Development of Selective Inhibitors of Dihydrofolate Reductase (DHFR) of Mycobacterium Tuberculosis

Abstract

Mycobacterium tuberculosis is the causative organism for one of the pandemic diseases in the world, tuberculosis (TB). The length of treatment often results in multi-drug resistance (MDR) and patient non-compliance. One of the most important enzymes as a drug target for tuberculosis is dihydrofolate reductase (DHFR), which plays an important role in the folate cycle and inhibition of the enzyme stops cell growth. DHFR inhibitors are usually 2,4-diaminopyrimidines, which have high binding affinity to the enzyme but have the potential to inhibit the human enzyme. This project focuses on the development of new inhibitors with improved potency and selectivity for the M. tuberculosis enzyme. Inhibitors containing a 5-phenyl group were targeted in order to increase lipophilicity and binding to the enzyme, whilst reducing binding to the human enzyme. Condensation of diethyl phenylmalonate with guanidine followed by chlorination and amination of the carbonyl group gave 2-amino-6-chloro-4-pmethoxybenzylamino- 5-phenylpyrimidine, which was deprotected to give 6-chloro-2,4- diamino-5-phenylpyrimidine. Reaction of 2-amino-6-chloro-4-p-methoxybenzylamino- 5-phenyl-pyrimdine with different aromatic and aliphatic amines was also investigated. Amination with an amino alcohol in presence of potassium carbonate in the absence of solvents was used to synthesise a number of analogues. Deprotection of the pmethoxybenzylamine was achieved by DDQ oxidation to give the desired 2,4-diamino- 5-phenyl-6-aminoalcohol-pyrimidine products. The synthesis of the triol motif began with protection of ribonolactone and reduction of the carbonyl group to give the diol. Derivatisation of the product with various protecting goups was investigated.

Date of Award	31 Dec 2013
Original language	English
Awarding Institution	University of Bath
Supervisor	Michael Threadgill (Supervisor), Matthew Lloyd (Supervisor) & Andy Thompson (Supervisor)