Medicinal chemistry I

(Phar 2111)

Dec 2023

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Medicinal Chemistry
 Medicinal Chemistry is a distinguished profile of
pharmaceutical chemistry that represents a link between
chemistry and biology.

 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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1.1 Definition of Medicinal chemistry

 Medicinal chemistry involves the identification, synthesis and

development of new chemical entities suitable for therapeutic
use.
 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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1.2. Definition classification and
nomenclature of drugs

What Is A Drug?
 A drug is any substance presented for:
 Treating, curing or preventing diseases in humans or animals.
 Correcting or modifying physiological functions of the body.
 Making a medical diagnosis.
 In medicinal chemistry, the chemist attempts to design and
synthesize a medicine or a pharmaceutical agent

to benefit humanity according to the above mentioned definition.

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Classification
 Drugs could be classified by

i. Pharmacological action
e.g. Analagesics, Diuretics, Bronchodilators. Hypnotics, Antivirals,
Antimalarials etc…

ii. Chemical structure

e.g. Steroids, Alkaloids, Quinolones, Glycosides,

Betalactam etc…

iii. Their target of action

e.g. Adrenergics, Dopaminergics, Cholinergics…..

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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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Sources of Drugs
2. Synthetic Sources (48.9%)
 The majority of drugs in use today are synthesized by
the medicinal chemist.
 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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Sources of Drugs
3. Semisythetic Sources (9.5%)
 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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How are New Drugs
Discovered?

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 Drug discovery: Finding a
lead
 When a pharmaceutical company or
university research group initiates a new
medicinal chemistry project through to the
identification of a lead compound, they will
consider the following steps in order:
 1-Choosing the disease
 2- Choosing drug target
 3-Identifying a bioassay
 4-Finding a lead compound
 5-Isolation and purification
 6-Structural determination
 7-Herbal medicine
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 I- Choosing the disease
 Pharmaceutical companies tend to concentrate
on developing drugs for diseases which are
prevalent in developed countries, and aim to
produce compounds with better properties
than existing drugs.
 Pharmaceutical companies have to consider
economic factors as well as medical ones
when they decide which disease to target
when designing a new drug.
 A huge investment has to be made towards
the research and development of a new drug.
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 I- Choosing the disease
 Therefore, companies must ensure that they get a good
financial return for their investment.
 As a result, research projects tend to focus on diseases
that are important in the developed world, because it is
the best market for new drugs.
 Thus, research is carried out on ailments such as
migraine, depression, ulcers, obesity, flu, cancer and
cardiovascular disease.
 Less is carried out on the tropical diseases of the
developed world. Only when such diseases start to
make an impact in richer countries, the pharmaceutical
companies sit up and take notice.
 Example: research in antimalarial drugs has increased
due to increase in tourism to more exotic countries and
the spread of malaria into southern states of US.
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 II- Choosing a drug target
 Choosing which disease to tackle is usually
a matter for company’s market strategists.
The science becomes important at the
next stage.
 A molecular target is chosen which is
believed to influence a particular disease
when affected by a drug.
 The greater the selectivity that can be
achieved, the less chance of side effects.
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 III-Identifying a bioassay

 Choosing the right bioassay or test system is

crucial to the success of a drug research program.
 The test should be simple, quick and relevant as
there are usually a large number of compounds to
be analyzed.
 Human testing is not possible at such early stage,
so the test has to be done in vitro first. Because in
vitro tests are cheaper, easier to carry out, less
controversial and can be automated than in vivo
one.
 In vivo tests needed to check the drugs interaction
with specific target and to monitor their 20
 III-Identifying a bioassay

 In vitro test
 In vivo tests
 Test validity
 High-through screening
 Screening by NMR
 Affinity screening

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 III-Identifying a bioassay
 In vitro tests: do not involve live animals. Instead,
specific tissues, cells, or enzymes are isolated and used.
 In vivo tests on animals often involve inducing a clinical
condition in the animal to produce observable symptoms.
 High throughput screening (HTS) involves the
miniaturization and automation of in vitro tests such that a
large number of tests can be carried out in a short time.
 Nuclear Magnetic resonance (NMR) was used as a tool
for determining the molecular structures of compounds
 Recently, compounds can be tested or screened for their
affinity to a macromolecular target by NMR spectroscopy. 22
 IV-Finding a lead compound
 Screening of natural products (the plant
kingdom, the microbial world, the marine world,
animal sources, venoms and toxins)

 Medical folklore
 Screening synthetic compound “ libraries”
 Existing drugs
 Starting from natural ligand or modulator
(natural ligands for receptors, natural
substrates for enzymes, enzyme products
as lead compounds, natural modulators as 23
IV-Finding a lead compound
 Combinatorial synthesis
 Computer aided design
 Serendipity and prepared mind
 Computerized searching of
structural databases
 Designing lead compounds by
NMR

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 Genesis of Drugs

 The procedure followed in drug design involves:

1. The search for the lead structures or prototype (a well-established
chemical substance of known biological activity)
2. Molecular manipulations aimed for optimizing pharmacokinetic and
pharmacodynamic (PD-PK) properties of the leads
3. Design of suitable pharmaceutical forms and dosage regimens.
 The discovery of new drugs or lead structure can be achieved
mainly by one of the following routes:

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A. Serendipity

 Accidental discovery of drugs in the laboratories or clinics

by pharmacists, physicians or other investigators.
 E.g. Antibacterial action of penicillin was first observed by
Fleming (1929) in a culture of bacteria that was
contaminated by a fungus.
 The anti-inflammatory, analgesic and antipyretic
activities of phenylbutazone were discovered while it was
being used solely as a solubilizing agent for aminopyrine.

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B. Random Screening

 All available chemical substances are submitted to a

variety of biological tests in the hope that some may
show useful activity.
 Not very rewarding.
 E.g. It is estimated that for a new anticonvulsant
discovery through this process it might be necessary to
screen 500,000 chemical compounds.

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C. Rationally directed random screening

 e.g. the search for new antibiotics from microorganisms

after the discovery of penicillin result in the recognition of
more than 600 antibiotics, more than 100 of which are
used in medicine.

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D. Natural Products as Leads for Drug
Discovery

 Morphine, atropine, ephedrine, curare

and many others
 have binding affinities to certain receptors,
enzymes, etc., and
 are thus useful as lead structures for drug
discovery.

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 E. Drug Metabolites as Leads for Drug
Discovery

 For example the acetanilide and acetophenetidin are

metabolized to acetaminophen, which exerts the main
analgesic actions.

OH OC2H5

O NH O NH O NH
CH3 CH3 CH3
Acetanilid Acetaminophen Acetophenetidin

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F. Clinical Observation of Side Effects
of Drugs

 Innumerable examples can be found in the

literature, such as
 the hypoglycemic effect of some antibacterial
sulfonamides, and
 the hypertensive effect of -blocking agents.
 the antidepressant effect of isoniazid

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 G. Me too drugs

 Many companies use established drugs from their

competitors as a lead compound in order to design
a drug.
 By modifying the structure in such way that avoids
the patent restrictions, retain the activity, and
improved the therapeutic properties.
 For example i) Captopril (Anti-hypertension) used
as lead compound by different companies to
produce their own anti-hypertension drugs.
 ii) Modern penicillins are more selective, more 32
H. Rational Approaches

 Rational approaches to drug design have now become the

major routes to lead discovery.
 The key information that permits rational approaches to
drug design is
 knowledge of the etiology of a given diseases or at least
the biochemical processes that are disturbed.

 Examples of the rational approach are the discovery of the

 inhibitors of the angiotensin-converting enzyme and

 histamine H2-receptors antagonists

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Molecular Modification or Manipulation

 A lead compound is one which shows some useful

biological activity.

The level of activity may not be very great and there may be
undesirable side effects

 The objectives of lead structures modification is 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

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 I. 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
N CH N CH O
O 3 O 3
N
O O O

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2- Conjunction or Molecular
Association

 It is the synthesis and evaluation of more and more

complex analogs of prototype. These analogs
incorporate certain or all features of the lead compound.
 Three main types of association can be distinguished:
i. Molecular addition:
 association of different moieties through weak forces
such as electrostatic attraction and hydrogen bonding,
example is methenamine mandelate.
O
N O
N
N NH HO

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ii. Molecular Replication:
 Association of identical moieties through covalent bond
formation (Identical twin drug) e.g., salicyl salicylate.
This is also can be found among several natural
products e.g., 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 (non-identical twin drug) e.g.,
acetaminosalol
O
(aspirin with acetaminophen).

O NH
O

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 II. Special Process
 Several special processes for molecular modifications were
grouped in two classes
A. Alterations which increase or decrease the dimensions and
flexibility of a molecule, this can be achieved through the
following:

i. Ring closer or opening:

 Several examples are found of new drugs designed by
either closure of a chain (e.g. nefopam from
diphenhydramine) or opening of a ring (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 in molecular formula.
 These may be produced by sequential chemical
changes, which include increasing or decreasing the
length of a carbon chain.
 For example, alkyltrimethylammonium analogs possess
different types of activity depending on the length of
alkyl groups:

CH3
H3C N+ (CH2)n CH3 Cl
CH3
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 If alkyl group is up to 6 carbons (n = 5) the compounds
are muscarinic agonists.
 With 7 to 8 carbons (n = 6 or 7), these compounds are
partial agonists.
 However, when the length is greater than 9 carbons (n
= 8) these compounds are muscarinic antagonists.

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iii. Introduction of Double Bonds:

 The introduction of double bonds may cause two main

effects:
 The possibility of the existence of geometrical isomers
with different activity
 e.g., unsaturated propylamine H1-antagonists, will be
discussed later.
 The synthetic estrogen diethylstilbestrol (DES) is a
tetrasubstituted ethane and exists in cis-trans forms.

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 The trans isomer is much more active than the cis
isomer.
 The reason is that the trans geometric isomer
resembles the estrogen (estradiol) structure and better
fits the estrogen receptor (designed by nature to fit
estrogens) to bring about estrogen-like response.
 Here the shape of trans-DES positions the two hydroxyl
groups for hydrogen
OH bonding to the receptor.
OH OH
OH

HO HO
HO
Estradiol E-DES HO
(Active) OH Estradiol and E-DES overlay
Z-DES
(Inactive)
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 Altering physicochemical properties,
 Another 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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 The binding of epinephrine isomers and epinine (the

desoxy analog of epinephrine) is illustrated below.

 Only R isomer can bind to all three sites, while both the

S isomer and the deoxy isomer, which show similar

activity, can bind to only two of these sites.

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 Enantiomers may have different therapeutic activities
as well. CH3
H3C
N N
H3C * * O O CH3
O O

(+)-Dextropropoxyphene (-)-Levopropoxyphene

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v- Introduction, Removal, or Replacement of Bulky
groups:
 This approach is used mainly to convert agonists into
antagonists and vice versa as illustrated by the following
examples: H
N H
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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Other possible modifications

i- Isosteric Replacements:
 Replacement or modification of a functional group with
another group having similar properties is known as
isosteric or bioisosteric replacement.
 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.

Grimm’s Hydride Displacement Theory

C N O F CH4
CH NH OH FH
CH2 NH2 OH2
CH3 NH3

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 Bioisosterism or nonclassical isosteres are groups or
molecules which have
 the same chemical and physical properties
 producing broadly similar biological properties.
 do not necessarily have the same number of atoms as the
substituent they replace.
H
OH
N OH

N S O
O
Phenyl Pyridyl T hiophenyl Carboxyl Carbamoyl

O O
S
Allyl Cyclopropylmethylene
O
Sulfonyl Carbonyl

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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.
 E.g 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.
 These effects can alter deeply physical and chemical
properties and therefore, biological activity.

Electronic Density
Solubility
M H M X Modifies: Conformation
Bioavailability
Interactions

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 For example, the duration of action of the oral
hypoglycemic sulfonylureas is mainly influenced by the
substituent group in the aromatic ring.
 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
R 25 hr). SO2NHCONH(CH2)nCH3

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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.

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Bioprecursor prodrugs

 Bioprecursor prodrugs are compounds that already

contain the embryo of the active species within their
structure.
 This active species is liberated by metabolism of the
prodrug

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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.
 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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 The design of prodrug systems
for specific purposes

 The introduction of a carrier into the structure of a drug to form a

prodrug may be used to change a drug’s bioavailability. In some
cases has been used to direct the drug to specific areas.
A. Improving absorption and transport through membranes
 The transport of a drug through a membrane depends largely on
its relative solubility in water and lipids.
 Good absorption requires that a drug’s hydrophilic–lipophilic
nature is in balance. The lipophilic nature of a drug may be
improved by combining a lipophilic carrier with a polar group (s)
on the drug.

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 However, it is difficult to select a lipophilic carrier that
will provide the degree of lipophilic character required. If
the carrier is too lipophilic, the prodrug will tend to
remain in the membrane.
 Similarly, improving the water solubility of a drug may
be carried out by introducing a carrier with a water
solubilizing group or groups.

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B. Improving patient acceptance

 Odour and taste are important aspects of drug

administration.
 A drug with a poor odour or too bitter a taste will be
rejected by patients, especially children.
 Furthermore, a drug that causes pain when
administered by injection can have a detrimental effect
on a patient.
 The formation of a carrier prodrug can sometimes
alleviate some of these problems. For example, palmitic
acid and other long chain fatty acids are often used as
carriers, since they usually form prodrugs with a bland
OH NHCOCHCl2
taste.
O2 N CH CH CH2 O CO(CH2)14CH3

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 C. Slow release
 Prodrugs may be used to prolong the duration of action by
providing a slow release mechanism for the drug.
 Slow release and subsequent extension of action is often
provided by the slow hydrolysis of amide and ester linked
fatty acid carriers.
 Hydrolysis of these groups can release the drug over a
period of time that can vary from several hours to weeks.
 For example, 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.

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 D. Site specificity

 In theory, it should be possible to design a carrier prodrug that

would only release the drug in the vicinity of its site of action.
 Furthermore, once released, the drug should remain mainly in
the target area and only slowly migrate to other areas. In
addition the carrier should be metabolized to nontoxic
metabolites.
 Unfortunately, these requirements have only been achieved in
a few cases.
 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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 E. 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

 QSAR (quantitative structural activity relationship) is a

mathematical relationship in the form of an equation between
biological activity and measurable physicochemical parameters.
 It is an attempt to remove the element of luck from drug design
 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.
 They are normally defined so that they are in the form of numbers,
which are derived from practical data that is thought to be related
to the property the parameter represents.

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 This makes it possible to either to measure or to
calculate these parameters for a group of compounds
and relate their values to the biological activity of these
compounds
 Using of mathematical equations using statistical methods
such as regression analysis.

 These equations may be used by the medicinal chemist

to make a more informed choice as to which analogues
to prepare.

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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).
 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.

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 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.

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 The parameters commonly used to represent
these properties are
1. Partition coefficients for lipohilicity,
2. Hammett s constants for electronic effects
and
3. TaftMs steric constants for steric effects

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 QSAR derived equations take the general form:

 In which the activity is normally expressed as

log[1/(concentration term)], where
 C is the minimum concentration required to cause a
specific biological response and
 k1, k2, k3 and k4 are numerical constants.

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