Introduction to Medicinal Chemistry

Dr. Soha Telfah

Assistant Professor,
Pharmaceutical Medicinal Chemistry,
Faculty of Pharmacy,
Philadelphia University-Jordan
 Learning Outcomes
At the end of this lesson students will be able to

 Outline the basic concepts of Medicinal Chemistry.

 Describe about drug, targets, roles of medicinal
chemistry in drug design and discovery.
 Describe the basic concepts of pharmacokinetics and
pharmacodynamics.
 Explain the fundamentals of receptors and drug-receptor
interactions.
 Introduction to Medicinal Chemistry

 Medicinal Chemistry is the science that deals with

the design and development and modification of
pharmaceutical agents that has a desired biological
effect on human body and other living systems.

 Drug is a compound that interact with a biological

target to produce a biological response:-
Biological target: Human, bacteria, fungi,
….(COX 1 COX 2: examples)
Biological response: desired or undesired
(side effect).

Medicinal chemists concern about the synthesis of
new molecules to investigate the relationships
between the chemical structure of these compounds
and their biological activities. SAR
CADD: computer aided drug design

Medicinal chemistry also involves isolation of
compounds from natural sources.
Relationship with phytochemistry


Ideal drug must be:-
 Not toxic
 Effective and potent
 Selective
 Easily administered
 Cheap

(example : Paracetamol)
Penicillin: one of the safest and most active
antibiotics……BUT….. Resistance developed to most
of them.

Morphine: a very effective pain killer….. BUT…. May

cause tolerance, addiction and respiratory
depression.

Heroin: the best pain killer we know….BUT….

addiction developed (still used in terminal cancer).
 Poisons can be drugs at lower doses:-
 Arsenicals: very toxic but used as antiprotozoal
agents.

Tubocurarine:- It used as muscle relaxant.

Arrow poison
 Drug might be harmful at higher doses:

 Therapeutic index =

it is the ratio of the dose leads

to toxic effect in 50% of cases to that leads to
therapeutic effect in 50% of the cases.
high dose
Drug poison
low dose

 Large therapeutic index…… safer drug.

 narrow therapeutic index…… more toxic drug.
(digoxin, warfarin)
 Selective Toxicity

Selective Drugs: that show toxicity against

abnormal cells without affecting normal cells.
Ex: anticancer drug ( low selectivity: still have side
effect)
Degrees of selectivity:-
 No effect on normal host cells (ex: Penecillin).
 Killing certain microbial strain without affecting
others (especially normal flora).
 Targeting certain metabolic pathway without
affecting others. : folic acid pathway (vitamin B9)
 Drug Targets

They are macromolecules (receptors,

enzymes, DNA or transport proteins).

Drugs interact and bind to the binding sites

through intermolecular bonds (ionic, H-bonds,
van Der Waals, dipole-dipole and hydrophobic).
Sterically (size, shape and orientation) and
electronically binding
The bonds mainly are weak, therefore in most of
the cases this binding is reversible.
 Interactions involved between
drug and receptor

Covalent bonding Irreversible bond

Anticancer, antimicrobial PPI

Ionic (electrostatic)
full opposite charges

Dipole-dipole interaction
Partial opposite

H-bonding
Partial negative with polarised hydrogen Reversible bonds

Hydrophobic interaction
Entropy not enthalpy

Van der Waals forces

Transient opposite charges
 Hydrophobic
Ionic bonding interaction

Dipole-dipole
interaction O N
H
OH
Aromatic
interaction or
pi –pi stacking
HN

O
Hydrogen bonding
H
X

Practolol inside the adrenergic B-receptor

N
OH Cl
HO N
O O
O
O Cl
Hyoscine Chlorambucil (Leukeran)
Anti-cholinergic for chronic leukemia

O O
H2N Pt O
NH2

Oxaliplatin
 Human FAS
fatty acid synthase

Orlistat
 Pharmacokinetics
Pharmacokinetics: How the drug distribute
and reach its target (AD ME) and what will
happen to the drug.
(Drug -receptor interaction) pharmacodynamics
Pharmacokinetics – what the body does to the
drug.
How does drug get into the body? absobrption
How long does it take to exert its action? Onset of
action
How long does it stay in the body? Duration of action
“pt compliance “
Where does it go to in the body? distribution
Is it metabolised to another form? Metabolism
Inactive. metabolism Active (Prodrug)
The [plasma drug] -time curve after
drug administration
 ADME Acronym
Pharmacokinetics
Which route?
Which formulation? Drug administered First pass effect

Metabolic
Drug absorbed
inactivation
Which barriers to cross? Passive diffusion?
Gut, skin, lungs? Active transport? By pumps, ex: proton pump
Stability at the site of absorption? Blood-brain barrier penetration?

Pool of non-available available

Drug in the tissues Drug in the plasma Excretion

•Plasma-protein
binding? Example zwitterion
• Electrostatic charge like penicillins
•Tissue-protein Decrease
binding? Drug at the site
•Fat storage?bone?
of action
 Pharmacokinetics
Drug administration: How is the drug to be
formulated? If as an injection, is it soluble in
aqueous solution? If as a tablet, will it dissolve
when released in the gut?
Tablet disintegration dissolution absoprption
Drug absorption: can the drug pass through the
barrier membranes in the GIT? Can it pass through
the skin barriers? These barriers are made up in a
large part by lipids, so the drug must be sufficiently
lipophilic/ unionized to diffuse through them.
Membranes have phospholipids bilayer that act as
barriers to the movement of drugs within the body
Polar head: phosphate (-)
Non-polar tail
 Pharmacokinetics

Drug metabolism: Metabolism increases the

water solubility of drugs by enzymatically
introducing polar functional groups so that
they can be excreted. What is the chemistry of
the drug? How fast is it inactivated? Is it
converted into more active or even toxic
components?

Drug excretion: Kidney excretes water-soluble

metabolites and the ionized forms of drugs.
*
 Pharmacodynamics
Pharmacodynamics: How the drug interacts
with its target.

Pharmacodynamics: What the drug does to

the body.

What is the therapeutic effect of the drug?

How does it exert its effect? Ex: Signal transduction
How does the drug interact with the
target?
Can the effect be modified? SAR
 Pharmacodynamics


More than 90% of drugs have biological targets to bind with
in order to exert their pharmacological effects.

Biological targets: are endogenous macromolecules including
DNA, RNA, enzymes, receptors, membrane proteins, etc…

The nature of drug-receptor binding

Either reversible or irreversible.
Reversible binding means that the drug-target
complex will dissociate to release the free functioning
target.
Irreversible binding means permanently blocking the
binding site of the target… irreversible damage.
DNA

Protein
1. An introduction to Medicinal Chemistry by Graham L. Patrick. 4th
edition, Oxford, 2009
2. Wilson and Gisvolds text book of organic medicinal and
pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th
edition, Lippincott Williams and Wilkings 2011.
3. Foyes principle of medicinal chemistry by David H. Williams, Thomas
L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th
edition, 2013.