• Medicinal chemistry is a chemistry-based discipline,
involving aspects of biological, medical and
pharmaceutical sciences. It is concerned with the
invention, discovery, design, identification and
preparation of biologically active compounds, the
study of their metabolism, the interpretation of their
mode of action at the molecular level and the
construction of structure-activity relationships (SARs).
Structure activity relationship
• SAR is the relationship between the chemical or 3D
structure of a molecule and its biological activity.
• The analysis of the dependence of biological effects
of a chemical upon its molecular structure.
• Molecular structure and biological activity are
correlated by observing the results of systematic
structural modification on defined biological
• Determination of the chemical groups responsible
for evoking a target biological effect in the
• Quantitative SARs (QSAR)as a special case of SARs
(when relationships become quantified)
WHY SAR Exist?
• The interaction of the drug molecule with protein depends
on its chemical structure
NEED OF SAR STUDY
• A study of the structure–activity relationship is mainly
done by lead molecule.
• It is used to determine pharmacophore, unwanted side
• To develop a new drug that has increased activity.
• To determine some different activity from an
• To fewer unwanted side effects
• To know the changes in pharmacological properties
by performing minor changes in the drug molecule
• Attempts to find consistent relationship between
the variations in the values of molecular properties
& the biological activities for a series of compounds
so that these “rules” can be used to evaluate new
• 3D QSAR –most powerful technique available for
analog – based drug design.
History of Medicinal Chemistry
Early investigations of natural products
In the so-called pre-scientific era
• Natural products having a history as folk remedies
were in use. Fore examples, opium, belladonna,
cinchona bark, etc. Many drugs originally used as
folk remedies, nowadays, have been abandoned.
• In the late eighteenth and early nineteenth centuries,
chemical experimentation led ultimately to its use in
the discovery of new drugs.
• In 1853, Henry How conceived the idea that
functional groups in natural products might be
modified by chemical reagents.
He heated morphine with methyl iodide, hoping to
convert the alkaloid to codeine. He obtained, however,
a new substance of the quaternary salt of morphine.
• In 1898, the first commercially available semisynthetic
morphine derivative (ethyl ether) was introduced as a
cough sedative in preference to codeine or other
• Meanwhile, diacetylmorphine was introduced as a
safer pain reliever than morphine. It quickly became
popular throughout the world.
• Four years passed before its addictive properties of heroin were
recognized. Laws were later passed by governments to restrict its
• During the 1840s, the first use of synthetic organic
chemicals were introduced for anesthesia during a
tooth removal, such as nitrous oxide, ether, and
• In 1864, barbituric acid had been synthesized as a
• In 1875, salicylic acid was introduced as a possible
cure for typhoid fever. It was found to be an effective
• In 1899, Aspirin (Acetyl salicylic acid) was marketed
as an antipyretic without the unpleasant side effects.
This indicated that the chemical structures from
natural products were changed into better drugs.
• Medicinal Chemistry began.
Selectivity of Drug Action and
• Similar molecules exert similar biological actions in
a qualitative sense.
• Both agonists and antagonists share common
• Composition and arrangement of chemical
functional groups, determines the type of
pharmacologic effect it possesses.
Screening is the systematic examination of a chemical
molecule to identify the lead molecule.
Methods of screening:
1. Identification by Random screening.
2. Identification by Non-Random screening.
3. Identification by drug metabolism
4. Identification by observing side effects.
The lead compound for the development of most drugs
is found by screening thousands of compounds
A random screen is a search for a pharmacologically
active lead compound without any information about
what structures might show activity
Identification by drug metabolism studies:
Identification by observing side effects:
Benzodioxanes Ethanolamines Ethylenediamine
Pruning is the refinement of lead structure.
It is done to determine the pharmacophore.
A pharmacophore is a spatial arrangement
of functional groups essential for biological
activity. It is a pattern that emerges from a
set of molecules with a common biological
PHYSICOCHEMICAL PROPERTIES OF
• Acid-Base Properties
• Water Solubility of Drugs
• Electronic parameters
• Possible to predict ,if a molecule gets ionized or
unionized at a given pH simply by knowing if the
functional groups on the molecule are acidic or
• Quantitatively predict the degree of ionization of a
• Henderson-Hassalbach equation
Water Solubility of Drugs
• It Greatly affects the routes of administration.
• Two key concepts :
• 1) hydrogen bond forming(Drugs with possibility of
more hydrogen bond formation will have more
• 2) ionization of functional groups.
OAldehyde / ketone
Ion - dipole bonds
Acidic form of amines
Basic form of carboxylic acid
Predicting Water Solubility:
• Based on carbon- solubilising potential of several
organic functional groups.
• Solubilising potential of the functional groups
exceeds the total number of carbon atoms present,
then the molecule is considered to be water
soluble. Otherwise, its water insoluble.
• Functional groups that can interact
either through intramolecular hydrogen
or ion-ion interactions will decrease the
solubilizing potential of each group.
Intramoleculare interact. reduce water sol.
Strong intramolec interact.
Predicting Water Solubility:
• PARTITION CO-EFFICIENT- It is the extent of distribution
of drug between oil phase and water phase.
• If the drug is more hydrophobic it will have high p
value and it can cross biological membranes easily.
• Partition co-effecient of a drug can be determined by
its distribution in an octanol-water mixture.
P= Concentration of drug in octanol
Concentration of drug in aqueous solution
Log P =Σπ(fragments)
• Log of the partition coefficient for a molecule
Predicts Water Solubility
• Log P is the sum of the hydrophobic and
hydriophilic characteristics of the organic functional
groups making up the structure of the molecule.
• Thus, logP is a measure of the solubility
characteristics of the entire molecule.
STEREOCHEMISTRY AND DRUG
• Stereo isomers are compounds containing
the same number and kinds of atoms, the
same arrangement of bonds, but different
• 2 types enantiomers and
• If functional groups are in the proper 3D
orientation, the drug can produce a very
strong interaction with its receptor.
• The physiochemical properties of a drug molecule
dependent on (a) functional groups in the molecule
(b)spatial arrangement of these groups.
• Enantiomers when introduced into an Asymmetric
environment(human body) ,it will display different
physiochemical properties, producing significant
differences in their pharmacokinetic and
Easson and Stedman Hypothesis
• reasoned that differences in biological activity
between enantiomers resulted from selective
reactivity of one enantiomer with its receptor.
• They postulated that such interactions require a
minimum of a three-point fit to the receptor.
(incerase potency of enantiomers)
Conformational Isomerism and
• dynamic process
• Isomerization takes place via rotation about one or
more single bonds.
• Neurotransmitter acetylcholine demonstrates
the concept of conformational isomers.
• Rotation around the central Cα-Cβ bond produces
the greatest spatial rearrangement of atoms.
• When the ester and trimethylammonium group are
180° apart, the molecule is said to be in the anti or
• maximum separation of the functional
• Rotation of one end of the Cα-Cβ bond by 120° or
240° results in the two gauche , or skew
• Gauche conformation is the form that binds to the
• Anti form, (achiral) binds to the muscarinic
• The electronic effects of various substituents will
clearly have an effect on a drug's ionization or
• This in turn may have an effect on how easily a
drug can pass through cell membranes or how
strongly it can bind to a receptor.
• After drug reaching its target site distribution of
electrons in its structure will control the type of
bond between them.
These SAR studies are done through Analog Approach.
2. Molecular fragmentation.
3. Addition of functional groups.
4. Isosteric Replacements.
ADDITION OF FUNCTIONAL GROUPS:
Permanently uncharged sulphide
WALL & WANI in
cuminata,Tree of Joy
STRUCTURE OF CPT WITH IUPAC NAME
A B C
Saturation of ring B< activity
necessary for activity
essential for activity, S N
D-ring pyridone is required for anti
Modifications in rings A, B are well tolerated
The stereochemistry at C-20 is very
crucial as 20(S) hydroxyl is active,
modifications at the C , D rings led
to complete loss of cytotoxicity.
Modification in rings A,B
Modification in rings C,D
In general, modifications at the C and D rings of
camptothecin led to complete loss of cytotoxicity.
If we see these rings, the only positions available
for modifications are C-5, C-14 and C-17. Several
derivatives have been reported either with less
activity or with loss of activity.
Modification in ring E
The α- hydroxyl lactone system of ring E has been
found to be important for the inhibition of the
topoisomerase enzyme as well as for in vivo
Derivatives having a lactam group instead of a
lactone, were devoid of topoisomerase inhibitor
Molecular Modification to Improve the Therapeutic
Properties of Cocaine
local anesthetic, but
bad effect on the
central nervous system
retains the local
Anesthetics Obtained through Molecular Modification
Replacing the ester linkage of procaine with an amide
linkage led to procainamide hydrochloride
Active as a cardiac depressant
Active as a local anesthetic
Used clinically as an antiarrhythmic
Molecular Modification of Morphine
Morphine and all the compounds prepared by molecular
modification of morphine have a structural feature in
Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most cough
The tranquilizer Librium was discovered accidentally
Structural modification of Librium leads to the generation
of other tranquilizers
Many drugs exert their physiological effects by binding
to a specific cellular binding site called a receptor
Excess histamine in the body causes the symptoms
associated with the common cold and allergic responses
Antihistamines alleviate the action of histamine by
binding to the histamine receptor
4-Methylhistamine is used as a lead compound to
develop antiulcer drugs
In screening modified compounds, it is possible to find a
compound with completely different pharmacological
activity than the lead compound
in 1942 by the chemist Marcel Janbon et al.
an antibiotic a drug with
Molecular modification of promethazine leads to the
discovery of an antipsychotic drug
Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the enzyme that
synthesizes bacterial cell walls
These nucleoside analogs interfere with DNA or RNA
- Quantitative structure-activity relationships
are mathematical relationships linking chemical
structure and pharmacological activity in a
quantitative manner for a series of compounds
- Biological activity can be expressed
quantitatively as the concentration of a substance
required to give a certain biological response
- When physicochemical properties or structures
are expressed by numbers, one can find a
mathematical relationship, or quantitative
structure-activity relationship, between the two
• SAR deals with the influence of the functional
groups present in the drug on its biological activity
• SAR studies are done to determine the pattern of
this influence which is employed in the drug design
and in the synthesis of many drugs of desired
• Medicinal Chemistry, Ashutosh Kar , 4th edi.
• Essentials of drug designing . V kothekar 1st Edition
• Paul Beringer, Linda Felton et al. The Science and
Practice of Pharmacy, 21st ed, Vol.1,
• Drug design vol.10, Ariens et al.
• Goodman & gillman’s the pharmacological basis of
therapeutics, 12th edition.