Year

2007

Degree Name

Doctor of Philosophy

Department

School of Chemistry

Abstract

Based on a lead tripeptide compound synthesised in-house during anti-bacterial studies, small peptidic inhibitors of the human immunodeficiency virus (HIV) integrase (IN) enzyme were investigated as potential treatments for acquired immunodeficiency syndrome (AIDS).

Initial design strategies were based on potential interactions of the inhibitor docked to a preliminary model of the enzyme. This resulted in forty eight first generation peptidic inhibitors containing stepwise changes in key regions of the lead compound. The IN inhibitory activities of these derivatives were then used in the development of a more refined model of the enzyme, which include the loop region of the enzyme which was missing in the preliminary model. A further ten second generation compounds were designed, synthesised and evaluated on the basis of this model.

IN inhibitory activity testing, via a combined 3′-processing (3′-P) and strand transfer (ST) assay identified some twenty seven compounds possessing moderate to good activity (i.e. IC50 < 25 μM). The most potent inhibitors were N-{(1S,4S)-1-(4- allyloxybenzyl)-8-amino-3-aza-4-[3-(methoxycarbonylmethyl)phenylcarbamoyl]-2- oxooctyl}acetamide hydrochloride (109) and methyl (7S,10S)-10-(4-allyloxybenzyl)-7- (4-aminobutyl)-5,8,11-triaza-12-[2-(benzyloxy)phenyl]-6,9,12-trioxododecanoate hydrochloride (163) with IC50 values of 4.5 and 4.0 μM respectively. A detailed structure activity relationship (SAR) assessment, with respect to IN inhibition, was conducted on all the tested compounds.

Studies done on a structurally diverse sample of the more active compounds indicated that these tripeptidic inhibitors selectively inhibited the strand transfer reaction of IN, with no observed inhibition of the 3′-processing reaction.

A limited study of anti-HIV inhibition in infected whole cells was also conducted. One compound, (4S,7S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-13- methoxy-5,8,13-trioxotridecanoic acid hydrochloride (134) was discovered with potent activity and low cell toxicity, strongly indicating the potential that these tripeptidic IN inhibitors have as viable HIV therapeutics.

A total of one hundred and sixty final and intermediate compounds were synthesised, of which one hundred and forty three were new structures.

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