INTRODUCTION TO

MEDICINAL
CHEMISTRY

Dr. SUNIL JUNAPUDI

[Link],PhD
Associate Professor
Department of Pharmaceutical Chemistry
1
Introduction to Medicinal Chemistry
Medicinal chemistry is best to be defined as an
interdisciplinary research area incorporating different
branches of chemistry and biology in the research for
better and new drugs (Drug Discovery).

In other words, medicinal chemistry is the science,

which deals with the discovery and design of new and
better therapeutic chemicals and development of these
chemicals into new medicines and drugs.

Generally Medicinal Chemists can:

•Make new compounds
•Determine their effect on biological processes.
•Alter the structure of the compound for optimum effect
and minimum side effects. 2

•Study uptake, distribution, metabolism and excretion of

Drug Classification
Pure organic compounds are the chief source of agents for the
cure, mitigation or the prevention of disease.

These remedial agents could be classified according to their

origin:

• Natural compounds: materials obtained from both plant

and animal, e.g. vitamins, hormones, amino acids,
antibiotics, alkaloids, glycosides…. etc.).

• Synthesis compounds: either pure synthesis or synthesis

naturally occurring compounds (e.g. morphine, atropine,
steroids and cocaine) to reduce their cost.

• Semi-synthesis compounds: Some compounds either can

not be purely synthesized or can not be isolated from natural
sources in low cost. Therefore, the natural intermediate of
such drugs could be used for the synthesis of a desired 3

product (e.g. semi synthetic penicillins).

 Drug Classification
Since there is no certain relation between chemical
structure and pharmacological activity therefore, it would
be unwise to arrange all drugs on the basis of their
structures or origin. Thus, it is better to arrange the drugs
according to their medicinal use.
Drugs can be classified according to their medicinal
uses into two main classes:

I-Pharmacodynamic agents: Drugs that act on the

various physiological functions of the body (e.g. general
anaesthetic, hypnotic and sedatives, analgesic etc.).

II-Chemotherapeutic agents: Those drugs which are

used to fight pathogenic (e.g. sulphonamides, antibiotics,
4

antimalarial agents, antiviral, anticancer etc.).

 Drug Classification
Drugs can treat different types of diseases:

1-Infectious diseases: Born (transmitted) from person

to person by outside agents, bacteria (pneumonia,
salmonella), viruses (common cold, AIDS), fungi
(thrush, athletes foot), parasites (malaria)
2-Non-infectious diseases: disorders of the human
body caused by genetic malfunction, environmental
factors, stress, old age etc. (e.g. diabetes, heart
disease, cancer. Haemophilia, asthma, mental illness,
stomach ulcers, arthritis).
3-Non-diseases: alleviation of pain (analgesic),
prevention of pregnancy (contraception) , anesthesia5 .
ADME CHARACTERS

 Distribution: The transfer of drug from blood to

extravascular fluids (i.e., extra-cellular and intracellular
water) and tissues is called distribution. Drug distribution
is usually a rapid and reversible process.

Drug in the plasma exists in a distribution equilibrium with

drug in the erythrocytes, in other body fluids and in
tissues. Changes of plasma drug concentration are
indicative of changes in drug level in other tissues
including sites of pharmacologic effect.
 Metabolism: It is the biochemical (enzymatic)
conversion of a drug to another chemical form.

Many tissues in the body are capable of metabolizing

drugs, but most drugs are mainly metabolized in the liver
by enzymes localized in hepatic microsomes.

Drug-metabolizing enzymes oxidize, reduce, hydrolyze,

or conjugate compounds. Reduction, oxidation, and
hydrolytic reactions (phase I pathways) result in
metabolites with functional groups (hydroxyl, amine, or
carboxyl) that can be conjugated (phase II).

In man the most common conjugation of drugs or

metabolites occur with acetate, sulfate, glycine, or
glucuronic acid.
ADME CHARACTERS
 Elimination: It is the irreversible loss of drug from the
site of measurement.

The transfer of drug from the blood to the urine or other

excretory compartments (i.e., bile, saliva, sweat, milk,
etc.) and the enzymatic or biochemical transformation of
drug in the issues or plasma to metabolic products, are
usually irreversible processes. The net result of these
irreversible steps is called drug elimination.

Elimination occurs by two processes , excretion and

metabolism. Elimination processes are responsible for
the physical or biochemical removal of drug from the
body
 Excretion: It is the irreversible loss of chemically
unchanged drug by various routes. This can occur
through urine, biliary secretion, saliva, sweat, milk,
respiratory route.

Routes of excretion and extent of excretion by any

route may vary from drug to drug depending on nature
and physicochemical properties of drugs.
 Physico-chemical properties in relation
to biological action
Drug action results from the interaction of drug molecules
with either normal or abnormal physiological processes.
Drugs normally interact with targets (which they are proteins,
enzymes, cell lipids, or pieces of DNA or RNA).

The ability of a chemical compound to elicit a pharmacologic

/therapeutic effect is related to the influence of its various
physical and chemical (physicochemical) properties

The most pharmacologically influential physicochemical

properties of organic medicinal agents (OMAs) are:

[Link]
[Link] and basicity
[Link]
10
 1- SOLUBILITY OF ORGANIC MEDICINAL
AGENTS
Importance of solubility:

(1) Formulation of the drug in an appropriate

dosage form and
(2) Bio-disposition: Disposition of OMAs in the
living system after administration (absorption,
distribution, metabolism, and excretion).
The solubility expression: in terms of its affinity/philicity
or repulsion/phobicity for either an aqueous (hydro) or
lipid (lipo) solvent.

♣hydrophilic....................water loving
♣lipophobic.....................lipid hating
♣lipophilic.......................lipid loving 11

♣hydrophobic..................water hating
 1- SOLUBILITY OF ORGANIC MEDICINAL
AGENTS
Majority of OMAs possess balanced solubility
(have some degree of solubility in both
aqueous and lipid media).

Because there is a need for OMAs to move

through both aqueous (plasma, extracellular
fluid, cytoplasm, etc.) and lipid media (biologic
membranes) in the biological system.

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1- SOLUBILITY OF ORGANIC MEDICINAL AGENTS

Solubility of OMAs should be viewed as being on a continuum

between high lipophilicity on one end of the spectrum and high
hydrophilicityMore
on thelipophilic
other. More hydrophilic
OMAs OMAs
Equally soluble
OMAs

Lipophilic Hydrophilic

In order for a chemical compound to dissolve in a

particular solvent/medium the compound must establish
attractive forces between itself and molecules of the
solvent.
13
1- SOLUBILITY OF ORGANIC MEDICINAL AGENTS

In order for a chemical compound to dissolve in a

particular solvent/medium the compound must
establish attractive forces between itself and
molecules of the solvent.

It is possible to estimate the solubility properties of an

OMA (hydrophilic vs. lipophilic) by examining the
structure of the OMA and noting whether its structural
features promote affinity for aqueous or lipid media.

The most important intermolecular attractive forces

(bonds) that are involved in the solubilization process14
are:
The most important intermolecular attractive forces
(bonds) that are involved in the solubilization process
:are

1. Van der Waals Attraction

■weakest intermolecular force (0.5-1.0 kcal/mole)
■electrostatic
■occurs between nonpolar groups (e.g. hydrocarbons)
■highly distance and temperature dependent

2. Dipole-Dipole Bonding
■stronger (1.0 to 10 kcal/mole)
■occurs electrostatically between electron deficient and electron
excessive /rich atoms (dipoles)
■hydrogen bonding is a specific example of this bonding and
 +
serves as a prime contributor to hydrophilicity
O H
 +
N: H O C + O H
H O H 
15
[Link] Bonding
■electrostatic attraction between cations and anions
■common in inorganic compounds and salts of organic
molecules O
+
■relatively strong (5 kcal/mole) N+ H Cl- C Na
-
O
[Link]-Dipole Bonding
■electrostatic between a cation/anion and a dipole
■relatively strong (1-5 kcal/mole)
■low temperature and distance dependence
■important attraction between OMAs and H2O
H
 O
O H
+ H C  O

N H O
-
H 16
Solubility Prediction

The relative solubility of an OMA is a

function of the presence of both lipophilic and
hydrophilic features within its structure, which
serve to determine the extent of interaction
of the OMA with lipid and/or aqueous phases.
The relative solubility of an OMA can be
determined in the laboratory, i.e. the
partition coefficient [P; the ratio of the
solubility of the compound in an organic
solvent to the solubility of the same
compound in an aqueous environment (i.e.,
P=[Drug]lipid/ [Drug]aqueous). P is often 17
 Solubility Prediction
A mathematical procedures also have been
developed to estimate the relative solubility of
an organic molecule based upon differential
contributions of various structural features to
overall solubility.

For example, the relative solubility of an OMA

is the sum of the contributions of each group
and substituent to overall solubility.
Example:
Examination of the structure of
chloramphenicol (indicates the presence of
18

both lipophilic (nonpolar) and hydrophilic

 Solubility Prediction
Lipophilic
Hydrophilic
Hydrophilic Lipophilic

OH O
O2N CH CH NH C CHCl2
CH2OH

Chloramphenicol

Hydrophilic

The presence of oxygen and nitrogen containing functional groups

usually enhances water solubility. While lipid solubility is enhanced
by nonionizable hydrocarbon chains and ring systems.

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 Solubility Prediction
[Link] Estimation of Relative
Solubility

The relative solubility of an organic compound is measured by

determining the extent of its distribution into an aqueous solvent
(usually pH 7.4 buffer) and a lipid solvent (usually n-octanol). These
experiments generate a value,Conc.
P, the of compunds
partition in C8for
coefficient H16 OH
that
Partition coefficient =
particular compound. Conc. of compunds in H2O

20
2- Mathematical Estimation of Relative
Solubility
Solubility contributions (groups and substituents) are expressed as
hydrophilic (negative value) or lipophilic (positive value) fragment
constants. Log Pcalc = 

Where; Log Pcalc = log of partition cofficient and = sum of

hydrophilic-lipophilic constants.
Hydrophilic-Lipophilic constants.

 Value
Fragment
C (aliphatic) +0.5
C6H5- +2.0

Cl +0.5
O2NO +0.2

Intramolecular hydrogen bonding (IMHB) +0.65

S +0.5
O=C-O -0.7
O=C-N -0.7
O(hydroxyl, phenyl, ether) -1.0
N (amine) -1.0
O2N (aliphatic) -0.85 21

O2N (aromatic) -0.28

Calculation steps of Log P for OMA
(i) The molecule is dissected into its various groups, functionalities
and substitutents
(ii) Appropriate hydrophilic/lipophilic fragment constants are
assigned and summed
(iii) Compounds with log Pcalc values greater than +0.5 are
considered water insoluble (lipophilic) and those with log
Pcalc values less than +0.5 are considered water soluble
(hydrophilic).
:Calculated log P Values for salicylic acid and p-Hydroxybenzoic acid

Salicylic acid p-Hydroxybenzoic acid COOH COOH

Fragment  Value Fragment  Value
OH

Phenyl +2.0 Phenyl +2.0 p-Hydroxybenzoic acid

OH -1.0 OH -1.0
OH
COOH -0.7 COOH -0.7 Salicylic acid
IMHB +0.65 - -

Sum +0.95 +0.3

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Prediction Water insoluble Prediction Water soluble
 Quantitative Structure Activity
Relationship (QSAR)
As shown we can estimate the relative solubility of drugs on the
basis of the structure features.

However, there is a relationship between the quantity of the drug

that binds to the active site and its structure and thus, the
biological activity.

This relationship is called quantitative structure activity

relationship (QSAR).

QSAR can be used:

1- To predict the design of new compounds and

2- To reduce the types of chemical process involved in the biological
activity.

Because, the biological activity of substances is related to oil water

distribution coefficient (distribution of the compound between the23
aqueous and the lipid phases of the tissue), which is an important
 2- Acidity and Basicity
Acidic and/or basic properties of OMAs are important in both:
1- Pharmaceutical phase (dosage formulation, etc.) and
2- Pharmacological phases (disposition, structure at target site, etc.).

The three aspects of acid-base chemistry:

(1) Definitions

(2) Recognition of acidic or basic organic functional groups and

(3) An estimation of the relative acid/base strength of these groups.

Definitions:
Acid: An organic compound containing a functional group that can donate a
proton (H+)
Base: An organic compound that contains a functional group that can accept
24

a H+
2- Recognition of acidic or basic organic functional
groups
1- Common acidic organic functional groups
◙Carboxylic acid (-COOH)
◙Phenol (Ar-OH)
◙Sulfonamide (R-SO2NH2)
◙Imide (R-CO-NH-CO-R)
◙-Carbonyl group (-CO-CHR-CO-)
O
O - + H3O+
R C + H3O+ R SO2 NH2 + H2O R SO2 NH
R C + H2O
O- Sulfonamide
O H
Carboxylic acid
O O
O O- R
H R
R N- + H3O+
R + H2O + H3O
+
N H + H2O
R R
O O
Phenol
Imide
NH3 + NH2
R + H2O R + H3O+

Anilinium cation

25
2-Recognition of acidic or basic organic functional
groups(cont)

2- Common basic organic functional groups

◙Aliphatic 1º (R-NH2), 2º (R2NH) and 3º (R3N)-

amines
◙Heterocyclic amines
◙Aromatic
R
aminesR
(Ar-NH2) NH NH 2 3
+

R N + H3O+ R N+ H+ H2O + H3O+ + H2O

R R
Aliphatic amines Aromatic amines

+ H3O+ + H2O
N NH
N N+
N N
Heteroaromatic amines R Pyridine H Imidazole
Piperidine

26
Estimation of the Relative Acid/Base
Strength
The ionization constant (ka) indicates the relative strength of the acid or
base.

An acid with a ka of 1x10-3 is stronger acid (more ionized) than one with a ka
of 1x10-5

A base with a ka of 1x10-7 is weaker (less ionized) than one with a ka of

1x10-9

The negative log of the ionization constant (pka) also indicates the relative
strength of the acid or base.

An acid with a pka of 5 (ka=1x10-5) is weaker (less ionized) than one with
pka of 3

Whereas a base with a pka of 9 is stronger (more ionized)

- than+one with a
pka of 7 CH3COOH CH3COO + H

E.g. Ionization of weak acid (e.g. acetic acid, pka =4.76) is as follows:
NH4+ + H2O NH3 + H3O+
27
Estimation of the Relative Acid/Base
Strength

The following chart is comparing acid/base

strengths:

INCREASEING ACIDITY
+
ACIDS H2SO 4, HCl, HNO 3, H3O , RCO 2H, ArOH, RSO 2NH2, CONHCO , H2O, ArNH2, RNH2, NaOH/KOH BASES

INCREASING BASICITY

28
The following chart is comparing acid strengths of various
functional
ACID NAME ACIDITY pKa
groups RSO3H Sulfonic acid 1
RCOOH Carboxylic acid 4.5
ArSO2NHR Aromatic sulfonamide 6-9
ArOH Phenol 8-11
O
R Imide 8-10
N H
R
O

The following chart is comparing base strengths of various

functional groups
ACID NAME Basicity pKa

RNH2, R2NH, R3N Aliphatic amines 3-4

ArNH2 Aromatic amines 9-13

Pyridine, piperidine, Heterocyclic amines 4-12

imidazole 29
Ionization of Acidic and Basic Functional
Groups
I-Acids
Carboxylic acids Sulfonamides
O
O + R SO2 NH- + H3O+
+ H2O R C + H3O ArSO 2 NHR + H2O
R C O -
O H

O O
O O- R
H R
N- + H3O+
+ H2O + +
H3O N H + H2O
R R
O O
Phenols
Imides

II-Bases

R NH2 NH3 +
R
R N + H3O+ R N+ H+ H2O + H3O+ + H2O
R R
Aliphatic amines Aromatic amines

+ H3O+ + H2O
+
N N 30

Heteroaromatic amines R
Acidic and Basic Functional Group - Salt
Formation
Salt: is the combination of an acid and a base
All salts are strong electrolytes (with few exceptions: mercuric and
cadmium halides and lead acetate)
The salt form of the drug is more soluble than its parent
molecule
Drug salts can be divided into two classes:
1)Inorganic salts: are made by combining drug molecules with
inorganic acids and bases, such HCl, H2SO4, KOH and NaOH.
Inorganic salts are generally used to increase the aqueous solubility
of a compound
2)Organic salts: are made by combining two drug molecules, one
acidic and one basic. The salt formed by this combination has
increased lipid solubility and generally is used to make depot
Sodium salt formation from carboxylic acid:
injections (e.g. procaine penicillin).
RCOOH + NaOH RCOO Na
- +
+ H2O

R3N + HCl
+
R 3NH Cl
-
31

Hydrochloric salt formation from an aliphatic amine

Structurally Non-Specific and Specific Activity
Drug activity can be classified as
(a)Structurally non-specific or
(b) Structurally specific

1-Structurally non-specific activity is dependent on

physical properties like solubility, partition coefficients and
vapour pressure and not on the presence or absence of some
chemical group.

Substances such as alkanes, alkenes, alkynes, alcohols, amides,

ethers, ketones and chlorinated hydrocarbons exhibit narcotic
activity and potency of each substance is related to its partition
coefficient.

Structurally non-specific action results from accumulation of a drug

in some vital part of a cell with lipid characteristics.
32

The structurally non-specific drugs include general anaesthetics, hypnotics together

 Structurally Non-Specific and Specific Activity

2-Structurally specific activity is dependent upon factors such as

the presence or absence of certain functional groups,
intramolecular distance, and shape of the molecules.

Activity is not easily co-related with any physical property and small
changes in structure often lead to changes in activity.

Structurally specific activity is dependent upon the interaction of the

drug with a cellular receptor.

33
 Drug-receptor Interaction
Receptor is the site in the biological system where the drug exerts its
characteristic effects or where the drug acts.

Receptors have an important regulatory function in the target organ or

tissue.

Most drugs act by combining with receptor in the biological system

(specific drugs).
1-cholinergic drugs interacts with acetylcholine receptors.
2-synthetic corticosteroids bind to the same receptor as cortisone and
hydrocortisone
3-non steroidal anti inflammatory drugs inhibit cyclooxygenase enzyme
that will inhibit the formation of prostaglandins which will lead to
inflammation symptoms.
Non-specific drugs do not act upon receptors.
The receptor substance is considered mostly to be a cellular constituent.
34
Recent studies, however, indicate that the receptors are proteins or
 Drug-receptor Interaction

The ability of a drug to get bound to a receptor is termed as the affinity of the drug for
the receptor.
The receptors are also dynamic in nature and have a special chemical
affinity and structural requirements for the drug. Thus, affinity
represents kinetic constants that relate to the drug and the receptor.
The drug elicits a pharmacological response after its interaction with
the receptor.
A given drug may act on more than one receptor differing both in
function and in binding characteristics (non-selective drugs).

There are also many factors effect changes in receptor concentration

and/or affinity.
A drug, which initiates a pharmacological action after combining with
the receptor, is termed agonist.
Drugs which binds to the receptors but are not capable of eliciting a
pharmacological response produce receptor blockage, these 35

compounds are termed antagonists.

 Structural features of drugs and their
pharmacological activity

Stereochemistry: Space arrangement of the atoms or three-

dimensional structure of the molecule.

Stereochemistry plays a major role in the pharmacological

properties because:

(1) Any change in stereospecificity of the drug will affect its

pharmacological activity
(2) The isomeric pairs have different physical properties (partition
coefficient, pka, etc.) and thus differ in pharmacological
activity.

The following steric factors influence pharmacological activity:

● Optical and geometric isomerism
● Conformational isomerism 36
 Structural features of drugs and their
pharmacological activity

I-Optical and geometric isomerism and

pharmacological activity

Optical isomers are compounds that contain at least

one chiral carbon atom or are compounds that differ
only in their ability to rotate the pollarized light.

The (+) or dextrorotatory: isomer rotates light to the right

(clockwise). The (-) or levorotatory: isomer rotates light
to the left (counterclockwise).

37
 I-Optical and geometric isomerism
and pharmacological activity

CH3 CH3
H H CH3
H3C
OH
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)

Enantiomers (optical isomers) can have large differences in

potency, receptor fit, biological activity, transport and
metabolism.
For example, levo-phenol has narcotic, analgesic, and
antitussive properties, whereas its mirror image, dextro-
phenol, has only antitussive activity.
38
I-Optical and geometric isomerism and pharmaco-
logical activity
Geometric isomerism (cis-trans isomerisms).
Occur as a result of restricted rotation about a chemical bond,
owing to double bonds or rigid ring system in the molecule.
They are not mirror images and have different physicochemical
properties and pharmacological activity. Because different
distances separate the functional groups of these isomers.
They generally do not fit to the same receptor equally well and if
these functional groups are pharmacophores the isomers will
differ in biologic activity.
For example, cis-diethylstilbestrol has only 7% of the oestrogenic
activity of trans- diethylstilbestrol
OH

HO OH HO 39
Ci s-die thylstil bestrol Trans -die thylstil bestrol
 II- Conformational isomersim and
pharmacological activity
Conformational isomersim is the non-identical space arrangement
of atoms in a molecule, resulting from rotation about one or more
single bonds.
Almost every drug can exist in more than one conformation and thus
the drug might bind to more than one receptor but a specific
receptor site may bind only to one of many conformations of a
drug molecule.
For example, the trans conformation of acetylcholine binds to the
muscarinic receptor, where as the gauche conformation binds to
the nicotinic receptor.
+ +
N (CH3) 3 N (CH3) 3

H H H H
H H
H OAc
OAc H
Trans Gauche
40
Conformations of acetylcholine
 III- Isosterism, Bioisosterism and
pharmacological activity
Isosterism: Any two ions or molecules having an identical number
and arrangement of electrons
(e.g. CO and NO2;
-
CO2(O=C=O) and N2O ( N=N+=O N= N+ O) ;
and N-3 and NCO- etc.).

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 functional groups which have similar spatial and
electronic character, but they retain the activity of the parent.

Bioisosterism is important in medicinal chemistry because:

41
1-Maintain similar biological properties.
III- Isosterism and pharmacological
activity
Friedman defined bio-isosterism as- the
phenomenon by which compounds usually fit the
broadest definition of isosteres and possess the same
type of biological activity.

E.g. (Antihistamine; A; B and C)

CH2 CH3 CH3

CHO CH2 CH2 N CHO CH2 CH2 N CHO CH2 CH2 N
CH2 CH3 CH3

A B C

Compound A has twice the activity of C, and many times greater than B42
 Classical and non-classical
bioisosteres
 for the classical ones, where size equivalence is the key,
the replacement should have roughly the same size.
 The key replacements (for example, the C, O, and N
replacements are seen for three of the classical
isosteres: CH3-,- OH,- NH2 for univalent;
 -CH2-, -O-, and -NH- for divalent;
 and -COCH2-R (ketone), -COOR (ester), and- CONHR
(amide) for the carbonyl containing compounds.
 You should also be able to make isosteric replacements
for the ring equivalents (single aromatic rings; single
aliphatic rings, or the general tricyclic replacement).
 For example we could change the ester alcohol oxygen
(not the carbonyl oxygen) with a CH2 (ketone), NH
(amide), or S (thioester).

43