Oct. 20141

PC 609

MEDICINAL CHEMISTRY -1

Pharmacists are the Drug Experts

3

Pharmacists are the drug

information specialists. Are we

qualified?

Oct. 20144

Medicinal chemistry is a discipline at the intersection

of chemistry, especially synthetic organic chemistry,

and pharmacology and various other biological specialties,

What is Med Chem?

involved with design, chemical

synthesis and development for

market

of pharmaceutical agents, or

bio-active molecules (drugs).

Oct. 20145

The objectives of the Medicinal Chemistry courses are to enable

the student to gain an understanding of the following general areas

of study:

Drug biotransformation.

Physicochemical properties and drug action.

The chemical structures of different drugs in each class;

their modes of action;

the correlation between chemical structures and biological activities (SAR);

evaluation of the activity of each drug and its selectivity

and the biotransformation.

Different synthetic pathways.

The drug-drug interaction.

Overall Aims of Course

What is Med Chem?

Medicinal Chemistry is the chemistry of Drugs

It deals with the chemical and biological aspects of drugs

It represents a link between chemistry and biology

Oct. 20146

Oct. 20147

What is Med Chem?

Medicinal Chemistry is the chemistry of Drugs.

What is important ?

Oct. 2014

The Chemical Structure; Why important?

Mode of action of Drugs. D-R interaction and Forces involved

Structure-Activity Relation (SAR)

Metabolism of drugs

Design of Drugs

Synthesis of Drugs

Analysis of Drugs

Nomenclature of Drugs (3 names)

8

Textbooks

Oct. 2014

Wilson and Gisvold’s Textbook of Organic Medicinal and

Pharmaceutical Chemistry

12th edition

by John M. Beale Jr. and John H. Block (Editors)

Lippincott Williams & Wilkins

2010

Foye’s Principles of Medicinal Chemistry

7th edition

T. L. Lemke, D. A. Williams (Editors)

Lippincott Williams & Wilkins

2012

9

Oct. 201410

Mid-Term Examination 10

Final-Term Examination 50

Oral Examination 15

Practical Examination(exam, activities, attendance, quizzes, …)

25

Total 100%

Weighting of Assessments

Oct. 201411

Topics Staff member

Drug biotransformation 3Prof. Dr. Said M. Bayomi

(7 x 3 = 21)β-lactam antibiotics and non β-lactam 4

Physicochemical properties and drug action 3

Prof. Dr. Eman R. El-bendary

(6 x 3 = 18)Antiviral 2

Antifungal 1

Sulfonamides 1

Dr. Moh. Abubakr

(7 x 3 = 21)

Antineoplastic agents 3

Antimycobacterial 1

Macrolides &Aminoglycosides 1

Tetracyclines 1

Important Terminology

Oct. 2014

• Pharmacophore

• Prototype (Lead)

• Prodrug

• Isosteric substitution

12

What is a drug (D)?

Drug is a chemical compound which is used to

prevent and / or treat diseases

( pharmacologically active compounds)

Sources of drugs

1- Natural source: Drugs obtained through the extraction

of plants such as Aspirin digitalis, quinine, morphine

2- Synthetic source: Drugs obtained through the random

screening of many synthetic chemicals and its

development

NOMENCLATURE OF DRUGS

-A drug is identified by three types of names:

1-Trade, Brand or Proprietary Name

This name is selected and used by the company that manufacturers it.

2- Generic or Non Proprietary Name

This name is chosen by official agencies e.g WHO (world and health organization)

3- Chemical nameThis name describes the exact chemical structure of the drug.Examples:

Generic name: diazepam.Trade names: valium, valpam, …, …., …..Chemical name:

N

N

Cl

O1 2

3

456

7

8

9

CH3

7-Chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one

H.W. 1

Trade name: tegretol, ….., …..

Generic name:

????

Chemical name:

???

Structure:

H.W. 2

Generic name: phenytoin

Trade name: ...., ….., ……

????

Chemical name:

????

CLASSIFICATION OF DRUGS:DRUGS CAN BE CLASSIFIED ACCORDING TO:(a) Chemical structure

e.g. penicillins, steroids…….etc.

(b) Pharmacological action

e.g. antihypertensive, analgesics….etc.

(c) Target system

e.g. cholinergic, adrenergic ………….etc.

(d) Mechanism of action at the molecular

level e.g. anticholinesterases, B-blockers……etc.

Where do drugs work?

Receptor (R):

Generally ,it is an integral biological macromolecule embedded in the biological

system. The four main targets (receptors) for drugs are lipids, carbohydrates, proteins and nucleic acids.

Receptor presents on the cell membrane or within the

cytoplasm or cell nucleus that binds to a specific

molecule (a ligand) such as a neurotransmitter or a

hormone or other substance, and initiates the cellular

response to the ligand.

TYPES OF RECEPTORS

a- Enzymes

e.g. Acetylcholeinestrase, carbonic anhydrase, adenylcyclase and monoamine oxidase.

b- Structural and functional component of a cell membrane which consists of lipoprotein.

c- Receptors of nucleic acid

e. g. DNA and RNA.d- Non enzymatic protein receptors

e. g. ( adrenergic receptors)

Drug Receptor Interaction

DRUG-RECEPTOR INTERACTION

Drugs interact with the receptors in a process known as binding forming D-R complexes which are responsible for the biological response.

There is usually a specific area of the receptor where this binding takes place and is known as binding site.

D + R D-R Complex

Biological Response

Drug-Receptor Interaction:

Not every drug that binds to a receptor activatesthe receptor.

Drug with good receptor fit, will produce apharmacological response and described as"agonist".

Drug which could deal with the receptor willproduce a reversed pharmacological response, andthe drug described as "antagonist".

Requirements for Drug-Receptor Interaction

1. Binding affinity:

Affinity of a drug to interact with receptor toform drug-receptor complex.

2. Intrinsic activity:

The exact fitness of the drug with the receptor. Itdifferentiates between agonist and antagonist,even both have the affinity towards the receptorbut they produce different responses.

3-Pharmacophoric group:

Is a part of the drug which associate with the receptor and considered as an essential part to produce pharmacological action e.g. Phenothiazine derivatives must have phenothiazine ring as a pharmacophoric group to produce their pharmacological action as tranquilizers.

N

S

Cl

CH2CH2CH2N(CH3)2

Chlorpromazine

STRUCTURE-ACTIVITY RELATIONSHIP (SAR):

Structure-Activity Relationship (SAR) is the relationship between the structure of a particular compound or a group of compounds and its (their) biological activity.

N

S

OCOOH

HN

O

N

S

O

COOH

HN

O

O

Benzylpenicillin Phenoxymethylpenicillin

What happens to the drug after its administration?

Liberation

Absorption

Distribution

Metabolism

Excretion

FATE OF DRUG

MAJOR PHASES INVOLVED IN DRUG ACTION

1. The Pharmaceutical Phase

2. The Pharmacokinetic Phase

3. The Pharmacodynamic Phase

PHARMACEUTICAL PHASE

-It involves the time from the administration of the drug till the release of the active principle.

Thus include processes of disintegration and dissolution, now the drug is available for absorption.

The liberation of the drug from the

pharmaceutical dosage form.

PHARMACOKINETIC PHASE

This phase include the time from the release of active principle till the drug reaches its site of action (receptor).

Pharmacokinetics describes how the body affects a specific drug (ADME)? after administration.

Pharmacokinetics includes the study of absorption, distribution, metabolism and excretion process of an administered drug.

PHARMACODYNAMIC PHASE

-It involves the interaction of the drug with the receptor.

The drug will be expected to dissociate from the receptor and re-enter the circulation to be excreted except ?

Physicochemical Properties of Drugs in Relation to Biological

Activity

Physico-Chemical properties

• Disintegration

• Dissolution

• Absorption

• Distribution

• Metabolism

• Excretion

• D-R binding

February 28, 2016M Bakr36

• Solubility

• pKa

• Lipophilicity

• Electronic effects

• Functional groups

• Steric effects

• Stereochemical properties

• …..

some factors affecting pharmaceutical and Pharmacokinetic phases

Disintegration, Dissolution, Absorption, Distribution,

Metabolism, Excretion

1. Solubility

2. Partition coefficient

3. Drug's pKa

4. Electronic and steric parameters

The term solubility refers to

solubilization of the drug in the

different media, polar solvent as water

(hydrophilic character) and non-polar

solvent as lipid (hydrophobic or

lipophilic character).

1- Solubility

A] Water solubility:

The solubility of a drug molecule in watergreatly affects the routes of administration thatare available as well as its absorption,distribution, and elimination

Two key concepts to keep in mind whenconsidering the water (or lipid) solubility of amolecule are:

1-The hydrogen bond.

2-The ionization of functional groups.

1- HYDROGEN BONDS

Each functional group capable ofdonating or accepting a hydrogen bondwill contribute to the overall watersolubility of the compound and increasethe hydrophilic nature of the molecule.

Hydrogen bonds are referred to asdipole-dipole bonds.

Fig. 1: Examples of Hydrogen-Bonding Between water and Hypothetical Drug Molecules.

N

H

H

O

HH

O

H

H

O

HH

O

RR

O

H

H

H

O

H

2- IONIZATION

Another type of bonding interaction plays animportant role in determining water solubility, it isan ion-dipole interaction. Basic drug accept protonand acidic drug loss proton at physiological pH andat the receptor.

Fig. 2: Examples of Ion-dipole Interactions.

N

H

HO

H

H

h

O

O

O H

H

Water and lipid solubility

In a drug structure, hetero-atoms (O, N) and functional groups capable of forming hydrogen bond and ionized bonds with water molecules represent the water solubleor hydrophilic part of the drug molecule.

Carbon skeleton (number of carbon atoms) & halogenatoms as F, Cl, Br or I represents the lipophilic or water insoluble part of the molecular structure since they are incapable to form any bonding with water molecules.

Water and lipid solubility

Ionizable and polar functional groups

increase water solubility e.g. OR,

NH2, COOH, C=O, -O-, O-C=O, OCH3, ..............etc.

• Halogens (F, Cl, Br & I), alkyl groups (CH3, CH3-CH2-, CH3-CH2-CH2-, ), cycloalkyl

(cyclopentanyl, cyclohexanyl, ), aryl gps(phenyl) and others, in addition to sulfur are

water insoluble.

PRODRUG APPROACH TO ALTER THE DRUG SOLUBILITY

Prodrugs are compounds that are inactive in their native form, but are easily metabolized to the active agent .

Example : Methylprednisolone

Methylprednisolone

Solu-Medrol

Water soluble

parenteral formula

HO

O

OH

O

O

O

O

O.Na

CH3

Methylprednisolone sodium succinate

HO

O

OH

O

O

O

CH3

Methylprednisolone acetate

February 28, 2016 M Bakr 46

Depo-Medrol

Lipid soluble

long-acting

In side the body, the ester linkage will be cleaved by the effect of esterase enzyme giving the active drug.

ON THE OTHER HAND SUCCINATE ESTER MAKES IT MORE SOLUBLE MAKING INTRAVENOUS FORMULATION

MORE EFFECTIVE

The active drug

HO

O

OH

O

O

O

O

O.Na

CH3

Methylprednisolone sodium succinate

esterase

B] LIPID SOLUBILITY AND ABSORPTION

OF DRUGS

Some drugs, even they are in the un-ionized

form, they are poorly absorbed by passive

diffusion from GIT, this is because of their low

lipid solubility.

A guide for the lipid solubility or the lipophilic

nature of a drug is known as partition

coefficient (p.c.).

[drug] lipid [drug] octanol

P.C. = =

[drug] water [drug] water

For simplicity log P.C. is used instead of P.C.

Hydrophobic (lipophilic) compounds will

have a high log P and achieve good

absorption from GIT.

[drug]octanollog P.C. log

[drug]water

The hydrophobicity constant (π)

Practical estimation

π = logPx – logPlogP is the log partition coefficient of unsubstituted compound e.g. benzene.

logPx is the log partition coefficient of substituted compound e.g chlorobenzene.

logP calculated of a drug of known chemical structure = Σπ

If The hydrophobicity constant of a particular

group ,π (fragment constants) is negative

value , (like COOH, CN, NO2, SO2CH3),

(hydrophilic). It means that the substituent

increases water solubilityof a parent

compound.

•If The hydrophobicity constant,π (fragment

constants) is positive value, (like CH3, C3H7, C4H9,

Cl), ( lipophilic). it means that the substituent

increases liposolubility of a drug.

Significance of π

3. DISSOCIATION CONSTANT (pKa ):

Henderson-hassalbach equation can be used to calculate the

percentage ionization of a compound at a given pH.

[conj. base]pH = pKa + log

[acid]

Because pKa is a constant for any given molecule, the ratio of

acid to base will determine the pH of the solution. Conversely,

a given pH determines the ratio of acid to base.

Drug's Ionization State (Drug's pKa):

• Most drugs are either weak acids that donate proton and form conjugated base or weak bases that accept proton and form conjugated acid.

-[A ] [ionized acid]pH=pKa+log =pka+log

[HA] [undissociated acid]

HA + H2O H3O+ + A-

weak acidunionized form

conjugated baseionized form

B + H2O BH+ + OH-

weak baseunionized form

conjugated acidionized form

B+H + H2O H3O++ Bprotonated acidionized form

conjugated baseunionized form

Model to understand how the environment can shift

the pKa of a functional group

pH=0 pH=14

-COOH -COO-

-NH3+ -NH2

pK = 4.76

pK = 10.66

PKa of strong acid < 2

PKa of weak acid 4-6

PKa of weak base 8-10

PKa of strong base >12

The stomach has a pH of 1-3,

in the duodenum pH from 5 to 7 and increase gradually till reaching pH 8 in the colon.

MANY DIFFERENT ORGANIC FUNCTIONAL

GROUPS BEHAVE AS ACIDS OR BASES

Organic functional groups that cannot give up

or accept a proton are considered to be "neutral"

or non-electrolyte with respect to their acid-base

properties.

AMPHOTERIC DRUG: THAT IS, ACT AS AN ACID OR

A BASE, DEPENDING ON THE CONDITION (PH OF THE MEDIUM).

Example: Ciprofloxacin, a fluroquinolone

antibiotic contains:

A secondary alkyl amine

Two tertiary arylamines

A carboxylic acid.

N

O

N

COOHF

HN20 amine

(basic)

Carboxylic

acid

(acidic)

30 arylamine

(weak base)

Fig. 1: Chemical Structure of Ciprofloxacin Showing the Various Organic Functional Groups.

4. ELECTRONIC AND STERICPARAMETERS

February 28, 201661

End of Part 1