The aim of this module is to introduce students to heterocyclic chemistry and the fundamental principles that underpin modern medicinal chemistry; these will include the synthesis of key heterocycles such as pyridines, diazines, pyrroles, imidazoles etc and their use within applied antiinfective medicinal chemistry. Drug design, including qualitative and advanced quantitative SAR techniques including computer-aided molecular design will be incorporated. The course will build on the principles taught in the introductory medicinal chemistry module CHEM248.

(LO1) To solve problems involving the use of heterocycles in modern synthetic methodology. Through this they will demonstrate an understanding of the structural features and reactivity of heterocyclic compounds, including stereochemistry, carbon-carbon and carbon-heteroatom bond formation, functional group interconversions and ring substitution.

(LO2) To critically analyse and evaluate the importance of heterocycles as key components in major drug classes and combinatorial libraries.

(LO3) To evaluate the importance of protease enzymes as drug targets as illustrated by examples including the falcipain 2 inhibitors (cysteine proteases) and HIV protease inhibitors (aspartate proteases). To analyse and compare drug discovery programmes focused on the SARS CoV2 main protease (cysteine protease).

(LO4) To outline approaches to anti-microbial drug design (anti-bacterial and anti-viral). To apply organic synthesis knowledge to the preparation of different classes of anti-microbial compounds.

(LO5) To understand and apply advanced techniques in computational drug design.

(S1) Students will develop their chemistry-related cognitive abilities and skills i.e. abilities and skills relating to intellectual tasks, including problem solving as required by the Chemistry subject benchmark statement. In particular they will gain the ability to adapt and apply methodology to the solution of unfamiliar problems

(S2) Communication skills

(S3) Organisational skills

(S4) IT skills through computational workshops, problem solving and literature searching exercises/techniques.

Lectures. 27 x 1 hr, delivered on campus with recordings available on Canvas.
Each lecture will have discussion points and questions which will be covered in subsequent lectures.

Tutorials. 2 x 3 hr in-person tutorials. Summative problems are attempted in the sessions then completed and uploaded later.
Two feedback sessions will provide students with answers to the tutorials and provide discussion points (2 x 1 hr).

Workshop. 1 x 2 hr, molecular modelling workshop with associated formative problems, submitted on canvas.

*Lectures: 27 hr
*Tutorials: 6 hr
*Computational Workshop: 2 hr
*Feedback: 2 hr

Aromatic heterocyclic chemistry

•Introduction to heterocycles (3 lectures)
-The concept of “Chemical Space.”
-Privileged scaffolds. Revision of the bonding and reactivity of 5 and 6-membered mono heterocyclic aromatic systems (pyrroles, furans, thiophenes and pyridines).
•Synthesis and reactions of pyridines and pyridine based drugs. Synthesis and uses of pyrimidines and related heterocycles (2 lectures).
•Chemistry of pyrroles, furans and thiophenes. The synthesis of drugs containing these ring systems (1 lecture).
•Lipitor (Atorvastatin): A case study in drug design and synthesis (1 lecture).
•Chemistry of diazoles (imidazoles, pyrazoles, thiazoles, oxazoles) and the synthesis of drugs containing these ring systems (2 lectures).
•Synthesis and reactivity of indoles. The synthesis of indole containing drugs (1 lecture).
•Synthesis and chemistry of quinolones and isoquinolines, with relevant examples of medicinally important compounds containing these heterocyclic units (2 lectures).

Medicinal Chemistry Applications

•Protease Enzymes as Drug Targets (8 lectures).
-Design and Synthesis of Small Peptide Inhibitors.
-Synthesis Aspects; Peptides and Peptidomimetics.
-Peptide and Peptidomimetic Inhibitors of Falcipains 2 and 3.
-Computer based design of novel inhibitor templates.
-HIV Protease Inhibitors 1; Mechanism of action and drug design.
-HIV Protease Inhibitors 2; SAR and Synthetic Approaches
-Project moonshot – (2 lectures of the 8 – Industrial speaker).
•Medicinal Chemistry of Antibacterials (2 lectures).
•Nucleoside analogues as antiviral agents (1 lecture).
•Advanced Techniques in Computational Drug Design (2 lectures)