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.
Development of Selective Inhibitors of Dihydrofolate Reductase (DHFR) of Mycobacterium Tuberculosis
Alfaraj, R. (Author). 31 Dec 2013
Student thesis: Masters Thesis › MPhil