to find the “best” matching between two molecules

 It includes finding the Right Key for the Right Lock

 To place a ligand (small molecule) into the binding site of a receptor in the manners
appropriate for optimal interactions with a receptor.

 To evaluate the ligand-receptor interactions in a way that may discriminate the

experimentally observed mode from others and estimate the binding affinity.

101 Urael G. 10/22/2023

 Cont’d…

102 Urael G. 10/22/2023

 Cont’d…
Molecular docking is a computational approach that can be used to-
➢ Predict the conformations and affinities of real or virtual molecules for the receptor
of interest.
➢ Perform a virtual screening of a large database of ligands for a specific target.
➢ Provide insights into the mechanism of ligand binding.
➢ Identify key receptor residues responsible for ligand activity.
➢ Enable ligand optimization to obtain a compound with optimal characteristics.
➢ It is very often employed as an initial step in many drug discovery programs.

103 Urael G. 10/22/2023

 Cont’d…

104 Urael G. 10/22/2023

 Cont’d…

105 Urael G. 10/22/2023

 Cont’d…
Druggability
• A ‘druggable’ target is a protein, peptide or nucleic acid with activity that
can be modulated by a drug,

106 Urael G. 10/22/2023

 Cont’d…
Web Resources For Target Hunting In Drug Discovery

BindingDB DrugCentral PharmMapper

ChEMBL DTO Pharos
DINIES ECOdrug PhID. PPB
DrugBank 3.0 HitPick PROMISCUOUS
DisGeNET iDrug-Target SLAP
BioGRID IUPHAR/BPS SuperDRUG2
canSAR MANTRA SuperTarget
Open Targets idTarget SwissTargetPrediction

107 Urael G. 10/22/2023

 Cont’d…
Here are some commonly used databases of chemical libraries for virtual
screening and ligand selection:
 ZINC Database
 PubChem
 ChemBank
 ChEMBL
 DrugBank
 ProteinDataBank(PDB)
 Available Chemicals Directory (ACD).
 Dr. Duke's Phytochemical and Ethnobotanical Databases
 ColleCtion of Open Natural Products (COCONUT)

108 Urael G. 10/22/2023

 • PDB is a database for three dimensional
structure of large biological molecules such as
proteins and nucleic acids.
• It contains:

Protein data
bank
• It holds data derived from mainly three sources
Computational Tools For Drug Designing

Draw Tools Docking and screening tools

 Autodock
 ACD/ChemSketch
 GOLD
 ChemDraw
 SwissDock
 MarvinSketch
 DockingServer
 Marvin molecule editor and viewer
 ChemWriter  Discovery Studio
 UCSFChimera ADME Toxicity tools
 Pymol
• GastroPlus
• SwissADME
• OSIRISPropertyExplorer

110 Urael G. 10/22/2023

 Cont’d…
Some examples of successful application of CADD include
➢ Ritonavir (anti-HIV) Zanamivir, Relenza® (influenza)

111 Urael G. 10/22/2023

 QSAR in drug design
➢ QSAR aim to relate biological activity of series of cpds to their physicochemical
parameters in quantitative fashion using a mathematical formula.
➢ These equations may be used by the medicinal chemist to make a more informed
choice as to which analogues to prepare.
➢ The main properties of a drug that appear to influence its activity are its,
lipophilicity, the electronic effects within the molecule and the size and shape of
the molecule (steric effects).

112 Urael G. 10/22/2023

 Cont’d…
➢ Lipophilicity is a measure of a drug’s solubility in lipid membranes.This is usually an
important factor in determining how easily a drug passes through lipid membranes.
➢ The electronic effects of the groups within the molecule will affect its electron
distribution, which in turn has a direct bearing on how easily and permanently the molecule
binds to its target molecule.
➢ Drug size and shape will determine whether the drug molecule is able to get close
enough to its target site in order to bind to that site.
➢ The parameters commonly used to represent these properties are partition coefficients for
lipohilicity, Hammetts constants for electronic effects and TaftMs steric constants for
steric effects.

113 Urael G. 10/22/2023

 Cont’d…
➢ QSAR derived equations take the general form:

➢ In which the activity is normally expressed as log[1/(concentration term)], usually

C, the minimum concentration required to cause a defined biological response.
1. Lipophilicity
➢ Two parameters are commonly used to represent lipophilicity, namely the
partition coefficient (P) and the lipophilicity substituent constant (p).
➢ The former parameter refers to the whole molecule whilst the latter is related
to substituent groups.

114 Urael G. 10/22/2023

 Cont’d…
1.1 Partition coefficient (P)
➢ Organic medium/aqueous system partition coefficients are the parameters to use as a
measure of the ease of movement of the drug through the membranes.
➢ The n-octanol–water system is frequently chosen because it appears to be a good mimic
of lipid polarity and has an extensive database.
➢ The relationship between P and drug activity for a wide range of p values is given by

Where k1, k2 and k3 are constants that are normally determined by regression analysis.

115 Urael G. 10/22/2023

 Cont’d…
1.2 Lipophilic substituent constants (p)
➢ Lipophilic substituent constants are also known as hydrophobic substituent
constants.
➢ They represent the contribution that a group makes to the partition coefficient and
were defined by Hansch and co-workers by the equation:

➢ Where PH and PX are the partition coefficients of the standard compound and its
substituted derivative respectively.
➢ However, when several substituents are present, the value of p for the compound
is the sum of the p values of each of the separate substituent’s.
➢ The value of p for a specific substituent will vary with the structural
environment of the substituent.

116 Urael G. 10/22/2023

117 Urael G. 10/22/2023
 Cont’d…
➢ A positive p value indicates that a substituent has a higher lipophilicity than
hydrogen and so will probably increase the concentration of the compound in the
n-octanol layer and by inference its concentration in the lipid material of biological
systems.
➢ Conversely, a negative p value shows that the substituent has a lower lipophilicity
than hydrogen and so probably increases the concentration of the compound in the
aqueous media of biological systems.
➢ Lipophilic constants are frequently used when dealing with a series of analogues
in which only the substituents are different.

118 Urael G. 10/22/2023

 Cont’d…
➢ As an example, consider the log P values for benzene (log P = 2.13),
chlorobenzene (logP = 2.84) and benzamide (logP = 0.64).

➢ Since benzene is the parent compound, the substituent constants for Cl and
CONH2 are 0.71 and -1.49 respectively.

➢ Having obtained these values, it is now possible to calculate the theoretical

logP value for meta-chlorobenzamide:

119 Urael G. 10/22/2023

 Cont’d…
2. Electronic effects
➢ The distribution of the electrons in a drug molecule has a considerable influence on
the distribution and activity of a drug.
➢ The first attempt to quantify electronic effects of groups on physicochemical
properties of compounds was made by Hammett.
The Hammett constant (σ)
➢ The distribution of electrons within a molecule depends on the nature of the
electron withdrawing and donating groups found in that structure.
➢ Hammett used this concept to calculate what are now known as Hammett constants
(σx) for a variety of monosubstituted benzoic acids.

120 Urael G. 10/22/2023

 Cont’d…

➢ Where KH and KX are the equilibrium constants for benzoic acid and
monosubstituted benzoic acids respectively.
➢ Its value varies depending on whether the substituent is an overall
electron donor or acceptor.
➢ A negative value for σX indicates that the substituent is acting as an
electron donor group since KH > KX.
➢ Conversely, a positive value for σX shows that the substituent is
acting as an electron withdrawing group as KH < KX

121 Urael G. 10/22/2023

122 Urael G. 10/22/2023
 Cont’d…
3. Steric effects
➢ The first parameter used to show the relationship between the shape and size
(bulk) of a drug, the dimensions of its target site and the drug’s activity was the
Taft steric parameter (Es).
➢ It was followed by Charton’s steric parameter (n), Verloop’s steric parameters and
the molar refractivity (MR) amongst others.
The Taft steric parameter (Es )
➢ Taft (1956) used the relative rate constants of the acid catalyzed hydrolysis of a-
substituted methyl ethanoates to define his steric parameter because it had been
shown that the rates of these hydrolyses were almost entirely dependent on steric
factors.

123 Urael G. 10/22/2023

 Cont’d…
➢ He used methyl ethanoate as his standard and defined Es as:

➢ Where k is the rate constant of the appropriate hydrolysis and the value of Es=0
when X = H.

124 Urael G. 10/22/2023

 Cont’d…
Hansch analysis
➢ Hansch analysis attempts to mathematically relate drug activity to measurable
chemical properties.
➢ It is based on Hansch’s proposal that drug action could be divided into two stages:

1. The transport of the drug to its site of action.

2. The binding of the drug to the target site.
➢ Hansch postulated that the biological activity of a drug could be related to these
parameters by simple mathematical relationships based on the general format:

125 Urael G. 10/22/2023

 Cont’d…

➢ Where C is the minimum concentration required to cause a specific

biological response and k1, k2, k3 and k4 are numerical constants obtained
by feeding the values of the parameters selected by the investigating team
into a suitable computer statistical package.

126 Urael G. 10/22/2023

Lipinski's rule of five
➢ Lipinski's rule of five (RO5) is a rule of thumb to evaluate drug likeness or
determine if a chemical compound with a certain pharmacological or biological
activity has properties that would make it a likely orally active drug in humans.
➢ The rule is important to keep in mind during drug discovery when a
pharmacologically active lead structure is optimized step-wise to increase the
activity and selectivity of the compound as well as to insure drug-like
physicochemical properties are maintained as described by Lipinski's rule.
➢ Candidate drugs that conform to the RO5 tend to have lower attrition rates during
clinical trials and hence have an increased chance of reaching the market.
127 Urael G. 10/22/2023
 Cont’d…
Lipinski's rule states that, in general, an orally active drug has no more than one
violation of the following criteria:
❖ MW < 500
❖ Fewer than five H-bond donating functions (nitrogen or oxygen atoms with one or
more hydrogen atoms)
❖ Fewer than 10 H-bond accepting functions (nitrogen or oxygen atoms)
❖ Calculated logP (ClogP) between –1 and +5

128 Urael G. 10/22/2023

 Stereochemistry and drug action
Stereochemistry
 Study about relative arrangement of atoms or groups in a molecule in three
dimensional space.
Isomers
 Are different compounds which have the same molecular formula.

129 Urael G. 10/22/2023

 Cont’d…

130 Urael G. 10/22/2023

 Cont’d…
Constitutional isomers
 Constitutional isomers have the different connectivity between atoms.

 Regioisomers are a class of constitutional isomers which have the same

functional groups but attached at different positions.

131 Urael G. 10/22/2023

 Cont’d…
Stereoisomers
 Stereoisomers have the same constitution (atom–bond connectivity) but the atoms
are oriented differently in space. Stereoisomers can be subdivided into two classes.
I Conformational isomers
 Can be interconverted by free rotation about single bonds.
 The interconversion of conformations usually occurs at room temperature because
the energy barrier to rotation is low and these isomers normally cannot be
separated from one another.

132 Urael G. 10/22/2023

 Cont’d…
II Configurational isomers
 Differ in the spatial arrangement of their atoms and can only be interconverted
by breaking bonds (and not by free rotation about single bonds).
 They do not interconvert at room temperature and can be separated.

Categorized as : enantiomers and diastereoisomers.

133 Urael G. 10/22/2023

 Cont’d…
Chiral centres (stereogenic centres)
 A carbon atom is a chiral (stereogenic) centre if it is tetrahedral (sp3) and has four
different groups (ligands) attached to it.
 A molecule is chiral if it is not superimposable on its mirror image.

Enantiomers
 These are stereoisomers which are non-superimposable mirror images of one
another.
 They have identical physical properties (solubility, m.p., b.p., NMR, IR etc.).
 ONLY isomers that are non-superimposable mirror images are enantiomers of each
other.

134 Urael G. 10/22/2023

 Cont’d…
Diastereoisomers
 Are stereoisomers which are not enantiomers.
 They have the same constitution but different configurations, are non-
superimposable and are not mirror images.
 They are possible when there is more than one stereogenic centre in a molecule.

 1 and 2 are enantiomers; 3 and 4 are enantiomers

 1 and 3 (or 4) are diastereoisomers; 2 and 3 (or 4) are diastereoisomers
135 Urael G. 10/22/2023
 Cont’d…
 Compounds with more than two stereogenic centres are common in nature.
 In general, for molecule with n stereogenic centres, 2n stereoisomers are possible.
 Glucose has four, and so is one of 16 possible stereoisomers.
 Cholesterol, with eight, has 28 (256) possible stereoisomers – and only one occurs
in nature.
 In this case, just roll your mouse over the image and the eight stereogenic centres
will be revealed.

136 Urael G. 10/22/2023

 Cont’d…
 Most receptor sites in mammals are proteins, and since these are built from
chiral amino acids, proteins are also chiral.
 The interaction between two different enantiomers and the same receptor is
therefore a diastereisomeric one, with the two alternative enantiomer–
receptor combinations having different binding energies.
 E.g, the antihistamine dexchlorpheniramine is highly stereoselective, the (S)-
enantiomer being about 200 times more potent that the (R)-form.
 The higher potency suggests more complementarity ('a better fit') with the
target receptor.
 Interestingly, the natural substrate for this receptor, i.e. histamine, is itself
is achiral.

137 Urael G. 10/22/2023

 Cont’d…

 Enantiomers can have biological activities which are altogether different.

 One enantiomer of a biologically active molecule may cause a particular
biological response, whereas the other enantiomer is usually completely
inactive.
 It is therefore wasteful, at best, to synthesize and use a racemic mixture of
stereoisomers as a drug.
 However, the 'wrong' enantiomer of a drug may be biologically active in a
completely unwanted way, which can be very dangerous.

138 Urael G. 10/22/2023

 Cont’d…
 The most infamous example of this is the sedative thalidomide, the
(S)-enantiomer of which is teratogenic.

139 Urael G. 10/22/2023

 Cont’d…
 (+)2R,3S propoxyphene have analgesic
while (-) 2S,3R propoxyphene has
antitussive action.

 D-Ethambutol is anti-tuberculosis drug

while L-ethambutol has been found to
cause blindness.

140 Urael G. 10/22/2023

 Drug metabolism
 Metabolism is defined as the structural (biochemical) modification of a
lipophilic drug (by enzymes) or foreign chemicals (xenobiotics) into easily
excreted hydrophilic drug
 Drug metabolism is generally considered as detoxification process, which
converts lipophilic chemical compounds into more readily excreted polar
products.
 Its rate is an important determinant of the duration and intensity of the
pharmacological action of drugs.
 Majority of the drugs metabolized in liver and some drugs get metabolized in
kidney, lungs and intestine.

141 Urael G. 10/22/2023

 Cont’d…
 Metabolism of drugs in human takes place by two different mechanisms,
 Phase I reactions include hydrolysis, reduction and oxidation of drug
molecule.
 Phase II reactions include conjugation of a drug molecule with highly polar
substance like glucuronic acid, glucose, sulfuric acid, amino acids etc
 Metabolism resulting in the production of a mixture of intermediate
metabolites and excreted products, including unchanged parent drug.
 Rarely only one metabolite produced from a single drug.

142 Urael G. 10/22/2023

 Cont’d…
Inactive Metabolites
 Some metabolites are inactive (active compound become inactivated or
detoxicated)
 The oxidation of 6-mercaptopurine to 6-mercapturic acid results in loss of
anticancer activity.
Metabolites that retain similar activity
 Certain metabolites retain the pharmacologic activity of their parent compounds to
a greater or lesser degree.
 Codeine is demethylated to the more active analgesic, morphine

143 Urael G. 10/22/2023

 Cont’d…
Metabolites with altered activity

 Some metabolites develop activity different from that of their parent drugs.

 The antidepressant iproniazid is dealkylated to the antitubercular, isoniazid

Bioactivated Metabolites

 Some pharmacologically inactive parent compounds are converted to active

species within the body. These compounds are known as prodrugs.

 The prodrug enalapril, is hydrolysed to enalaprilat, a potent antihypertensive

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 Biotransformation Pathways
Phase I reaction.
In which polar functional groups are introduced into the molecule by oxidation,
reduction, or hydrolysis.
Oxidation- is the most common phase of phase I biotransformation
 Majority of oxidations occur in the liver, however, intestinal mucosa, lungs
and kidney also involved in the metabolism.
 Majority of oxidations are catalysed by mixed-function oxidases known as
cytochrome P450.
 Some oxidations (eg. ethanol to acetaldehyde) are catalysed by
nonmicrosomal oxidases located in mitochondria of extrahepatic tissues

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Reduction- is less common than oxidation.
 Cytochrome P450 system might be involved in some reductions.
 Bacteria present in the GIT involved in azo and nitro reductions.

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Enzymatic hydrolysis- the addition of water across a bond, also results in
more polar metabolites.
 Esterase enzymes, present in plasma, hydrolyse esters into two polar
metabolite, i.e., an alcohol and an acid.
 Esterases are responsible for converting many prodrugs into their
 active forms.
 Amidase enzymes, hydrolyse amides into amines and acids (deamidation),
which occur primarily in the liver.
N.B Ester drugs susceptiple to plasma esterases (eg. procaine) are usually
shorter acting than structurally similar amide drugs (eg. procainamide) which
are not significantly hydrolysed until they reach the liver.

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Phase II reactions
 In phase II reactions, the functional groups of the original drug (or metabolite
formed in phase I reaction) are masked by a conjugation reaction.
 Most phase II conjugates are very polar, resulting in rapid elimination from the
body.
Conjugation reactions
 The parent drug (or its metabolites) combine with certain natural endogenous
substance, such as glucuronic acid, glycine, glutamine, sulfate, glutathione, acetyl
group or methyl group.
 These reactions generally require both high energy and an enzyme.
 The enzymes (called transferases) that catalyze conjugation reactions are found
mainly in the liver and, to a lesser extent, in the intestines and other tissues.
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 Most conjugates are highly polar and unable to cross the cell membrane,
making them almost pharmacologically inactive.

 These conjugates (metabolites) are little or no toxicity.

 Exceptions are acetylated and methylated conjugates.

 These conjugates do not possess increased polarity;however, they are usually

pharmacologically inactive.

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Glucuronidation
 Is the most common conjugation pathway.
 Drugs that having hydroxyl or carboxyl functional groups readily undergo
glucuronidation to form ethers and esters, respectively. In addition, N-, S- & C-
glucuronides are also possible.
 The high energy form is uridine diphosphate glucuronic acid and the reaction is
catalyzed by glucuronyl transferase.

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Sulfate conjugation
 Phenols, alcohols, arylamines, and N-hydroxyl groups form highly polar
metabolites.
 The high energy form is 3’-phosphoadenosine- 5’phosphosulfate (PAPS), and the
reaction is catalyzed by sulfotransferase.

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Amino acid conjugation
 Involves the reaction of either glycine or glutamine with aliphatic or
aromatic acids to form amides.
 A drug molecule is first converted to an acyl coenzyme A intermediate.
 An N-acyltransferase enzyme then catalyzes the conjugation of the activated
drug molecule with the amino acid.

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Glutathione conjugation
 Is extremely important in preventing toxicity from a variety of harmful
electrophilic agents.
 Glutathione is a tripeptide containing a nucleophilic sulfhydryl group.
 Under the influence of glutathione S-transferase, glutathione reacts with halides,
epoxides and other electrophilic compounds to form harmless inactive products

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Methylation

 Takes place in oxygen, nitrogen and sulfur containing functional groups.

 It produces metabolites that are usually less polar than the unaltered drugs.

 It plays a minor role in the elimination of drugs.

 The high energy form is S-adenosylmethionine (SAM) and the reaction is

catalyzed by methyltransferase enzymes

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Acetylation

 Takes place in primary amine, hydrazides, sulfonamides and occasionally

amides and forms N-acetylated products.

 These products are usually less polar than the unaltered drug and can retain
pharmacological activity.

 The high energy form for acetylation is acetyl-CoA and the reaction is
catalyzed by N-acetyltransferase.

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