JAIPUR COLLEGE OF PHARMACY, JAIPUR

B.PHARMACY, SECOND YEAR, FOURTH SEMESTER

MEDICINAL CHEMISTRY-I
Prepared by: Mrs. Nisha Dhir

UNIT-I
Introduction to Medicinal Chemistry

What is medicinal chemistry? • The science that deals with the discovery or
design of new therapeutic chemicals and the development of these chemicals
into useful medicine.

What is “medicine”? Drugs, pharmaceutics, Media distinction between drugs

that are used in medicine and drugs that are abused (addiction). A compound
that interacts with a biological system, and produces a biological response
(ideally desired and positive)

“Good” vs. “Bad” Drugs. No medicine has only benefits or drawbacks.A

“good” medicine would have to satisfy the following criteria, it would have to
do what it is meant to do and have no toxic or unwanted side effects and be easy
to take. For example, Morphine in low dose it is an Excellent analgesic, but
have serious side effects such as, Addiction, tolerance (the effect of the drug
diminishes after repeated doses and so we need to increase the size of the dose
to achieve the same results.), Respiratory depression and it may kill if taken in
excess. There is a long history of plants being used to treat various diseases.

Basically, the subject of medicinal chemistry explains the design and production
of compounds that can be used for the prevention, treatment or cure of human
and animal diseases. Medicinal chemistry includes the study of already existing
drugs, of their biological properties and their structure-activity relationships.
Medicinal chemistry was defined by IUPAC specified commission as “it
concerns the discovery, the development, the identification and the
interpretation of the mode of action of biologically active compounds at the
molecular level”.

Medicinal chemistry covers the following stages:

(i) In the first stage new active substances or drugs are identified and
prepared from natural sources, organic chemical reactions or
biotechnological processes. They are known as lead molecules.
(ii) The second stage is optimization of lead structure to improve potency,
selectivity and to reduce toxicity.

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(iii) Third stage is development stage, which involves optimization of

synthetic route for bulk production and modification
modifi of
pharmacokinetic and pharmaceutical properties of active substance to
render it clinically useful.
Medicinal chemistry is the application of chemical research techniques to the
synthesis of pharmaceuticals. During the early stages of medicinal chemistry
ch
development, scientists were primarily concerned with the isolation of
medicinal agents found in plants. Today, scientists in this field are also
equally concerned with the creation of new synthetic compounds as drugs.
Medicinal chemistry is almost always geared toward drug discovery and
development. Medicinal chemists apply their chemistry training to the
process of synthesizing new pharmaceuticals. They also work on improving
the process by which other pharmaceuticals are made. Most chemists work
with a team of scientists from different disciplines, including biologists,
toxicologists, pharmacologists, theoretical chemists, microbiologists, and
biopharmacists. Together this team uses sophisticated analytical techniques
to synthesize and test new drug
drug products and to develop the most cost-cost
effective and eco-friendly
friendly means of production.

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MEDICINAL CHEMISTRY-I
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History and Development of Medicinal Chemistry

In the Middle Ages various 'MateriaMedica and pharmacopeas brought together

traditional uses of plants. The herbals of John Gerard (1596), John Parkinson
(1640) and Nicolas Culpeper (1649) provide an insight into this widespread use
of herbs. Exploration in the seventeenth and eighteenth centuries led to the
addition of a number of useful tropical plants to those of European origin.

The nineteenth century saw the beginnings of modern organic chemistry and
consequently of medicinal chemistry. Their development is intertwined. The
isolation of a number of alkaloids including morphine (1805), quinine (1823)
and atropine (1834) from crude medicinal plant extracts was part of the
analytical effort to standardize drug preparations and overcome fraud. General
anaesthetics were introduced in surgery from 1842 onwards (diethyl ether
(1842), nitrous oxide (1845) and chloroform (1847)). Antiseptics such as iodine
(1839) and phenol (1860) also made an important contribution to the success of
surgery. The hypnotic activity of chloral (trichloroethanal) (1869) was also
reported. Many of the developments after the 1860s arose from the synthesis of
compounds specifically for their medicinal action. Although the use of willow
bark as a pain-killer was known to the herbalists, the analgesic activity of its
constituent salicin and of salicylic acid were developed in the 1860s and 1870s.
p-Hydroxyacetanilide (paracetamol) and phenacetin (1886) were also
recognized as pain-killers. Acetylation of salicylic acid to reduce its deleterious
effect on the stomach led to the introduction of aspirin in 1899. However its
mode of action was not established until 1971.The local anaesthetic action of
cocaine was reported in 1884 although its structure was not known at the
time.Various modifications of the dialkylamino esters of aromatic acids
modelled on part of the structure of cocaine led to benzocaine (1892) and
procaine (1905). The barbiturates, veronal (1903) and phenobarbital (1911)
were introduced as sleeping tablets. The action of acetylcholine on nerve tissue
had been recognized in the late nineteenth century. Barger and Dale (1910)
examined the response of various tissues to acetylcholine agonists and showed
that there were different receptor sub-types; some responding to muscarine and
others to nicotine.

The 1920s and 1930s saw the recognition of vitamin deficiency diseases and the
elucidation of the structure of various vitamins. It was also a period in which
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there was exposure of many Europeans to tropical diseases. The iodinated

quinolines such as entero-vioform were introduced to combat amoebic
dysentary and complex dyestuff derivatives such as suramin and germanin were
developed in the 1920s to treat sleeping sickness. Synthetic anti-malarials such
as pamaquine (1926), mepacrine (1932) and later chloroquine (1943) and
paludrine (1946) were introduced as quinine replacements. In 1935 Domagk
observed the anti-bacterial action of the sulfonamide dyestuff, prontosil red,
from which the important family of sulfonamide anti-bacterial agents were
developed. The activity of these compounds as inhibitors of folic acid
biosynthesis was rationalized by Woods (1940) as anti-metabolites of p-
aminobenzoic acid. With the onset of the Second World War, there was a need
for new antibiotics. In 1929 Fleming had observed that a strain of
Penicilliumnotatum inhibited the growth of a Staphylococcus. In 1940-1941
Chain, Florey and Heaton isolated benzylpenicillin. After considerable chemical
work, the b-lactam structure for the penicillins was established. The relatively
easy bio-assays for anti-bacterial and anti-fungal activity led to the isolation of a
number of antibiotics including streptomycin (1944), chloramphenicol (1949)
and the tetracyclinessuch as aureomycin (1949). Several different aspects of
medicinal chemistry developed in parallel through the second half of the
twentieth century. Although they did not develop independantly, it is easier to
follow their progression by considering them separately. The structures of the
steroid hormones were established in the 1930s and 1940s. The discovery in
1949 of the beneficial effect of cortisone in alleviating the inflammation
associated with rheumatism provided the stimulus for synthetic activity in this
area. A number of anti-inflammatory semi-synthetic corticosteroids such as
prednisolone, betamethasone and triamcinolone became available in the late
1950s and 1960s.A number of developments took place in the 1960s, which
changed medicinal chemistry. It was found that a drug, thalidomide , which had
been introduced as a sedative, when used by pregnant women, led to the birth of
deformed children. The consequences of this teratogenic effect brought about a
major tightening of the regulations regarding drug registration and the safety of
medicines. Unfortunately there was some tardiness in the recognition of this
side-effect. Second in 1964 Hansch published correlations between substituent
effects (Hammett parameters) and the biological activity of some
aromaticcompounds. These QSAR began to provide a framework for the

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MEDICINAL CHEMISTRY-I
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systematic development of drugs and for decisions to be made in the planning

of a research programme.

The logical development during the 1960s of histamine antagonists for the
treatment of peptic ulcers led to cimetidine (1976) and then ranitidine (1981).
The reasoning behind this work had a major impact on the development of
medicinal chemistry. Paul Ehrlich was such a scientist who got fascinated by
the ability of colourful dyes to interact with cellular and histological structures.
He procured hundreds to thousands of dyes for his research from several
chemical companies for several decades. Ehrlich found that the biological
effect of a chemical compound depends on its chemical composition and the
cell on which it acts. He established a connection between chemistry, biology,
and medicines in a creative way. He was also inspired by his colleagues who
were conducting researches in immunology including Louis Pasteur, Robert
Koch, Emil Von Behring, and Shibasaburo Kitasato. In the 20th century,
Ehrlich came up with the receptor theory; and this theory became influential to
make understand how drugs bind to receptors based on their chemical
structures and compositions.

Structure of Biological Membrane

Biological Membrane (or cell membrane, plasma membrane, and plasma

membrane) is a selectively permeable membrane which allows only certain
substances to pass through it, and also acts as a barrier between the inner and
outer surface of the cell. Celt membrane comprises of lipids and proteins along
with other living molecules, which participate in the normal functioning of cells
such as cell signalling, ion channel conductance, and cell adhesion. The inner
cytoskeleton of the cell connects to its outer cell wall via cell membrane. Cell
membrane defines the external boundaries of the cells and regulates traffic of
molecule across the boundary. In eukaryotic cells, cell membrane divides the
internal space into discrete compartments to segregate processes and
components. It regulates the sequences of complex biochemical reactions and
participates m conservation of biological energy and participates in cell-to-cell
communication.

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Models Depicting Structure of Cell Membrane

l. Danielli and Davson Model: Danielli and Davson (early 1930s-40s) have
given the Lamellar theory in which they studied the arrangement of triglyceride
lipid bilayer on the water surface. This model States that the plasma membrane
has bimolecular phospholipids made up of two protein layers present as folded
ß-chains. By electrostatic bond, these protein molecules are attached to the lipid
at polar hydrophilic ends.

2. Unit Membrane Model: According to this model, cell membrane is a

continuous structure having cytoplasm on one side and extra cellular fluid on
the other. Under the electron microscope, it appears as a thin, triple-layered
structure with 7.5- 10 nm thickness. The membrane has two parallel dense strata
each with 2.5nm thickness; these strata are separated by a light inter- zone of
nearly same thickness. Isolated vesicles are formed in the cell by the folding of
plasma membrane into the cytoplasm; these vesicles store extracellular material
by endocytosis process.

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3. Robertson's Model: Through an electron microscope. Robertson revealed

the tri-laminar structure of biological membrane. He observed two parallel dark
hydrophili layers (of 20-25Å width) and a middle light hydrophobic layer (of
25-35Å width) comprising the biological membrane. Organelles like nucleus,
mitochondria. endoplasmic reticulum etc. also have same tri-laminar membrane.
Robertson stated that biological membrane is composed of bimolecular lipid
layers sandwiched between outer and protein-layers.

4. The Fluid mosaic model– It was first proposed by S.J. Singer and Garth L.
Nicolson in 1972 to explain the structure of the plasma membrane. The model
has evolved somewhat over time, but it still best accounts for the structure and
functions of the plasma membrane as we now understand them. The fluid
mosaic model describes the structure of the plasma membrane as a mosaic of
components including phospholipids, cholesterol, proteins, and carbohydrates
that gives the membrane a fluid character. Plasma membranes range from 5 to
10 nm in thickness. For comparison, human red blood cells, visible via light
microscopy, are approximately 8 µm wide, or approximately 1,000 times wider
than a plasma membrane. The proportions of proteins, lipids, and carbohydrates
in the plasma membrane vary with cell type. For example, myelin contains 18%
protein and 76% lipid. The mitochondrial inner membrane contains 76% protein
and 24% lipid. The main fabric of the membrane is composed of amphiphilic or
dual-loving, phospholipid molecules. The hydrophilic or water-loving areas of
these molecules are in contact with the aqueous fluid both inside and outside the
cell. Hydrophobic, or water-hating molecules, tend to be non- polar. A
phospholipid molecule consists of a three-carbon glycerol backbone with two
fatty acid molecules attached to carbons 1 and 2, and a phosphate-containing
group attached to the third carbon. This arrangement gives the overall molecule
an area described as its head (the phosphate-containing group), which has a
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polar character or negative charge, and an area called the tail (the fatty acids),
which has no charge. They interact with other non-polar
non polar molecules in chemical
reactions, but generally do not interact with
with polar molecules. When placed in
water, hydrophobic molecules tend to form a ball or cluster. The hydrophilic
regions of the phospholipids tend to form hydrogen bonds with water and other
polar molecules on both the exterior and interior of the cell. Thus, Thu the
membrane surfaces that face the interior and exterior of the cell are hydrophilic.
In contrast, the middle of the cell membrane is hydrophobic and will not interact
with water. Therefore, phospholipids form an excellent lipid bilayer cell
membrane thathat separates fluid within the cell from the fluid outside of the cell.

Physiochemical properties.

The ability of a chemical compound to elicit a pharmacological/ therapeutic

effect is related to the influence of various physical and chemical
(physicochemical) properties of the chemical substance on the bio molecule that
it interacts with.

1) Physical Properties: Physical property of drug is responsible for its action

2) Chemical Properties: The drug react extracellularly according to simple
chemical
hemical reactions like neutralization, chelation, oxidation etc.
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Various Physico-Chemical Properties are

1. Solubility
2. Partition Coefficient
3. Dissociation constant
4. Hydrogen Bonding
5. Ionization of Drug
6. Redox Potential
7. Complexation
8. Surface activity
9. Protein binding
10. Isosterism

1.Solubility: The solubility of a substance at a given temperature is defined as

the concentration of the dissolved solute, which is in equilibrium with the solid
solute. Solubility depends on the solute and solvent as well as temperature,
pressure, and pH. The solubility of a substance is the ratio of these rate
constants at equilibrium in a given solution. The solubility of an organic
medicinal agent may be expressed in terms of its affinity/philicity or
repulsion/phobicity for either an aqueous (hydro) or lipid (lipo) solvent.
K
SOLUBILITY= KSOL/KPPT
The atoms and molecules of all organic substances are held together by various
types of bonds (e.g. London forces, hydrogen bonds, dipole-dipole, etc.). These
forces are intricately involved in solubility because it is the solvent-solvent,
solute-solute, and solvent-solute interactions that govern solubility.

Methods to improve solubility of drugs

1) Structural modification (alter the structure of molecules)
2) Use of Cosolvents (Ethanol, sorbitol)
3) Employing surfactants
4) Complexation

Importance of solubility
1) Solubility concept is important to pharmacist because it govern the
preparation of liquid dosage form and the drug must be in solution before it is
absorbed by the body to produce the biological activity.
2) Drug must be in solution form to interact with receptors.
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2.Partition coefficient: The ability of a drug to dissolve in a lipid phase when

an aqueous phase is also present, often referred to as lipophilicity. The
lipophilicity can be best characterized by partition coefficient. Partition
coefficient can be defined as the equilibrium constant of drug concentrations for
“unionizable” molecules in the two phases.

and for “ionizable” molecules (acids, bases, salts), where alpha (α) is the degree
of ionization in aqueous solution. It is basically a constitutive property.

Naturally, the partition coefficient is one of the several physicochemical

parameters influencing drug transport and distribution. The contribution of each
functional groups and their structural arrangement help to determine the
lipophilic or hydrophilic character of the molecule. Partition coefficient majorly
influence drug transport characteristics; the way in which the drugs reach the
site of action from the site of application (e.g. injection site, gastrointestinal
tract, and so forth). Since the blood distributes drugs, they must penetrate and
traverse many cells to reach the site of action.

Factors affecting Partition Co-efficient

1) pH
2) Co solvents
3) Surfactant
4) Complexation

Importance of partition coefficient

1) It is generally used in combination with the Pka to predict the distribution of
drug in biological system.
2) The factor such as absorption, excretion & penetration of the CNS may be
related to the log P value of drug.
3) The drug should be designed with the lowest possible
4) Log P, to reduce toxicity, nonspecific binding &bioavailability.
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3.Ionization of drug: The accumulation of an ionized drug in a compartment of

the body is known as”ion trapping”. The ionization of a drug is dependent on its
pKa and the pH. The pKa is the negative Logarithm of Ka. The Ka is the acidity
constant of a compound, its tendency to release a proton. The ratio of ionized/
non ionized drug may be determined by the Henderson- Hasselbalch
relationship. This may be used to derive an Effective partition coefficient : Ex:
Phenobarbital pKa is 7.4. It is evident that phenobarbital would be
predominantly in the unionised form in acidic environment.

Importance of ionisation of drugs

1) The lower the pH relative to the pKa greater is the fraction of protonated
drug (protonated drug may be charged or uncharged)
2) Weak acid at acidic pH : more lipid-soluble, because it is uncharged—the
uncharged form more readily passes through biological membranes. Note that a
weak acid at acidic pH will pick up a proton and become uncharged.
RCOO+H RCOOH
3) Weak base at alkaline pH : more lipid-soluble, because it is uncharged—the
uncharged form more readily passes through biological membranes. Note that a
weak base at more alkaline pH will lose a proton, becoming uncharged

RNH3 RNH2+H+

4. Hydrogen Bonding: The hydrogen bond is a special type of dipole-dipole

interaction between the hydrogen atom in a polar bond such as N—H, O—H,or
F—H and an electronegative atom O, N, or F atom. This interaction is written
as A—H ·············B. A and B represent O, N or F. A—H is one molecule (or)
part of a molecule and B is a part of another molecule; and the dotted line
represents the hydrogen bond. These three atoms usually lie along a straight
line, but the angle AHB can deviate as much as 30° from linearity.
Ex: Hydrogen bonding in NH3, H2O and HF.
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Generally the hydrogen bonding is classified into 2 types

a) Intermolecular hydrogen bonding
b) Intramolecular hydrogen bonding

(A) Intermolecular hydrogen bonding. In this type, hydrogen bonding occurs

between two or more than two molecules of the same compound and results in
the formation of polymeric aggregate. Intermolecular hydrogen bonding
increases the boiling point of the compound and also its solubility in water. The
molecules that are able to develop intermolecular hydrogen bonding improve
their solubility by the formation of intermolecular hydrogen bonding with
water. Ex: Ethanol shows higher boiling point and higher solubility in water
than dimethyl ether even though both have the same molecular weight.
(B) Intramolecular hydrogen bonding. In this type, hydrogen bonding occurs
with in two atoms of the same molecule. This type of hydrogen bonding is
commonly known as chelation and frequently occurs in organic compounds.
Sometimes intramolecular hydrogen bonding develops a six or 5-membered
ring. Ex:o-chlorophenol,o-nitro phenol.
Intramolecular hydrogen bonding decreases the boiling point of the compound
and also its solubility in water. This is because of the fact that the chelation
between the ortho substituted groups restricts the possibility of intermolecular
hydrogen bonding with water and thus prevents association of the molecules,
which would have raised the melting point, boiling point. o-Nitrophenol.-
215°C,p-Nitrophenol-279°C,m-Nitrophenol-279°C.

Effects of hydrogen bonding. Almost all physical properties are affected by

hydrogen bonding. Here only those properties that are prominently altered such
as boiling points, melting point, water solubility etc., are discussed. In addition
to physical properties several chemical properties like acid character, basic
character, properties of carbonyl group are also affected by hydrogen bonding.

5. Protein binding
The reversible binding of protein with non-specific and nonfunctional site on
the body protein without showing any biological effect is called as protein
binding.
Protein + drug Protein-drug complex
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Depending on the whether the drug is a weak or strong acid, base or is neutral, it
can bind to single blood proteins to multiple proteins (serum albumin, acid-
gycoprotien or lipoproteins). The most significant protein involved in the
binding of drug is albumin, which comprises more than half of blood proteins.
Protein binding values are normally given as the percentage of total plasma
concentration of drug that is bound to all plasma protein.

Free drug(Df) + Free protein(Pf) Drug /protein complex (Dp)

Total plasma concentration (Dt) = (Df) + (Dp)

6.Complexation or chelation:-Complexes or coordination compounds result

from a donor acceptor mechanism (donating accepting electron or, rather, an
electron pair) or Lewis acid-base reaction (donating-accepting protons). Any
non-metallic atom or ion, whether free or contained in a neutral molecule or in
an ionic compound, that can donate an electron pair, may serve as the donor.
The acceptor, or constituent that accept the pair of electrons, can be a metallic
ion or sometimes also a neutral molecule. In addition to “coordinate covalence”
(i.e., bonds formed by the classical electron donor-acceptor mechanism),
intramolecular forces can also be involved in the formation of complexes.
Complexes may be divided broadly into two classes depending on whether the
acceptor compound is a metal ion or an organic molecule.
The compounds that are obtained by donating electrons to metal ion with the
formation of a ring structure are called chelates. The compounds capable of
forming a ring structure with a metal atom are termed as Ligands. Most of the
metals are capable of forming chelates or complexes (if the metal is not in a
ring, the compound is called a metal complex), but the chelating property ís
restricted to atoms like N, O and S, which are electron donating.

Applications of chelation
The phenomenon of chelation ís significantly involved in biological system and
to some extent in explaining drug action.
1) Dimercaprol is a chelating agent. It is an effective antidote for organic
arsenical, Lewisite, but can aleo be used for treatment of poisoning due to
antimony, gold and mercury.
2) Penècillamine is an effective antidote for the treatment of copper poisoning
because it forms water-soluble theist. with copper and other metal ions.
3) 8-hydroxyquinoline and its analogs act as antibacterial and antifungal agents
by complexing with iron or copper.

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Bioisosterism
Bioisosterism is defined as compounds or groups that possess near or equal
molecular shapes and volumes, approximately the same distribution of electron
and which exhibit similar physical properties.
They are classified into two types.,
i) Classical biososteres
ii) Non classical bioisosters.

1.Classical Bioisosteres: They have similarities of shape and electronic

configuration of atoms, groups and molecules which they replace. The classical
bioisosteres may be,

A). Univalent atoms and groups:

i) Cl, Br, I
ii) CH3, NH2, -OH, -SH
B).Bivalent atoms and groups:
i) R-O-R,R-NH-R, R-S-R, RCH2R
ii) –CONHR, -COOR, -COSR
C).Trivalent atoms and groups:
i)-CH=, -N=
ii) –p=, -AS=
D).Tetravalent atoms and groups: =c=, =N=, =P=

E).Ring equivalent: -CH=CH-, -S-, -O-, -NH, -CH2-

Application of Classical Bioisosteres in drug design

i) Replacement of –NH 2 group by –CH3 group

Carbutamide R= NH2
Tolbutamide R= CH3
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ii)Replacement of –OH & -SH

Guanine= -OH
6-Thioguanine = -SH

2. Non classical Bioisosteres: They do not obey the stearic and electronic
definition of classicalisosteres.Non-classical biosteres are functional groups
with dissimilar valence electron configuration. Specific characteristics are

a) Electronic properties
b) Physicochemical property of molecule
c) Spatical arrangement
d) Functional moiety for biological activity.

Examples: Halogens Cl, F, Br, CN

Ether -S-, -O-
Carbonyl group
Hydroxyl group –OH, -NHSO2R, CH2OH
Catechol

Stereochemistry of drugs: Stereochemistry involve the study of three

dimensional nature of molecules. It is study of the chiral molecules.
Stereochemistry plays a major role in the pharmacological properties because;
1. Any change in stereo specificity of the drug will affect its pharmacological
activity
2. The isomeric pairs have different physical properties (log p, pKa etc.) and
thus differ in pharmacological activity.
The isomer which have same bond connectivity but different arrangement of
groups or atoms in the space are termed stereoisomer.

Conformational Isomers: Different arrangement of atoms that can be

converted into one another by rotation about single bonds are called
conformations. Rotation about bonds allows inter conversion of conformers.
A classical example is of acetylcholine which can exist in different
conformations
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Optical Isomers: Stereochemistry, enantiomers, symmetry and chirality are

impotant concept in therapeutic and toxic effect of drug. A chiral compound
containing one asymmetric centre has two enantiomers. Although each
enantiomer has identical chemical & physical properties, they may have
different physiological activity like interaction with receptor, metabolism &
protein binding. A optical isomers in biological action is due to one isomer
being able to achieve a three point attachment with its receptor molecule while
its enantiomer would only be able to achieve a two point attachment with the
same molecule.

The category of drugs where the two isomers have qualitatively similar
pharmacological activity but have different quantitative potencies.

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Geometric Isomerism: Geometric isomerism is represented by cis/trans

isomerismresulting from restricted rotation due to carbon-carbon doublebond or
in rigid ring system.

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Drug Metabolism

Metabolism is the body’s mechanism for processing, using, inactivating, and

eventually eliminating foreign substances, including drugs. Drug exerts its
influence upon the body, it is gradually metabolized, or neutralized. The liver,
the blood, the lymph fluid, or any body tissue that recognizes the drug as a
foreign substance can break down or alter the chemical structure of drugs,
making them less active, or inert. Drugs also can be neutralized by diverting
them to body fat or proteins, which hold the substances to prevent them from
acting on body organs. Once a drug is metabolized, it is the kidneys that
normally filter the neutralized particles, called metabolites, as well as other
waste and water, from the blood. Drugs can also be excreted out of the body by
the lungs, in sweat, or in feces. Drug metabolism is basically a process that
introduces hydrophilic functionalities onto the drug molecule to facilitate
excretion. Metabolism is defined as the process of polarization of a drug. This
results in the formation of a metabolite that is more polar and, thus, less able to
move into tissues and more able to be excreted from the body. Drug metabolism
is a detoxification function the human body possesses to defend itself from
environment hostility. Metabolism is a major mechanism of drug elimination.
The first human metabolism study was performed in 1841 by Alexander Ure,
who observed the conversion of benzoic acid to hippuric acid and proposed the
use of benzoic acid for the treatment of gout.

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PHASE I : REACTIONS

Phase I metabolism is likely to be the predominant pathway of

biotransformation. The enzymes involved in Phase I reactions are primarily
located in the endoplasmic reticulum of the liver cell, they are called
microsomal enzymes. Phase I reactions are non-synthetic in nature, and
generally produce more water soluble and less active metabolite. The most
common phase I reactions are oxidative processes (aromatic hydroxylation;
aliphatic hydroxylation; N—, O—, and S-dealkylation; N-hydroxylation; N-
oxidation; sulfoxidation; deamination; and dehalogenation), reductive (azodye-
reduction, nitroreduction) and hydrolytic reactions

Oxidation: Oxidation is normally the first step of drug metabolism. Mixed-

function oxidases or monooxygenases is an important complex enzyme
catalyses metabolic oxidation ofa large variety of endogeneous substances
(steroidal hormones) and exogeneous substances(drugs). Some important
metabolic oxidations are represented here:

Oxidation of carbon-heteroatom systems. Carbon-heteroatom systems (N, O,

S) are commonly present in many drugs. They are metabolized by any of the
following oxidation processes :

(a)Oxidation or hydroxylation of heteroatom: Ex: N-oxidation, N-

hydroxylation, S-oxidation.

(b)Hydroxylation of carbon atom attached to the heteroatom followed by

cleavage of carbon-heteroatom bond. Ex: N-dealkylation, S-dealkylation, O-
dealkylation.

1. Oxidation and hydroxylation of heteroatom

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N-Hydroxylation: Drugs containing non-basic

non basic nitrogen atom (amides), non-
non
basic aromatic amines and basicamines are metabolized by N-hydroxylation.
N
Ex:

N-Oxidation: Compounds possessing of basic nitrogen are metabolized by N-

N
oxidation process.

Ex: Tertiary amines yield N-oxides.

N

Compounds possessing of carbon-sulfur

S-Oxidation:Compounds carbon sulfur bonds are metabolized to
sulfoxides by S-oxidation.The
oxidation.The sulfoxides may be excreted as urinary
metabolites or oxidized to sulfones (—SO2—).
(

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2. Dealkylations. The second type of oxidative biotransformation comprises

dealkylations.

S-Dealkylation. S-Dealkylation involves oxidative cleavage of alkyl carbon-

sulfur bonds

N-Dealkylation. In the case of primary or secondary amines, dealkylation of an

alkyl group starts at the carbon adjacent to the nitrogen; in the case of tertiary
amines, with hydroxylation of the nitrogen (ex: Lidocaine).

O-Dealkylation. O-Dealkylation of drugs possessing C—O bond involves

hydroxylation of α-carbon to form an unstable hemiacetal or hemiketal
intermediates. These intermediates spontaneously cleave to form alcohol and
carbonyl compound.

Aromatic Hydroxylation: Aromatic hydroxylation is oxidation of aromatic

compounds into phenols through the intermediate formation of highly reactive
immediate i.e. arene oxide

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Ex: Many drugs containing phenyl groups (phenylbutazone,

(phenylbutazone, phenytoin,
amphetamine, phenformin etc.) are metabolized by aromatic hydroxylation.
hydroxylation

Oxidation of benzylic carbons: The carbons directly attached to aromatic rings

are oxidized to aldehydes and carboxylicacids via alcohols.
alcohols

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Oxidation of olefins:Alcofenac is oxidized to dihydroxyalcofenac.

2. Reductive reactions: Drugs containing carbonyl, nitro, and azo groups are
metabolized by reduction to alcohols and amines respectively. The reduced
compounds are conjugated and eliminated from the body. Ex :

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PHASE II : REACTIONS: Conjugation reactions are also known as phase-II

reactions. Phase II pathways are synthetic reactions where the product or the
metabolite from Phase I gets conjugated. This always produces a large, polar,
metabolite that is readily excreted from the body. Some drugs are mainly
conjugated and undergo very little oxidative metabolism.

Phase II occurs by glucuronidation, sulfation, aminoacid conjugation,

acetylation, methylation or glutathione conjugation to facilitate elimination.
Phase II conjugation introduces hydrophilic functionalities such as glucuronic
acid, sulfate, glycine, or acetyl group onto the drug or drug metabolite
molecules. These reactions are catalyzed by a group of enzymes called
transferases. Most trasferases are located in cytosol, except the one facilitates
glucuronidation, which is a microsomal enzyme. This enzyme, calleduridine
diphosphate glucuronosyl transferase (UGTs), catalyzes the most important
phase II reaction, glucuronidation.

Glucuronidation. Glucuronidation involves conjugation of metabolite or drug

molecule with glucuronic acid. In these reactions glucuronic acid molecule is
transferred to the substrate from a cofactor (uridine-51-diphospho-α-D-
glucuronic acid). Glucuronidation is catalyzed by various microsomal
glucuronyl transferases. Glucuronides are generally inactive and are rapidly
excreted into the urine and bile. Molecules associated with phenolic hydroxyl,
alcoholic hydroxyl, and carboxylic acid groups undergo glucuronidation
reaction.

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Sulfate Conjugation:Sulfate conjugation involves transfer of a sulphate

molecule from the cofactor (31- phosphoadenosine-51-phosphosulfate) to the
substrate (metabolite or drug moiety) by the enzymes (sulfotransferases).
Sulphate conjugation is the common conjugation reactions of substrate
molecules possessing of alcoholic hydroxyl, phenolic hydroxyl and aromatic
amine groups. Ex:

Hydrolysis: Hydrolysis is also observed for a wide variety of drugs. The

enzymes involved in hydrolysis are esterases, amidases, and proteases. These
reactions generate hydroxyl or amine groups, which are suitable for phase II
conjugation.

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Acetylation: Acetylation is an important metabolic pathway for drugs

containing primary amino groups. The acetylated conjugates are generally non-
toxic and inactive. Ex: histamine, procainamide, para aminosalicylic acid
(PAS), hydralazine, isoniazid.

Cytochrome p450: The cytochromes P450s [CYPs] are membrane bound

proteins with an approximate molecular weight of 50 kD, and contain a heme
moiety. There are about 30 human cytochrome P450enzymes out of which only
six, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4are the
metabolising enzymes.

Factors affecting the drug metabolism

A number of factors may influence the rate of drug metabolism. They are ;

1. Physicochemical properties of drugs. Molecular size, shape, acidity or

basicity, lipophilicity, pKa, and steric and electronic characteristics of drugs
influence its interaction with the active sites of enzymes.

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2. Chemical factors. A large number of chemical substances such as drugs,

insecticides etc. can increase the rate of drug metabolism due to increased rate
of formation of newer enzymes or decreased rate of degradation of drug
metabolising enzymes. Ex. Alcohol enhances metabolism of phenobarbitone,
phenytoin etc.

3. Diet. The enzyme content and activity is altered by a number of dietary

compounds. Fat free diet depresses cytochrome P450 levels since
phospholipids, which are important components of microsomes become
deficient.

4. Genetic or hereditary factors. Genetic and hereditary factors are the most
significant factors in drug metabolism. Genetic differences among individuals
or ethnic groups can lead to an excessive or prolonged therapeutic effect or
toxic overdose.Ex: The enzyme CYP2D6 metabolises a large number of drugs.
The activity of this enzymevaries widely among ethnic groups. About 1% of
Arabies, 30% Chinese and 7-10% caucasionsare poor metabolizers of CYP2D6
drugs.

5. Environmental factors: Environmental factors such as smoking, alcohol

consumption and concomitant drug therapy also influence the outcome of drug
metabolism. Ex: Cigarette smoke produces polynuclear aromatic hydrocarbons.
CYP1A2 metabolises the polynuclear aromatic hydrocarbons to carcinogens
responsible for lung and colon cancer.

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