International University of

Africa
Faculty of Pharmacy
Medicinal Chemistry
MCHM 311
Siddieg Omer Elsiddieg, M. Sc,
B. Sc (Honors)
 Class Policies and Rules
 Language of Instruction

 Attendance Policy

 In-Class Conduct

 Class Materials

 Office Hours

 Laboratory, Homework, Assignments, and Term Paper

 Exams and Grading Policy

 Academic Integrity
 Class Contents
 Introduction to Medicinal Chemistry
 Physicochemical Properties of Drugs in Relation to
Biological Activities
 Receptors: Structures and Functions
 Principles of Drug Design
 Drug Metabolism
 Factors Influencing Drug Metabolism
 Toxic Effects of Drug Metabolism
What Is Medicinal Chemistry?
 “ A chemistry-based discipline, involving aspects of
biological, medical and pharmaceutical sciences. It is
concerned with the invention, discovery, design,
identification, and preparation of biologically active
compounds, the study of their metabolism, the
interpretation of their mode of action at the molecular
level and the construction of structure activity
relationships (SARs), the relationship between chemical
structure and pharmacological activity for a series of
compounds.”
“is the applied science that is focused on the design (or
discovery) of new chemical entities (NCEs) and their
optimization and development as useful drug
molecules for the treatment of disease processes”.
In achieving this mandate, the medicinal chemist must:
 Design and synthesize new molecules.
 Ascertain how they interact with biological
macromolecules (such as proteins or nucleic acids).
 Elucidate the relationship between their structure
and biological activities.
 Determine their absorption and distribution
throughout the body.
 Evaluate their metabolic transformations.
 Medicinal Chemistry is Interdisciplinary:

 Theoretical Chemistry
 Organic Chemistry
 Analytical Chemistry
 Molecular Biology
 Pharmacology
 Biochemistry

Bottom Line:
Design and synthesis of new drugs
 How Did we Arrive Here?
A brief History of Medicinal Chemistry
Ideas, tools, and knowledge that advanced contemporary
medicinal chemistry
Drugs of Antiquity
 Fats, Oils, honey, wax and milk were used
 Mud, and Salts were used for wound dressing
 Fried Ox Liver for blidness
The Middle Ages
 The use of Antimony salts as alixirs
The Nineteenth Century
 Expansion of chemical knowledge
 Focus on finding the active ingredients in the plants
and animal remedies (e.g. isolation of morphine).
 Increased use of pure substances
 Birth of pharmaceutical industry
The twentieth Century
 Domagk discovery of sulfa drugs (Prontosil)
 Discovery of penicillin
 Modern medicinal chemistry
What are Drugs?
A drug molecule possesses one or more functional
groups positioned in three-dimensional space on a
structural framework that holds the functional groups
in a defined geometrical array that enables the
molecule to bind specifically to a targeted biological
macromolecule, the receptor.
The structure of the drug molecule thus permits
a desired biological response, which should be
beneficial (by inhibiting pathological processes) and
which ideally precludes binding to other untargeted
receptors, thereby minimizing the probability of
toxicity.
The framework upon which the functional groups are
displayed is typically a hydrocarbon structure (e.g.,
aromatic ring, alkyl chain) and is usually chemically
inert so that it does not participate in the binding
process. The structural framework should also be
relatively rigid (“conformationally constrained”) to
ensure that the array of functional groups is not
flexible in its geometry, thus preventing the drug
from interacting with untargeted receptors by altering
its
molecular shape
To be successful in countering a disease process,
however, a drug molecule must have additional
properties beyond the capacity to bind to a defined
receptor site.

It must be able to withstand the journey from its point

of administration (i.e., the mouth for an orally
administered drug) until it finally reaches the
receptor site deep within the organism (i.e., the brain
for a neurologically active drug)
Receptor macromolecules are frequently proteins or
glycoproteins. Certain properties must be present if a
macromolecule is going to have what it takes to be a
druggable target. The receptor macromolecule must
be intimately connected with the disease in question,
but not integral to the normal biochemistry of a wide
range of processes.
A drug is most effective when its structure or a
significant part of its structure, both as regards
molecular shape and electron distribution
(stereoelectronic structure), is complementary with
the stereoelectronic structure of the receptor
responsible for the desired biological action.
The section of the structure of a ligand that binds to a
receptor is known as its pharmacophore.
Drug Discovery and Design
 Know what properties turn a molecule into a drug

 Know what properties turn a macromolecule into a

drug receptor.

 Know how to design and synthesize a drug to fit into

a receptor
Lead Compounds
 What are the lead compounds?
Promising starting compounds
 How to identify them?
Rational drug design
Random high throughput screening,
Focused library screening
 How to optimize them?
QSAR studies
Sources of Drugs and Lead
Compounds
Natural Sources:
Are still important sources of lead compounds and new
drugs.
The large diversity of potential natural sources in the
world makes the technique of random screening a
rather hit or miss process.
Eethnopharmacology offers the basis of a more
systematic approach.
Identifying a material containing an active
compound:
Extraction
Purification
Assessment of the pharmacological activity
The isolation of useful quantities of a drug from its
land or sea sources can cause ecological
problems.
Yew Tree
Drug Synthesis
 Start with the pathology of the diseased state and
determine the point where intervention is most likely
to be effective.
 Lead compounds are then synthesized and their
pharmacological activity evaluated.
 Analogues are produced and screened.
 Labor intensive
Me-Too Drugs
 A way to cut the cost of producing drugs

 By synthesizing and marketing drugs that are similar

in structure and activity to those produced by
competitors.
Classification of Drugs
Drugs are classified in a number of different ways
depending on where and how the drugs are being
used.
Chemical structures
Pharmacological Action (site of action, targeted
system).
 Drugs with similar chemical structures may have
different pharmacological activities.
Routes of Administration
Pharmacokinetics Phase
 The pharmacokinetic phase of drug action includes
the Absorption, Distribution, Metabolism and
Elimination (ADME) of the drug.
Absorption
Absorption is the passage of the drug from its site of
administration into the plasma after enteral
administration.
It involves the passage of the drug through the
appropriate membranes.
Good absorbance requires that a drug molecule has
the correct balance between its polar (hydrophilic)
and
nonpolar (hydrophobic) groups.

Drugs that are too polar will tend to remain in

the bloodstream, whilst those that are too nonpolar
will tend to be absorbed into and remain within the
lipid interior of the membranes.
Distribution
 Distribution is the transport of the drug from its
initial point of administration or absorption to its site
of action.
 The main route is the circulatory system; however,
some distribution does occur via the lymphatic
system.
Metabolism
 Drug metabolism is the biotransformation of the drug
into other compounds referred to as metabolites.

 These biotransformations occur mainly in the liver

but they can also occur in blood and other organs
such as the brain, lungs and kidneys.
Elimination
 Elimination is the collective term used for metabolic
and excretion processes that irreversibly remove a
drug from the body during its journey to its site of
action. It reduces the medical effect of the drug by
reducing its concentration at its site of action.
 Slow Elimination
 Rapid Elimination
Bioavailability of Drugs
 The bioavailability of a drug is defined as the
fraction of the dose of a drug that is found in general
circulation It is influenced by such factors as ADME.
 Bioavailability is not constant but varies with the
body’s physiological condition.
Pharmacodynamic Phase
 Pharmacodynamics is concerned with the result of
the interaction of drug and body at its site of action,
that is, what the drug does to the body.
 A drug is most effective when its shape and
electron distribution, that is, its stereoelectronic
structure, is complementary to the steroelectronic
structure of the active site or receptor.
THE END