Medicinal Chemistry I (Phar 2111)

Introduction to Medicinal Chemistry

By Fetene A.

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Medicinal Chemistry

 Medicinal Chemistry is a distinguished profile of pharmaceutical

chemistry that represents a link between organic chemistry and
biology/pharmacology.

 It deals with:
 The chemical and biological aspects of drugs.
 Designing new drugs.
 Studying deeply their mode of action at the molecular level.
 Construction of their structure-activity relationship and
metabolism.

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Definition of Medicinal chemistry
 Medicinal is a discipline at the intersection of chemistry and
pharmacology involved with designing, synthesizing, identification
and developing new pharmaceutical drugs.
 It also includes the study of existing drugs, their biological
properties, and their quantitative structure-activity relationships
(QSAR).
 Medicinal chemistry is a highly interdisciplinary science combining
organic chemistry with biochemistry, computational chemistry,
pharmacology, pharmacognosy, molecular biology, statistics, and
physical chemistry.

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4
 Definition, classification and nomenclature
of drugs
Definition of Drugs
 There is no single, precise definition
 Compounds which interact with a biological system to
produce a biological response.
 A drug, broadly speaking, is any substance that, when
absorbed into the body of a living organism, alters normal
bodily function.
 A drug is "a chemical substance used in the treatment, cure,
prevention, or diagnosis of disease or used to otherwise
enhance physical or mental well-being.
 In medicinal chemistry, the chemist attempts to design and
synthesize a medicine or a pharmaceutical agent which will
benefit humanity according to the above mentioned
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definition.
 Classification of drugs
1.By biological effect
 Analgesics, anti-asthmatics, antipsychotics, etc.
 Large and varied assortment of drugs
 Many mechanisms of action

2. By chemical structure
 Penicillins, opiates
 Common skeleton
 Functions similar or different
 Classifying drugs according to their chemical structural type has the
disadvantage, members of the same structural group often exhibit very
different types of pharmacological activity.
 Steroids for example, may act as hormones (testosterone), diuretics
(spironolactone) and antibacterial agents (fusidic acid).
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3. By target system
Antihistamines
Affect a target system (synthesis, release, receptor)
Variety of structures due to large number of stages
in system
4. By target site of action
Anticholinesterases (inhibit acetylcholinesterase in
CNS)
Target enzyme or receptor 7
Usually common mechanism
Nomenclature
 Drugs have 3 or more names:
1. Code number or code designate
2. Chemical name
3. Proprietary, trial, brand or trade name/mark
4. Non proprietary, generic, official or common name

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1. Code Number

 Usually formed with initial name of a laboratory, the chemist or

research team that prepared or tested the drug the first time and
followed by a No.

 It does not identify the chemical nature or structure of the drug.

 It is discontinued as soon as an adequate name is chosen.

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2. Chemical name

 It describes unambiguously the chemical structure of a drug.

 It is given according to the rules of nomenclature of chemical

compounds.

 Not suitable for routine use.

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3. The proprietary name [trade name, brand name] ®

 Is the individual name selected and used by the manufacturer.

 If a drug is manufactured by more one company, as frequently

happen, each firm assigns its own proprietary name.

 It should be written with capitalization of the first letter of each word

of the name.

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4. The nonproprietary name [generic name]

 Refers to the common established name, which a drug is known as an

isolated substance, irrespective of its manufacturer.

 It should be simple, concise, and meaningful but often it is not.

 The first letter is not capitalized.

 It is chosen by official agencies, such as the

 U.S. Adopted names (USAN) council, sponsored by American Medical Association
(AMA), the American Pharmaceutical Association (APA), the U.S. Pharmacopeia
(USP) convention and the U.S. Food and Drug Administration (FDA).

 The World Health Organization (WHO) is the official agency to select,

approve and disseminate names of drugs.

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Sources of Drugs
1. Natural Sources
 Drugs of natural origin can come from three sources:
 Mineral sources(9.1%)
 Various simple inorganic substances such as sulfur,
iodine and phosphates, calcium, sodium, magnesium,
iron and bismuth salts, etc.
 Animal Sources(8.7%)
 Some hormones (e.g. insulin) and fish liver oils
(vitamins A and E).
 Plants Sources(11.1%)
 The majority of natural compounds are of plant origin

e.g. alkaloids, cardiac glycosides, antibiotics and

anticancer drugs.
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2. Synthetic Sources
 The majority of drugs in use today are synthesized by
the medicinal chemist.
 The development of a synthesis offers challenge and
intellectual satisfaction. Design and synthesis can be
regarded as an art form.
 Synthetic drugs replace the natural compounds in
providing improved and simplified synthetic analogues.
The production of which is not dependent on
unpredictable botanical supplies.

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3. Semisythetic Sources
 Include microbial (antibiotics), vaccines and sera.
 Recently, bacteria have been enlisted as chemists to
produce complex natural products, e.g., recombinant
insulin by genetic engineering.
 The technology is called Recombinant DNA
Technology.
 It involves gene transfer to bacteria, production of the
peptide product formed by expression of the transferred
gene, and yielding the peptide product. It is worthy to
mention that laboratory peptide synthesis is tedious and
results in low yields.
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Drug targets-where do drugs work??
 Drug targets are macromolecules
– Drugs generally much smaller than targets
 Drug targets can be one of the following :
 Enzymes – proteins that catalyzed the body's chemical reactions.

 Receptors – most of them are proteins and are crucial to the body's
communication process.

 Nucleic acid – are two types DNA – act as the genetic blueprint for the
cell & RNA.

 Lipids and Carbohydrates

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 Drugs interact with targets through IFs
– Binding groups (functional groups on Binding
regions
drug) bind to binding sites/regions on
target Drug Binding
groups

 Most drugs are in equilibrium between

Intermolecular
forces
being bound and unbound to their
target Binding site

Binding Drug
site

Drug

Macromolecular target Macromolecular target

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Unbound drug Bound drug
Intermolecular forces

 Electrostatic interactions
 Ion-dipole
 Dipole-dipole
 Hydrogen bonding
 van der Waals/dispersion forces/hydrophobic
 Induced dipole interactions

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Electrostatic interactions
 Strongest of the intermolecular forces
 Attraction vs. repulsion
 Strength is inversely proportional to the distance between the ions
 Stronger interactions occur in hydrophobic environments
 Electrostatic attractions are the most important initial interactions as
a drug enters the binding site

O
Drug Drug NH3 O
O H3N Target Target
O

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Ion-dipole interactions
 Charge on one molecule interacts with the dipole of another

 Involved in solvation of ions in water

 Stronger than a dipole-dipole interaction

R O d-
C
d+
R R O d-
C
d+
O H 3N
O C R

Binding site Binding site

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Dipole-dipole interactions
 Occurs if the drug and the binding site have dipole moments
 Dipoles align as the drug enters the binding site
 Strength decreases with distance

d- O Dipole moment

d+ C
R R

Localized
d ipole moment R O
C

Binding site Binding site

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Hydrogen bonds
 Strongest dipole-dipole interaction
 Occurs between an electron-deficient hydrogen and an electron-rich
heteroatom
 The electron-deficient hydrogen is attached to a heteroatom (O or N)
 Hydrogen bond donor (HBD)

 The electron-rich heteroatom is O or N

 Hydrogen bond acceptor (HBA)

d- d+ d-
d- d+ d- Drug Y H X
X H Y Target Target
Drug
HBD HBA HBA HBD

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Hydrogen bonds

 Vary in strength
 The interaction involves orbitals and is directional

 Optimum orientation
 X-H bond points directly to the lone pair on Y
 Angle between X, H and Y is 180°

X H Y X H Y
Hybridized 1s Hybridized
orbital orbital orbital

HBD HBA

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van der Waals interactions
 Weakest IF
 Occur between hydrophobic regions
 Often hydrophobic pockets on the surface of target
 Transient areas of high and low electron densities
 Temporary dipoles
 The overall contribution of van der Waals interactions can be crucial
to binding

Hydrophobic regions DRUG

d+ d- Transient dipole on drug
d+ d-
van der Waals interaction

d- d+
Binding site
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 Drug design
and
Physicochemical properties of drugs
in relation with Biological action
Drug Design
A logical effort or approach adopted to develop therapeutic chemicals (drugs).

Two approaches of drug design.

Classical approach- Is known as a structure based drug design.
 Pharmacophore based drug design
Modern approach of drug design- Is target based drug design
needs:
Clear understanding of physiological and biochemical basis of the
disease process.
Understanding of the target properties (i.e.molecular characteristics,
3D)
An explicit chemical starting point

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 Physico-chemical properties in relation to
biological action
• 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:

 1.Solubility

 2.Acidity and basicity

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 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
♣hydrophobic..................water hating
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• 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.
• 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
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.).
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 a H+ 30
 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 SO2 NH2 + H2O R SO2 NH - + H3O
+ H2O R C
R C -
O
O H Sulfonamide
Carboxylic acid
O O
-
O O R
H R -
R + H2O R + H3O
+
N H + H2O
N + H3O+
R R
O O
Phenol
Imide
+ NH2
NH3
+
R + H2O R + H3O

Anilinium cation
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 2- Common basic organic functional groups

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

◙ Heterocyclic amines
◙ Aromatic amines (Ar-NH2)

R NH2 NH3 +
R +
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

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 Main Stages of drug design & development
 Searching the lead structures
 Optimizing pharmacokinetic and pharmacodynamic (PD-PK)
properties of the leads
 Design of suitable pharmaceutical forms and dosage regimens

 Successful process may take more than 10 years, spent

more than $300 million and tested more than 10000
compounds to get a single drug

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The discovery of new drugs or lead structure can
be achieved mainly by one of the following
routes
 Serendipity
 Random Screening
 Natural Products as Leads for Drug Discovery
 Drug Metabolites as Leads for Drug Discovery
 Clinical Observation of Side Effects of Drugs

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Molecular Modification or
manipulation(Lead Modification)
 Objective
 To obtain drugs having more desirable properties than
the prototype in
 Potency

 Toxicity

 Specificity

 Duration of action

 Ease of application, stability and cost of production

 Once the lead compound is in hand two main aspects

can be differentiated in molecular manipulation
A. General process
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B. Special process
A. General process
 Two general processes may be used in the method of
variation
1. Disjunction or molecular simplification
 It is the systematic synthesis and evaluation of the
simpler and simpler analogs of the lead compound.

H3CO2OC H3CO2OC
O N CH N CH O
3 O 3
N
O O O

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Another example is derivation of vitamin K3
from Vitamin K1

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2- Conjunction or Molecular Association
 It is the synthesis and evaluation of more and more complex
analogs of prototype. Three main types of association can be
distinguished:
i- Molecular addition: association of different moieties
Example is methenamine mandelate
O
N O
N
N NH HO
ii. Molecular Replication: association of identical moieties
through covalent bond formation (Identical twin drug). e.g.,
salicyl salicylate and Dicumarol
O HO
OH O

O CH2
O
CO2H
OH O
Salicylate salicylate Dicumarol
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Iii- Molecular Hybridization: association of
different or mixed moieties through covalent
bond formation. e.g., acetaminosalol (aspirin
with acetaminophen)

O O
O

O O
N
H

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B. Special process
 Several special processes for molecular modifications were
grouped in two classes
1- Alterations which increase or decrease the
dimensions and flexibility of a molecule
i- Ring closer or opening: e.g. nefopam from
diphenhydramine and diethylstilbsterol from
estradiol
OH
H OH
O O

N N
HO
Diphenhydramine Nefopam Estradiol DES

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ii- Formation of Lower or Higher Homologues:
 A homologous series is analogs that differ in their structure by
simple increment of molecular formula.
 For example, alkyltrimethylammonium analogs possess
different types of activity depending on the length of alkyl
groups:
CH3
H3C N+ (CH2)n CH3 Cl
CH3
 If alkyl group is up to 6 carbons (n = 5) the compounds are
muscarinic agonists
 With 7 to 8 carbons (n = 6 or 7), Compounds are partial
agonists
 Greater than 9 carbons (n = 8) these compounds are
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muscarinic antagonists
 iii. Introduction of Double Bonds: may cause
two main effects
 A- The possibility of the existence of geometrical isomery with different
activity-Trans (opposite side) and cis (same side) isomers.

 Example the synthetic estrogen diethylstilbestrol (DES) is a

tetrasubstituted ethene and exists in cis-trans forms.
OH
OH OH
OH

HO HO
HO
Estradiol E-DES HO
(Active) OH Estradiol and E-DES overlay
Z-DES
(Inactive) 42
 B- Altering physicochemical properties,
It can modify biological activity
Example is the conversion of morphinic receptor
agonists into the corresponding antagonists in
case of morphine.

HO O OH
Morphine
Nalorphine

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iv. Introduction of Chiral centers
 Receptors are chiral entities and the interactions of many drugs at
specific sites exhibit chirality of interaction.
 They clearly prefer synthetic compounds with absolute configuration
corresponding to the natural mediator. Thus changing the
stereochemistry of the drug molecule may significantly alter its
pharmacological activity.
 For example, the R(-)-isomer of epinephrine is more potent on both
- and -adrenergic receptors than the S(+)-isomer.

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45
 Enantiomers may have different therapeutic activities as
well levopropoxyphene (antitussive) and
dextropropoxyphene(analgesic)
H3C CH3
N N
H3C * * O O CH3
O O

(+)-Dextropropoxyphene (-)-Levopropoxyphene

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V- Introduction, Removal, or Replacement of Bulky
groups:
 used mainly to convert agonists into antagonists and vice versa
H H
N N
N N

Tolazoline Naphazoline
-Adrenergic antagonist -Adrenergic agonist
H3C H H
H3C NH2 N N
S
HN N HN N N
CN
4-Methylhistamine Cimetidine
H2-receptor agonist H2-receptor antagonist
 Another interesting example is found in -lactamase
resistant penicillin due to the introduction of bulky groups to
position 6 of penicillinic acid.

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2. Alteration of physico-chemical properties
i- Isosteric Replacements:
 Isosteres are molecules or groups of atoms that have the same
number and arrangements of electrons.
 For example, N2 and CO, N3- and NCO-. These substances have similar
physical properties.
 Bioisosterism or nonclassical isosteres are groups or molecules
which have chemical and physical similarities producing broadly
similar biological properties.
 In other words, they are compounds which fit the broadest definitions for
isosteres and have the same type of biological activity. H
-CO2H and –SO3H, as well as –CO- and –SO2-. OH
N OH

N S O
O
Phenyl Pyridyl T hiophenyl Carboxyl Carbamoyl

O O
S
Allyl Cyclopropylmethylene
O 48
Sulfonyl Carbonyl
Some of the examples of isosteric replacement that have provided
useful drugs are include
 A fluorine replacement of the hydrogen in uracil to give 5-
fluorouracil (5-FU), anticancer drug
 The exchange of the OH in hypoxanthine to give 6-
mercaptopurine (6-MP),
 A potent antitumor antimetabolite.

O
O OH SH
H
NH F N N
NH N N
N O N N
H N O N N
H H H
Uracil 5-FU Hypoxanthine 6-MP

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 The replacement of the ester function of procaine, a local
anesthetic, with an amide function produced
procainamide which has found an important role in the
treatment of cardiac arrhythmias.
O O
H2N N H2N N
O HN
 One of the oldest nonclassical isosteric replacements which
provided an important class of antibacterial agents was the
replacement of carboxylic acid group of p-aminobenzoic
(PABA) with sulfonamide group to give sulfanilamide.

H2N CO2H H2N SO2NH2

PABA Sulfanilamide

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ii- Change of Position or Orientation of Certain
groups:
 The position of certain groups is sometimes essential for
a given biological activity.
 For example, of the three isomers of hydroxybenzoic
acid only the o-hydroxy is active,
 Because it can form an intramolecular hydrogen bond
and in this way, it can act as a chelating.

O
HO O
CO2H CO2H H O
O M O
O
O
OH
OH Active O
Inactive

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iii- Modification toward Inhibition or
Promotion of Various Electronic states:
 Certain chemical groups produce two important electronic
effects, inductive and conjugative.
Electronic Density
Solubility
M H M X Modifies: Conformation
Bioavailability
Interactions

 Eg. The duration of action of the oral hypoglycemic

sulfonylureas - influenced by the substituent group in the
aromatic ring.

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 R SO2NHCONH(CH2)nCH3
The half-life of tolbutamide (R = CH3, n = 3, t1/2 5.6 hr) can be
significantly increased by replacement of methyl group by
chlorine as in chlorpropamide (R = Cl, n = 2, t1/2 25 hr)

O O O
S O O O
N N CH3
H H S CH3
N N
H3C H H
Tolbutamide Cl
Chlorpropamide

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Structure-Activity Relationships (SAR)
 Basically, activity of a drug either increases or decreases
as a result of some structure change (relative to the
prototype).
 A structure-Activity relationship (SAR) is a statement
of the effect of structure change on biological activity
within a congeneric series (a family) of compounds.
 With the structure change known and the biological
activity that accompanies this change, the medicinal
chemist can use the information to discover the optimum
drug.

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Introduction to prodrug design
 Prodrugs

 Prodrugs are compounds that are biologically inactive but are

metabolized to an active metabolite, which is responsible for
the drug’s action.
 They are classified as either bioprecursor or carrier prodrugs.
 Prodrugs may be designed to improve absorption, improve patient
acceptance, reduce toxicity and also for the slow release of drugs in
the body
 Drug latentiation- chemical modification to get prodrug

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Bioprecursor prodrugs
 Bioprecursor prodrugs are compounds that already contain the
embryo of the active species within their structure.
 Bioprecursors result from a molecular modification of the
active principle itself
 This modification generates a new compound, able to be a
substrate for the metabolizing enzymes (often, oxidation and
reduction)
 Examples for bioprecursor design based on oxidative bioactivation are the
cytotoxic agent cyclophosphamid. The activation involved oxidative
dealkylation followed by a spontaneous hydrolysis to the parent active
nitrogen mustard as shown in the following scheme:

Cl
Phosphamidase
HN

Cl

Nitrogen mustard
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 Sulindac (NSAID), on the other hand, is a representative
example for bioprecursor bioactivated by reduction

CO2H CO2H
F F
CH3 CH3
In vivo
Reduction

O
S S
CH3 CH3
Inactive Active

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Carrier prodrugs
 Carrier prodrugs are formed by combining an active drug with a carrier
species to form a compound with the desired chemical and biological
characteristics, for example, a lipophilic moiety to improve transport
through membranes.
 The link between carrier and active species must be a group, such as an
ester or amide, that can be easily metabolized once absorption has
occurred or the drug has been delivered to the required body compartment.
 The overall process may be summarized by:

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 Carrier prodrugs that consist of the drug linked by a functional
group to the carrier are known as bipartate prodrugs (Figure
below).
 Tripartate prodrugs are those in which the carrier is linked to
the drug by a link consisting of a separate structure.

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 Ampicillin Bacampicillin
amphoteric, 30-55% absorption week base, oral absorption 80-98%

hydrolysis

Ampicillin CO2 CH3 CHO C2H5OH

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A well designed carrier-prodrug satisfies the following criteria:
1. The linkage between the drug substance and the transport
moiety is usually a covalent bond.
2. As a rule the prodrug is inactive or less active than the parent
compound.
3. The linkage between the drug and the transport moiety must be
broken in vivo.
4. The prodrug as well as the transport moiety released in vivo
must be non-toxic.
5. The generation of the active form must take place with rapid
kinetics to ensure effective drug levels at the site of action.

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Applications of carrier – prodrug design
1- Improvement of lipophilicity
Dipivefrin HCl (Dipivaloylepinephrine) is a prodrug of epinephrine used in
treatment of open-angle glaucoma.

OH CH3
O O NH2 Cl
OH CH2
O
Esterase HO NH Cl
O O
+ OH
HO
Pivalic Acid
Epinephrine HCl
Dipivefrin HCl
2- Enhancement of water solubility-Water solubility of prednisolone, for
example, can be overcome through its C-21 hemisuccinate sodium prodrug.
This water-soluble derivative is extremely useful for parenteral
administration.
CH2OCOCH2CH2COONa
CHC
3
O
HO OH
CH3

O
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 3- Increased metabolic stability
 The antibacterial agent ampicillin decomposes in
concentrated aqueous solution as a result of
intramolecular attack of the side chain amino group on
the lactam ring, can be improved by designing Hetacilin
prodrug
bioactivity
depends on
this ring

acetone
as carrier

 The use of glycine as a carrier for the anti-inflammatory

tolmetin sodium results in the duration of its peak
concentration being increased from about one to nine hours.

short half-life 63
long half life
4. Improving patient acceptance
-Chloramphenicol has been derivatized to its palmitate ester to
minimize its bitter taste and to improve its palatability in
pediatric liquid suspensions
cause bitter taste sweetener
OH NHCOCHCl2
O2N CH CH CH2 O CO(CH2)14CH3

-Corrosive effect of acetic acid that hindered its topical

application as fungicidal agent has been overcome by its
glyceryl triacetate ester

CH2OCOCH3
CHOCOCH3
CH2OCOCH3
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5- Increased site-specificity
 Prodrug approach is a means to achieve targeting of drugs for
specific sites in the body
 Two targeting possibilities can be considered:
Site-Directed drug delivery-Prodrugs that affords an increased
or selective transport of the parent drug to the site of action or
localization of the parent drug in certain organs
Representative example is liver specific targeting which can be
achieved by coupling of drugs to modified bile acids
OH
CO2H

O H H
(CH2)n
Drug N H
H
Bile acids for liver specific targeting

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 Site-specific drug release-A derivative that goes everywhere but
undergoes bioactivation only inside the target organs
E.g. colon drug release by incorporation of the drug into azo
linkage as in case of sulfasalazine.

HO NH2 Amino salicylic acid

O N
H H3C
HO N N S N +
O N
O H
H2N S N Sulfapyridine
H3C
Sulfasalazine O

 One area where the site specific carrier prodrug approach has
been used with some degree of success is to design drugs
capable of crossing the blood–brain barrier.

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 This barrier will only allow the passage of very lipophilic
molecules unless there is an active transport mechanism
available for the compound.
 A method developed by Bodor and other workers involved the
combination of a hydrophilic drug with a suitable lipophilic
carrier, which after crossing the blood–brain barrier would be
rapidly metabolized to the drug and carrier.
 Once released, the hydrophilic drug is unable to recross the
blood– brain barrier.
 The selected carrier must also be metabolized to yield nontoxic
metabolites.

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68
6. Minimizing side effects
 Prodrug formation may be used to minimize toxic side effects.
For example, salicylic acid is one of the oldest analgesics
known.
 However, its use can cause gastric irritation and bleeding.
 The conversion of salicylic acid to its prodrug aspirin by
acetylation of the phenolic hydroxy group of salicylic acid
improves absorption and also reduces the degree of stomach
irritation, since aspirin is mainly converted to salicylic acid by
esterases after absorption from the GI tract.
 This reduces the amount of salicylic acid in contact with the
gut wall lining.

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QSAR in drug design
 The QSAR approach attempts to identify and quantify the
physicochemical properties of a drug and to see whether any
of these properties has an effect on the drug's biological
activity by establishing a mathematical relationship in the form
of an equation between biological activity and measurable
physicochemical parameters
 These parameters are used to represent properties such as
lipophilicity, shape and electron distribution, which are
believed to have a major influence on the drug’s activity.

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 The main properties of a drug that appear to influence its

activity are its, lipophilicity, the electronic effects within the

molecule and the size and shape of the molecule (steric

effects).

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 Lipophilicity is a measure of a drug’s solubility in lipid
membranes. This is usually an important factor in determining
how easily a drug passes through lipid membranes.
 The electronic effects of the groups within the molecule will
affect its electron distribution, which in turn has a direct
bearing on how easily and permanently the molecule binds to
its target molecule.
 Drug size and shape will determine whether the drug
molecule is able to get close enough to its target site in order to
bind to that site.
 The parameters commonly used to represent these properties
are partition coefficients for lipohilicity, Hammetts
constants for electronic effects and TaftMs steric constants
for steric effects 72
 QSAR derived equations take the general form:

 In which the activity is normally expressed as

log[1/(concentration term)], usually C, the minimum
concentration required to cause a defined biological response.
Lipophilicity
 Two parameters are commonly used to represent lipophilicity,
namely the partition coefficient (P) and the lipophilicity
substituent constant (p).
 The former parameter refers to the whole molecule whilst the
latter is related to substituent groups.

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Partition coefficient
 The relative distribution of drugs in organic medium/aqueous
system and can be obtained

 The n-octanol–water system is frequently chosen because it

appears to be a good mimic of lipid polarity and has an
extensive database.
 The relationship between P and drug activity for a wide range
of p values is given by

 Where k1, k2 and k3 are constants that are normally

determined by regression analysis.

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 too lipophylic

too polar

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Lipophilic substituent constants (p)
 Lipophilic substituent constants are also known as
hydrophobic substituent constants. They represent the
contribution that a group makes to the partition coefficient and
were defined by the equation:

 Where PH and PX are the partition coefficients of the standard

compound and its monosubstituted derivative, respectively.
 However, when several substituents are present, the value of p
for the compound is the sum of the p values of each of the
separate substituents.
 The value of p for a specific substituent will vary with the
structural environment of the substituent

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 A positive p value indicates that a substituent has a higher
lipophilicity than hydrogen and so will probably increase the
concentration of the compound in the n-octanol layer and by
inference its concentration in the lipid material of biological
systems.
 Conversely, a negative p value shows that the substituent has a
lower lipophilicity than hydrogen and so probably increases
the concentration of the compound in the aqueous media of
biological systems.
 Lipophilic constants are frequently used when dealing with a
series of analogues in which only the substituents are different.

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 As an example, consider the log P values for benzene (log P =
2.13), chlorobenzene (logP = 2.84), and benzamide (logP =
0.64).

 Since benzene is the parent compound, the substituent

constants for Cl and CONH2 are 0.71 and —1.49 respectively.

 Having obtained these values, it is now possible to calculate

the theoretical logP value for meta-chlorobenzamide:

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2. Electronic effects

 The distribution of the electrons in a drug molecule has a

considerable influence on the distribution and activity of a

drug.

 The first attempt to quantify the electronic effects of groups on

the physicochemical properties of arromatic compounds was

made by Hammett.

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The Hammett constant (σ)
 The Hammett substitution constant is a measure of the
electron withdrawing or electron donating ability of a
substituent and has been determined by measuring the
dissociation of a series of substituted benzoic acids compared
to the dissociation of benzoic acid itself.
 The distribution of electrons within a molecule depends on the
nature of the electron withdrawing and donating groups found
in that structure.
 Hammett used this concept to calculate what are now known
as Hammett constants (σx) for a variety of monosubstituted
benzoic acids

Where KH and KX are the equilibrium constants for benzoic acid

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and monosubstituted benzoic acids respectively.
 Its value varies depending on whether the substituent is an

overall electron donor or acceptor(withdrawing)

 A negative value for σX indicates that the substituent is acting

as an electron donor group since KH > KX.

 Conversely, a positive value for σX shows that the substituent

is acting as an electron withdrawing group as KH < KX.

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3. Steric effects
 In order for a drug to interact with an enzyme or a receptor, it
has to approach, then bind to a binding site.
 The bulk, size, and shape of the drug may have an influence on
this process.
 The first parameter used to show the relationship between the
shape and size (bulk) of a drug, the dimensions of its target
site and the drug’s activity was the Taft steric parameter
(Es).

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The Taft steric parameter (Es )
 Taft (1956) used the relative rate constants of the acid
catalysed hydrolysis of a-substituted methyl ethanoates to
define his steric parameter because it had been shown that the
rates of these hydrolyses were almost entirely dependent on
steric factors.
 He used methylethanoate as his standard and defined Es as:

 Where k is the rate constant of the appropriate hydrolysis and

the value of Es=0 when X = H.

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Hansch analysis
 Hansch analysis attempts to mathematically relate drug
activity to measurable chemical properties. It is based on
Hansch’s proposal that drug action could be divided into two
stages:
1. the transport of the drug to its site of action;
2. the binding of the drug to the target site.
 Hansch postulated that the biological activity of a drug could
be related to these parameters by simple mathematical
relationships based on the general format:

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 Where C is the minimum concentration required to cause a
specific biological response and k1, k2, k3 and k4 are
numerical constants obtained by feeding the values of the
parameters selected by the investigating team into a suitable
computer statistical package.

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 Metabolism of Drugs
Introduction
 Metabolism is the process of preparing foreign chemicals
for removal from the body.
 The function of drug metabolism:
 To transform into water-soluble derivatives, which can be
readily eliminated via renal route
 Partly responsible to terminate drug action
 one factor in determining the duration of action of drugs.

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Sites of metabolism
 The major site of drug metabolism: Liver
 Most drugs are metabolized by enzymes
 Which are intracellular
 normally associated with the metabolism of endogenous
constituents.
 Steroids, biogenic amines, etc.

 Classification of drug metabolism

• Drugs (xenobiotics) rarely undergo a single
metabolic pathway.

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Classification of drug metabolism
Phase I: Functionalization reaction
 New polar groups are introduced or revealed
 COOH, OH, NH2

 occurs via oxidative, reductive and hydrolytic reactions

Phase II: Conjugation reaction
 Links a solubilizing moiety
 Glucouronic acid, aminoacid, sulfuric acid
 To original drug (if polar group present) or
 phase I metabolite
 The general result of phase I and II metabolism:
 Inactivation and detoxication
 Activation [bioactivation of active or prodrugs]
 Toxic metabolites may also result
 Bioactivation of Non therapeutic chemicals.
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 fatts sterically hinders the
metabolizing enzyme

unable to cross cell membrane

92
see each
individually
couse its
fundamental
knowledge
from O. chem
93
THE END

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