Course title: Medicinal Chemistry (PCHxxx)

Level: Year 3-Semester 2

Prerequisites:

Course Description:

The course is concerned with studying different pharmacological classes of drugs, and their
mechanisms of action and structure-activity relationships. These classes include antiviral agents,
antibacterial, anticancer and antiparasitic agents etc.

Objectives [Intended Learning Outcomes] (ILOs)

At the end of the course of lectures the students will be able to:

1. Be familiar with applied reaction kinetics relevant to pharmacy

2. Be able to explain chemical structure activity relationships in drug delivery and action,
ionisation and solubility, bonding and drug macromolecular interaction.

Content

I. Structure-Activity Relationships

II. Drug Metabolism -

III. Antibacterial agents

IV. Antiviral agents

V. Anticancer agents

VI. Cholinergics, anticholinergics, and anticholinesterases

VII. Drugs acting on the adrenergic nervous system

VIII. The opioid analgesics

IX. Anti-ulcer agents

X. Vitamins and Coenzymes

XI. Parasite Chemotherapy

XII. Antifungal agents

XIII. Cancer chemotherapy

Reading

1. An introduction to medicinal chemistry by Patrick G.L.

2. Principles of Medicinal Chemistry, 7th Edition, edited by T.L. Lemke, D. A. Williams, V. F. Roche,
and S.W. Zito, Williams and Wilkins: Philadelphia, 2013.
REQUIREMENTS TO COMPLETE THIS COURSE

A. COMPULSORY READING

Read and discuss the following four chapters in groups of 5 (mix boys and girls in a 2:3 ratio). Send
the lists of the groups by February 28 at 4pm.

1. Antibacterial agents – chapter 19

2. Antiviral agents – Chapter 20

3. Anticancer agents – Chapter 21

4. The opioid analgesics – Chapter 24

B. ASSIGNMENT

DUE DATE: 29 March at 9am

Answer and submit ALL questions. Spiral bound your set.

Please Note the following:

1. Any form of cheating or plagiarism will lead to ZERO (0%) percent in your CA. Its individual
work. No sharing of answers.

2. Everyone to submit in person on the day.

3. A test will be written on the day of submission

Question 1
a. Briefly discuss the evolution of drug discovery of anti-neoplastic agents. Your discussion
should include at least 3 examples of drugs and technologies. [5]
b. Using the structure of mechlorethamine hydrochloride and guanine, illustrate the
mechanism of DNA alkylation by nitrogen mustards.

bi) What are 2 potential effects of DNA alkylation? [2]

bii) Name an analogue of mechlorethamine, and explain how it improves on the prototypical
molecule? [3]
c. i) What is the function of ribonucleotide reductase, and which vital element is required to
initiate the catalytic cycle? [2]
ii) Using the chemical structure illustrate the mechanism by which hydroxyurea stops the catalytic
cycle. [2]
iii) Which position on pyrimidine analogues is modified in order to inhibit of ribonucleotide
reductase? [1]
d. The structure of imatinib is provided below. Using the chemical structure as well as a
narrative to illustrate structure activity relationships of the molecule with tyrosine kinase
enzyme. [10]

Question 2

a. What are antimetabolites? Classify the chemotherapeutic agents acting as antimetabolites with
examples (8)

b. Write notes on the following:

i. HIV protease inhibitors (8)

ii. Explain how changes in metabolic pathways (e.g., induction, inhibition) can impact the
therapeutic activity, toxicity, and/or drug interactions (9)

Question 3

a. Explain how genetic differences in drug metabolism result in predictable differences in drug
response (5)

b. Describe the differences in the ways that bacteria and viruses multiply (3)

c. The effect of some drugs used to treat cancer depends on geometrical isomerism. One successful
anti-cancer drug is cisplatin, whose formula is PtCl2 (NH3)2. Describe the structure of cisplatin by
referring to the following:

i. The meaning of the term geometrical isomerism as applied to cisplatin

ii. Diagrams to show the structure of cisplatin and its geometrical isomer

iii. The types of bonding in cisplatin. (6)

d. Explain the catalytic mechanism of CYP450 enzyme (11)

Question 4

a. Describe how the following factors affect the action local anaesthetics

i. Lipid solubility [5]

ii. pH [4]

iii. Vasodilation [5]

b. Discuss the structure activity relationship of thyroid analogues in terms of

i. Bridging atom [3]

ii. 3’ and 5’ substitutions [5]

iii. Phenolic hydroxyl group [3]

Question 5.

ai. Using the structure of mechlorethamine hydrochloride and guanine, illustrate the mechanism of
DNA alkylation by nitrogen mustards. [6]

aii) What are 2 potential effects of DNA alkylation? [2]

aiii) Name an analogue of mechlorethamine, and explain how it improves on the prototypical
molecule? [3]

b. Which structure is necessary for intercalating activity of anti-tumour antibiotics? [3]

c. Name the species of bacteria doxorubicin and bleomycin were first isolated from? [2]

d. Anthracyclines generally have the structure presented below. Which R group(s) differ for
doxorubicin and daunorubicin? How do the functional groups differ? [3]

ei) What is the mechanism by which antimetabolites such as gemcitabine inhibit ribonucleotide
reductase, and which structural modification is required [4]

ii) What is the active form of 5-fluorouracil? [2]

Question 6

a. State the structure activity relationship (S.A.R) of the compound below. [8]
b. Classify antiviral agents. Explain the mechanism of action and synthesis of one drug from 2
different classes [9]

c. Describe the types of drug receptor interactions of antilipidemic drugs. [8]

Question 7

a. The figure below shows Thyroxine (T4). Describe the metabolism and excretion pathways of
this hormone. (15)

Fig. 1: Thyroxine (T4)

b. Describe the general structure-activity relationship of local anaesthetics. (10)

Fig. 1: Lignocaine HCL

Question 8

a) Draw an illustrated diagram of insulin and describe how it work. [15]

b) Discuss three mechanisms for drugs that are used to treat Diabetes Mellitus (DM). In
each case, name the drug or class involved. [10]

Question 9

a) Discuss any three (3) conditions that promote drugs entry into the Central Nervous System
(CNS). [10]

b) Benzylpenicillin is a narrow spectrum antibiotic. Discuss, illustrating and naming any three
changes to transform its activity to a broad spectrum antibiotic class. [15]

Question 10

a. Differentiate phase I and phase II Metabolic reactions, giving examples [8]

b. Briefly outline how potency and efficacy can be optimized. [5]

c. Discuss what causes attrition of drugs during preclinical and clinical trials [6]

d. Prontosil, a sulfonamide derivative with the structure shown below, is inactive against
microorganisms in vitro, but shows activity in vivo. Explain why this is so and draw the structure of
the active compound derived from Prontosil [6]