Doctoral Degrees (Chemistry and Polymer Science)

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Browsing Doctoral Degrees (Chemistry and Polymer Science) by Subject "AIDS-associated retrovirus"

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    Design and Synthesis of potent benzimidazolone HIV Non-nucleoside reverse transcriptase inhibitors
    (Stellenbosch : Stellenbosch University, 2018-12) Pribut, Nicole; Pelly, Stephen C; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Since the 1980’s, HIV has plagued the population on a global scale, with millions of newly infected individuals reported every year. However, with the introduction of combination therapy, which can significantly suppress viremia to almost undetectable levels in the infected populace, the disease can be managed to a point where the infected population can live almost normal lives. Unfortunately, although able to improve quality of life and prevent the onset of AIDS, combination therapy is not curative as issues related to drug resistance and adherence can lead to the re-emergence of high viremia, AIDS and, inevitably, death. Consequently, there remains a need for the continued development of new and superior ARVs that are effective against wild-type and resistant strains of HIV and are well tolerated for chronic use. In an effort to address this need, our group has focused on the design and synthesis of new NNRTIs. In the clinic, NNRTIs are an important part of first-line regimens employed in the treatment of HIV. In particular, our group focused on the synthesis of a series of small benzimidazolone-containing NNRTIs which were initially designed to address lability issues exhibited by a series of potent indole-based NNRTIs. These first-generation benzimidazolones were readily synthesized over five steps and, following evaluation in an HIV whole cell assay, were found to be potent inhibitors of HIV RT, but were susceptible to clinically relevant resistant strains such as K103N and Y181C. As a result, we synthesized a series of second-generation benzimidazolone NNRTIs which were designed to overcome, specifically, the Y181C resistant strain. Starting from 2-amino-3-nitrophenol, the benzimidazolone precursor for these compounds was synthesized over six steps. This precursor was then coupled to various aryl or heteroaryl halides by way of an Ullmann reaction or SNAr. Of this small library, one compound in particular was found to be potent (with low nanomolar activity), not only against wildtype, but also against Y181C, Y188C and the double mutant K103N/Y181C. Furthermore, this compound, 3-chloro-5-((3-ethyl-2-oxo-1-((2-trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4- yl)oxy)benzonitrile, exhibited only low levels of susceptibility against the most problematic K103N resistant strain. We envisaged that by introducing additional electrostatic interactions between our potent lead compound and the NNIBP we would succeed in optimizing the efficacy of our compound against wild-type and resistant strains of HIV. In order to achieve these additional interactions we adopted two different approaches. The first approach focused on targeting a lysine residue located at the top of a narrow hydrophobic chimney towards the back of the NNIBP. To this end, we installed a cyanovinyl substituent onto our lead compound which, based on docking studies, would protrude into the chimney and form a hydrogen bond with the targeted lysine. Installation of the cyanovinyl substituent was achieved using the well-established Heck coupling reaction. Although this compound, (E)-3-(2-cyanovinyl)-5-((3-ethyl-2-oxo-2,3-dihydro-1Hbenzo[ d]imidazol-4-yl)oxy)benzonitrile, was also a potent inhibitor of HIV RT, it was unfortunately not significantly more potent than our existing lead compound. The second approach employed a molecular hybridization technique to form a combination of our lead compound and efavirenz, in order to achieve additional hydrogen bonding to the backbone of Lys101. This new hybrid compound, 3-chloro-5-((4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5- yl)oxy)benzonitrile, was successfully synthesized over seven steps and found to be slightly more potent than our lead compound with an improved selectivity index.