Introduction: History & Development: Physicochemical Properties in relation to biological action: Ionization Solubility Partition Coefficient Hydrogen Bonding: Protein Binding: Chelation: Bioisosterism: Optical & Geomentrical Isomerism Drug Metabolism: Drug Metabolism Principles: Phase I & Phase II Factors Affecting Drug Metabolism including steriochemical Aspects

1. Introduction of Medicinal
Chemistry
Presented BY…….
Prof. Namrata Baravkar
Department- Pharmaceutical Chemistry
RJSPM College of Pharmacy

2. • Content –
• Introduction:
• History & Development:
• Physicochemical Properties in relation to biological action:
1. Ionization
2. Solubility
3. Partition Coefficient
4. Hydrogen Bonding:
5. Protein Binding:
6. Chelation:
7. Bioisosterism:
8. Optical & Geomentrical Isomerism
• Drug Metabolism:
• Drug Metabolism Principles: Phase I & Phase II
• Factors Affecting Drug Metabolism including steriochemical Aspects

3. Introduction:
• A branch of chemistry in which the features of
biological, and pharmaceutical sciences are studied, is
termed as medicinal chemistry.
• The study of invention discovery, design, and
preparation of biologically active compounds. Their
metabolism, mode of action at the molecular level, and
the structure - activity relationships are also covered
under this branch.
• The studies in medicinal chemistry involve a
combination organic chemistry with biochemistry,
computational chemistry pharmacology,
Pharmacognosy molecular biology, statistics, and
physical chemistry.

4. History & Development:
• Medicinal chemistry is a discipline or intersection of organic chemistry, biochemistry, anatomy-physiology and
pharmacology.
• There is a long history of plants being used to treat various disease, specially in early civilizations of Egypt, India,
China.
• In beginning of 19th century, the isolation of a no. of alkaloids including:
➤ 1803 →Morphine
➤ 1823→Quinine
➤ 1833→Atropine
Was used in Medicinal Chemistry.
• In 1860:- Synthesize the semi-synthetic/fully synthetic derivatives of these plant origin.
Example:
➤ 1892 → Benzocaine from cocaine
➤ 1899 → Aspirin from salicin
• In 1869:- Crum-Brown & Fraser
Proposed that cells can respond to the signal from molecule specific
1890:- Ehrlich
Expressed the idea of specific receptor for biologically active compounds.
Lock and Key relation

5. • In 1890-1940:- 1st Phase of Modern Medicinal Chemistry.
The development of effective drugs for the treatment of Tuberculosis, Typhoid, Malaria,
Infective Tetanus, Cholera etc. hepatitis,
• In 1910-1946: → Dale and Ablquist
1st proposed the receptor sub-types for cholinergic receptor.
• In 1936 → Sulphonamide.
• In 1940 → Penicillin Antibiotics.
• In 1949 → Chloramphenicol & Tetracycline.
• In 1940-1980 → Second Phase of Modern Medicinal Chemistry.
• In 1945-1965 → Golden Era
Introduction of all modern therapeutic classes.
Examples:
 1949 → Corticosteroids
➤1950 → Antipsychotics
➤ 1955 → Antidepressants
➤1957 → Hypoglycemic
➤ 1959 → Contraceptives
In 1960: The teratogenic effect (Birth of deformed children when mother consumed the drug during pregnancy)
came to limelight after thalidomide (Sedative).
In 1964:- "Birth of QSAR" By Haunch.

6. Physicochemical properties of relation to Biological action.
• Physicochemical properties & stereochemistry of drug molecules influence
on it's Biological Activity.
• 1] Ionization
• 2] solubility
• 3] Partition coefficient
• 4] Hydrogen bonding
• 5] Protein Binding
• 6] chelation
• 7] Bioisosterism
• 8] Optical & Geometrical isomerism.

7. 1] Ionization-
The property of any atom or molecule losing / gaining electrons acquiring +ve+ -ve
charge.
ExampleCH3-COOH → H+ +CH₃Coo
Drug Intake
( Unionized)
Absorption-Drug
Reaches in Blood
(Ionized)
→
↓
Distribution-Drug
reaches to site of
action
←
Drug need to cross the
cell membrane which
is made up of
phospholipids which is
turns in lipiphilic in
nacture
Drug-
Unionized=Lipophilic
Ionized=Hydrophilic

8. • Ionization state of drug molecule influences it's water solubility as well as ability to traverse membrane-
• The ionized form gives the of medication gives strong water solubility which is necessary for effective drug-
receptor binding.
• Ionized & non-ionized form allows the drug is required for improved pharmacodynamics & pharmacokinetic
propertis.
• most of the drugs favors passive transportation for the un-ionized form of drug.
Relation in biological Action:
i] ionization plays important role in pharmacokinetics
ii] Good balance of ionized unionized form is better for pharmacokinetics.
iii] unionised form of drugs- lipophilic- easily cross cell membrane
iv] ionised form of drugs - Hydrophilic →Better water solubility of drug which is necessary for binding of drugs
& it's receptor
V) Drug must be weakly acidic or basic in nature. Acid base properties of drug molecules directly affect
absorption, excretion and compatibility with other drugs in the solution.
Weakly acidic:
• present in non-ionic form
• diffuse more rapidly through cell membrane
• have higher absorption in stomach.
• eg- Aspirin

9. Weakly Basic
• present in non-ionic form
• diffuse more rapidly
• have higher absorption in intestine.
• eg Diazepam
eg- Biological activity of salicylic acid increases in acidic PH as compared to basic or neutral PH While Basic
drugs increase at Basic PH.
. 2] solubility:
Maximum amount of solute that can be dissolved in loo ml of solvent at given temp called solubility of drug.
solubility depends on-
 Nature of solute & solvent
 Temperature.
 PH
 Pressure
Methods to improve solubility of drug-
1]Altering structure of drug
2] complexation
3] Addition of surfactants
4) Use of co-solvents

10. • Relation in biologication Action
1) Drugs must be in solution & interact with receptor
2) Drug must be in solution before it can be absorbed by biological Membrane & shows activity.
3) Higher solubility = Higher Bioavailability.
As the bioavailability of drugs from liquid orals mainly depends on their solubility in the given solvent system,
it is one of the important parameters for assessing the absorption of drugs into the systemic circulation.
Lipinski et al. found that poor absorption or permeability is seen when –
(i) Compound has molecular weight above 500 (Atomic mass unit)
(ii) Compound has log P > 5
Sparingly soluble salts derived from weak acids tend to be more soluble in an acidic solution.
(i) Acidic drugs: e.g., barbiturates, NSAIDs
(ii) Basic drugs: e.g., phenothiazine, β-blockers
(iii) Amphoteric: e.g., tetracycline, ACE-Is
Insufficient solubility of the compound influence both pharmacokinetic and pharmacodynamic properties of the
compound. Hence, good solubility ensures good bioavailability and good ability of the drug to react its target
sites at effective concentrations

11. Partition coefficient
The Partition coefficient is defined as the ratio of unionized drug distributed between
organic Phase & aqueous phase at equilibrium
Formula:
Partition coefficient = concentration of Drug in organic phase / concentration of drug in
aqu.Phase.
K= Co/Cw
If – K>L= lipophilic
K<L = Hydrophilic.

12. Importance-
1]Affect drug absorption & distribution.
2] Help to know whether the drug is lipophilic or Hydrophilic.
3] Partition coefficient determines what tissues a given compound can reach.
4]It is important in explaining MOA of Anticonvulsants & general anaesthetics.
• The partition coefficient determined in the solvent system having pH nearly in the range of pH at
the site of absorption gives a better understanding of drug absorption. Hence partition coefficient
serves as a good physicochemical guide to estimate % absorption of the drug.
Barbiturate Partition
Coefficient
% Absorption
1. Barbital 0.7 12
2.Phenobarbital 4.9 17
3. Butethal 11.7 24
4.
Cyclobarbitone
13.9 24
5. Pentobarbital 28 30
6. Secobarbital 507 40

13. 4] Hydrogen bonding:
The hydrogen bond is a special dipole-dipole interaction between the hydrogen atom in a polar bond such as
N-H, O-H or F-H & electronegative atom O, N, F atom.
Dipoles result from unequal sharing of electrons between atoms within a covalent bond.
These are weak bonds and denoted as dotted lines. O-H.......O, ΗΝ-Η...Ο,• The compounds that are capable,
of forming hydrogen bonding is only soluble in water.
Hydrogen bonding is classified into 2 types:
1. Intermolecular
2. Intramolecular
1) Intermolecular hydrogen bonding:
It is occur between two or more than two molecules of the same or different compound.• Due to this increase
the boiling point of the compound & increase the molecular weight of compound hence more energy is
required to dissociate the molecular for vaporization.

14. Intermolecular Hydrogen Bonding
2) Intramolecular Hydrogen bonding:
1. H-bonding occurs within two atoms
of the same molecules.
2. This type of bonding is known as
chelation and frequently occurs in
organic compounds.
3. Sometimes H-bonding develop six or
five member rings• Due to decrease
the boiling

15. • In relation to biological :
• Intramolecular hydrogen bonding decrease the melting-boiling point and solubility.
• Intermolecular hydrogen bonding increase the melting-boiling point and solubility
• Important for drug receptor interaction
• Though H-bonds are relatively weak bonds their presence may have a profound effect on the
biological action of a drug.
• For Example: (1) 1-phenyl-3-methyl-5-pyrazolone shows no analgesic properties while 1-phenyl-
2,3- dimethyl-5-pyrazolone (antipyrine) is a well known analgesic agent. This effect appears to be
best explained by the fact that the first compound through intermolecular H-bonding forms a linear
polymer

16. • The resulting large attractive force between molecules lowers the solubility, especially in the non-
polar solvents which are not capable of breaking the H-bonds
• (2) Salicylic acid (o-hydroxy benzoic acid) has quite an appreciable antibacterial activity, but the
para isomer (p-hydroxyl benzoic acid) is inactive, because salicylic acid is the ortho isomer that can
form intramolecular H-bonds.
• The m- and the p-isomers can form only intermolecular H-bonds.
• Salicylic acid is less soluble in water than the p-isomer but its partition coefficient (benzene water) is
approximately 300 times greater, while p-hydroxy benzoic acid has low partition coefficient and
hence low anti-bacterial action. In salicylic acid, intramolecular H-bond has the phenolic hydroxyl
group masked but the carboxylic acid group is free and can function as an anti-bacterial agent similar
to benzoic acid.

17. 5] Protein Binding:
• Protein Binding: process by which drug molecule gets attach protein molecule and forms a
complex
After the absorption of drugs, when drug reaches into systematic circulation binds with
plasma protein and forms a plasma protein drug complex.

18. • 2 types of complex are formed
• ➤ Reversible
• ➤ Irreversible
• REVERSIBLE- in this the bonding between protein and drug is very weak like van-
derwaals force or hydrogen bonding which can detach easily. Drug become free and then this
drug bind with receptor and give its pharmacological action.
• IRREVERSIBLE- in this the bonding between protein and drug is very strong like covalent
which does not detach easily. So that drug does not become free hence no binding occurs
resulting to no pharmacological action.
• In relation to biological Action-
• Influence the bioavailability and distribution of active compounds.
• Complex and free drug form are important for complete pharmacological action.
• Facilitate the distribution of drugs.
• Develop at a receptor site.
• Retard the excretion of a drug
• The interaction of drugs to protein may cause:

19. • Inactivates the drug biologically by forming a drug-protein complex.
• 6] chelation:
• Chelation/Complexation basically traps metal ions and can either solubilize them or prevent their
precipitation and thus, can deprive the microorganisms from getting metal ions If the complex of the metal
ion and the ligand (electron donor molecule to the metal); is cyclic then it is called as a chelates.
• However complex is cyclic then it is called as organo metallic complex.
Drug Complexing Agent Drug Complex
• In relation to biological action:
• complexes of drug molecules cannot cross the natural membranous barriers, they render the drug biologically
ineffective.
• The rate of absorption is therefore, proportional to the concentration of the free drug molecules i.e., the
diffusible drug.
+ →

20. • Due to the reversibility of the complexation, there always exists an equilibrium between
the free drug and the drug complex.
• Such equilibrium is represented below:
Drug + Complexing Agent ←→Drug Complex
Complexation reduces the rate of absorption of the drug but does not affect the total
availability of it, because the absorption of the free drug molecules shifts the equilibrium to
the right, causing the free drug molecules to be released from the drug complex.
Example:
Tetracycline have been known to form complexes with divalent and trivalent cations, which
are much less effectively absorbed

21. Bioisosterism:
• Bio means life and sterism means same electronic configuration
• Eg- N2 and CO have same electronic configuration
• Bio-isosteric replacement is the principal guide followed by medicinal chemists in developing analogues of
the 'lead' compound, whether as agonists or antagonists of biological effects.
• While any change or modification of critical part of the drug molecule will result in the change of its
biological activity, only those groups having similar steric, electronic and solubility characteristics can be
interchanged. The study of such groups (bio-isosters) and their application in medicinal chemistry is
known as Bio-isosterism.
• More recently Burger classified and subdivided bio-isosters as:
• (1) Classical bio-isosters: Physical, Chemical Properties, Biological Action, Electronic Configuration
same
• (a) Monovalent atoms and groups, e.g. CH2 , NH2 , OH and SH.
• (b) Divalent atoms and groups, e.g. R–O–R', R–NH–R', R–CH2–R' and R–Si–R‘
• (c) Trivalent atoms and groups, e.g. R – N = R', and R – CH = R'
• (d) Tetrasubstituted atom, e.g., = C =, = N r =, and = P r =
• (e) Ring equivalents, e.g. – CH = CH –, – S –, – O – , – NH and – CH2 –
• Example- Guanine and Thioguanine

22. • (2) Non-classical bio-isosters: Physical, Chemical Properties,Biological Actionsame but differ in Electronic
Configuration
• These non-classical bio-isosters do not rigidly fit the steric and electronic rules of the classic bio-isosters.
These are further subdivided into,
• (a) Exchangeable groups
(b) Rings versus non-cyclic structures.
Isoproterenol Sorterenol

23. • In relation to biological Action:
• To change bioavailability and reduce toxicity
• In drug design, the purpose of exchanging one bioisosters for another is to enhance the
desired properties with
• out change in their structure

24. 8) Optical & Geomentrical isomerism.
• Stereochemistry helps to define the structure of a molecule and orientation of the atoms and functional
groups present, in three dimensions.
• Stereoisomers possess the same molecular and structural formulae and the same functional groups but
differ in the threedimensional spatial orientation of these atoms or groups within the molecule.
• Due to the difference in orientation of the functional group and geometry of the molecule, stereoisomers
differ in their physical, chemical, physicochemical and biochemical properties
• (a) Geometrical isomers (cis-trans isomerism) :
• Maleic acid (m.p. 130°C) and fumaric acid (m.p. 287°C) have the same molecular formula but differ in
the arrangement of functional groups around double bond. They have different physical and, to some
extent, chemical properties. This type of isomerism is known as geometrical isomerism.
Example-cis-Diethylstilbestrol has only 7% of the
oestrogenic activity of trans- diethylstilbestrol
cis-Diethylstilbestrol
trans-
diethylstilbestrol

25. (b) Optical Isomerism (enantiomerism) :
• A carbon atom connected to four chemically different functional groups is known as asymmetric or chiral
carbon and the presence of at least one asymmetric carbon atom in the structure is the pre requirement for
a molecule to show optical isomerism.
• If there is one asymmetric carbon then two optically active isomers are possible. Isomer rotating plane of
polarized light to the right is said to be dextrorotatory.
• while isomer showing rotation to the left is known as levorotatory.
• Both isomers are mirror images of each other yet are not superimposable. They are called as enantiomers
and the pair of enantiomers is called as enantiomorph. An enantiomer does not possess a plane or center
of symmetry.
Example:
L-Dopa is rapidly absorbed from gut by active
transport processes, whereas dextro enantiomers
of dopa are more slowly absorbed