MEDICINAL CHEMISTRY

• Lecturer: Andrew
Banyikwa, PhD

• CHE 226 Medicinal

Chemistry
• Text book: An Introduction
to Medicinal Chemistry,
Fifth Edition- Graham L.
Patrick

• I have a digital copy of the

book (pdf)
 Mode of assessment
• 2 written exams (30 %)

• 4 Quizzes (10%)
–Quality control

• Final exam (60%)

 Lecture 1
• By the end of the lecture, these are some of the questions
you should be able to answer clearly

– What are drugs?

– What is the difference between a drug and a medicine

– Where are they coming from?

– Why do we take them?

– How do they work?

– Why do their structures look the way they look?

 Drugs vs. Medicine
• Drugs are compounds that interact with a biological
system and produce a desired biological response.

• Medicines are drugs that are prescribed by the

doctor.
Drugs can treat different types of diseases:

1-Infectious diseases: transmitted from person to

person by outside agents
– bacteria (pneumonia, cholera, tuberculosis)
– viruses (common cold, AIDS),
– fungi (thrush, athletes foot),
– parasites (malaria)
Drugs can treat different types of diseases:

• 2-Non-infectious diseases: disorders of the human

body caused by genetic malfunction, environmental
factors, stress, old age etc. (e.g. diabetes, heart
disease, cancer, mental illness, stomach ulcers,
arthritis).
Drugs can treat different types of diseases:

• 3-Non-diseases: alleviation of pain (analgesic),

prevention of pregnancy (contraception),
anesthesia.
 Abuses of drugs
• Self medication
– Using medicine without consultation with medical
doctor
• Using medicine outside the intended purpose
– Eg. Opiates (morphine, codeine, and thebaine) are used
clinically to relieve both acute and chronic pain.

– Abuse: In higher dosages opiates cause euphoria

(intense feelings of well-being, happiness, and
excitement)
 Classification of drugs
There are four main ways in which drugs might be classified
or grouped.
• By pharmacological effect for example analgesics
(painkillers), antipsychotics, antibiotics etc.
• By chemical structure common skeleton
– penicillins, barbiturates, opiates, steroids, and catecholamines.
• By target system Drugs can be classified according to
whether they affect a certain target system in the body.
• By target molecule Some drugs are classified according to
the molecular target with which they interact.
– anticholinesterases are drugs which act by inhibiting the enzyme
acetylcholinesterase
 Introduction to medicinal chemistry
Medicinal chemistry
• Is the study of how novel drugs are designed and developed.
• It is an interdisciplinary research area incorporating different
branches of chemistry, biology, biochemistry, and medicine in
the research for better and new drugs.
• Is the science, which deals with the discovery and design of
new and better therapeutic chemicals and development of
those chemicals into new medicines and drugs.
Drugs are compounds that interact with a biological system and
produce a biological response.
 Introduction to medicinal chemistry
cont.
Medicinal Chemists can:

• Synthesize and characterize new compounds

• Extract, purify and characterize compounds from
natural sources (plants, algae, fungus, bacteria, etc)
• Alter the structure of the compounds derived from
natural sources in order to increase efficacy for
optimum effect and minimum side effects.
• Determine their effect of compounds on biological
processes.
• Study uptake, distribution, metabolism and excretion
of drugs.
 Source of drugs
• Drugs are classified according to their origin:

• Synthetic compounds: Simple and relatively small

molecules (can also be natural product)
• Simple structures with few to no stereogenic centers
• Synthesized in the laboratory at low cost (cost effective).
• Easy to scale up if large quantity (in tons) of drugs are
needed (industrial scale)
• Affordable drugs
 Source of drugs
• Drugs are classified according to their origin:

• Natural products: Extracted from natural world

(plants, algae, fungus, bacteria)
• Too complex and costly to be synthesized in the laboratory
• Costly to obtain raw materials (require bio-reactors to
grow algae, fungus, bacteria in sterile environment)
• Costly to isolate and purify active ingredient (drug)
• More costly to scale up.
• Expensive drugs
 Source of drugs
• Drugs are classified according to their origin:

• Semi-synthetic: Chemical and biological modification of

natural products
• Increase efficacy and potency of drugs derived from
natural sources
• Decrease the amount of effective dose a patient will ultimately
need
• Decrease cost of drugs

Salix alba 'Vitellina-Tristis'
salicylic acid (drug)
Aspirin
• Source: Willow bark tree.
• Medicinal properties known for centuries.
– Medicinal properties named in ancient
texts from Assyria, Sumer and Egypt
(around 400 BC.
• Remedy for aches, fever and inflammation
• Useful to humans
• Active ingredient is salicylic acid
– Isolated from the bark of the willow
tree in 1763 (1.5-12% in extract)
• Side effect:
– Too acidic
– Irritates throat and stomach.
 Aspirin
• Aspirin is used throughout the
world
– There is no enough trees that can
satisfy global demand for salicylic acid,
a natural product which is a precursor
of aspirin
– There is so much bark a tree has to
Salix alba 'Vitellina-Tristis' harvest
– Limited supply of starting material=
expensive drugs
– (law of supply and demand)
– Bad news for third world countries

salicylic acid (drug)

 Synthetic compounds: Aspirin
• Small scale (laboratory scale)
• A German chemist named Felix Hoffman is credited with being the
first to synthesize aspirin in 1897 using salicylic acid as starting
material

Salicylic acid from Acetic anhydride Acetylsalicylic acid

willow bark extract (Industrial chemical) (Aspirin)
(Drug) (Pro drug)
A prodrug is a drug that is administered in inactive form, then
metabolized into a pharmacologically active drug inside the
body (cell).
 Synthetic compounds: Aspirin
• Industrial scale: Kolbé–Schmidt reaction

Phenol Salicylic acid

• Phenol, CO2, NaOH and H2SO4 are industrial chemicals
• Salicylic acid and aspirin can be made at much larger scale
• Bypass the need to plant trees and harvest Salicylic acid
 Natural product: Quinine-Anti malarial
drug

Bark of the cinchona tree

medicinally active

Cinchona trees farm. A sources for

quinine.
http://nephicode.blogspot.com/2012/08/more
-covino-comments-answered-part_22.html
Quinine
http://www.chemistryviews.org/details/ezine/4701281/From_Pharmacy_to_the_Pub__A_Bark
_Conquers_the_World_Part_1.html
 Malaria

• Infects ~500 million people ever year

worldwide
• Strong demand for antimalarial
medication
• Quinine, a natural product contains 4
stereogenic centers
• Too difficult to synthesize in the
lab and in industrial scale
Quinine
 Quinoline

Quinoline
Both Quinine and
chloroquine contains
quinoline group
 Synthesis- Quinoline derivatives
.

Quinolines are synthesized from simple anilines

 Anti-malarial drugs
Quinoline derivatives

Quinine Chloroquine

Amodiaquine Primaquine
Natural products: Opiates
• Opiates are alkaloid compounds found
naturally in the opium poppy plant
Papaver somniferum.

• Known and used since antiquity.

Mentioned in Sumerian text dated
around 4,000 BC

• Used as strong stimulant to central

nervous system and mood elevating.

• The psychoactive compounds found in

the opium plant include morphine
(major), codeine, and thebaine (minor)
Natural products: Opiates
• Approximately 24 other alkaloids are also
present in opium but have little to no
effect on the human central nervous
system

• Medically opiates are used to relieve

both acute pain and chronic pain.

• Abuse: In higher dosages of opiates

cause euphoria (intense feelings of well-
being, happiness, and excitement)
 Natural products:
Active ingredient of opium

Morphine Codein Thebaine

Major active ingredient of Treat mild to severe pain Not used
opium poppy. Methyl group in 3 therapeutically
Medically significant position Methyl group in
opiate Administered in higher position
Treat severe pain doses 3 and 6
Strong affinity to μ-opioid Less addictive Less active
receptors Obtained through
Free 3-hydroxy group prescription.
Natural products: Opiates

Up until now
• Total synthesis of opiates is too complex
and expensive to be viable economically
• Raw material are still harvested from
opiate plants.
• From those plants chemical
modification are done to improve the
efficacy of the drugs (semi synthesis)
 Semi-synthesis compounds

Hydromorphone
More soluble in water than
morphine.

Cross blood brain barrier

faster than morphine
Fast acting
4 times more potent than
Morphine: Morphine
Target is opioid Used as an illicit drug
receptors in the because of its euphoric
brain effect
 Semi-synthesis compounds
(Metabolite of Heroin)

6-Monoacetylmorphine
Free 3-hydroxy group
Most active metabolite
Heroin is a pro drug of
morphine.

Easy pass through blood Morphine (Active drug)

brain barrier. Strong affinity to μ-opioid
Weak affinity to μ-opioid receptors.
receptors No easy pass through
3-hydroxy group 3-Monoacetylmorphine blood brain barrier.
necessary for effective Least active metabolite
receptor is masked by acetyl-group in 3-position
the acetyl group relatively weak affinity to μ-opioid receptors.
 Semi-synthesis compounds

Oxycodone Oxymorphone

Thebaine
A minor constituent of
opium
Buprenorphine Nalbuphine
Medicine derived from chemical modification of Thebaine
 Branches of medicinal chemistry
• Pharmacodynamics is the study of how a drug binds to its
target binding site and produces a pharmacological effect.
– Overall structure and stability of drug backbone
– Spatial arrangement of binding groups

• Pharmacokinetics is The study of how a drug is absorbed,

distributed, metabolized, and excreted (ADME).

– For an orally administered drug, the drug has to survive stomach acids then
digestive enzymes in the intestine. It has to be absorbed from the gut into the
blood supply and then it has to survive the liver where enzymes try to destroy
it (drug metabolism). It has to be distributed round the body and not get
mopped up by fat tissue. It should not be excreted too rapidly or else frequent
doses will be required to maintain activity. However, it should not be excreted
too slowly or its effects could linger on longer than required.
End of lecture 1