Browsing by Author "Wessels, Petronella Magdalena"
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- ItemIndole- and diaryl ether-derived non-nucleoside reverse transcriptase inhibitors(2018-03) Wessels, Petronella Magdalena; Van Otterlo, Willem; Pelly, Stephen; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Since the discovery of the Human Immunodeficiency Virus (HIV) as the cause of Acquired Immune Deficiency Syndrome (AIDS) in the early 1980s, no cure has been found. This disease has thus claimed the lives of millions of people and has gained the reputation as one of the worst pandemics in human history. There has, however, been considerable success in reducing the viral load of infected individuals through the use of combination therapy, known as highly active antiretroviral therapy (HAART). A main target of this drug regimen is the reverse transcriptase (RT) enzyme, which is inhibited by two of the three drug classes typically employed by HAART, namely nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). However, as the viral population diversifies through mutations introduced during viral replication, drug resistant viral strains emerge and limit the use of currently effective drugs. These resistant strains thus require new small molecule inhibitors to keep them in check. In light of the need for new therapeutic agents to continuously enter the drug development pipeline, we set out to improve upon current NNRTIs through the lead optimization of an indole core structure and the design of a diaryl ether NNRTI using molecular modelling. The first focus was to overcome the acid-catalysed indole-mediated degradation of the current lead compound, ethyl 5-chloro-3-[(methylthio)(phenyl)methyl]-1H-indole-2-carboxylate (designed in an earlier research project), thereby making the small molecule suitable for oral intake. We successfully synthesised twelve acid stable derivatives of this lead compound by replacing the thiomethyl group with an alkyl or alkene chain in the benzylic position. Four of these newly synthesised derivatives proved to be more potent (0.010 – 0.019 μM) than the lead compound (0.039 μM) against wild-type HIV-1, while six of these compounds were more potent than nevirapine (0.091 μM) under the same conditions. The next study involved modifications to the 2-position of a lead indole based NNRTI, ethyl 5-chloro- 3-[(3,5-dimethylphenyl)(methylthio)methyl]-1H-indole-2-carboxylate, through the introduction of various pyridinyl groups to determine the effects on efficacy. Three of the five resultant compounds performed better against wild-type HIV-1 (0.030 – 0.043 μM) than the lead compound, with an ethyl ester in the 2-position (0.060 μM), and two of these three compounds remained potent against HIV-1 viruses harbouring the prevalent NNRTI resistant mutations V106M, Y188C/H, G190A and K103N. Due to the positive results obtained when an indole was used as a core structure in NNRTIs, ethyl 3-(1-aminopropyl)-5-chloro-1H-indole-2-carboxylate was chosen for the incorporation of electrophilic warheads as amides with the aim of synthesising the first irreversible NNRTIs. Three proof-of-concept compounds were successfully synthesised with electrophilic warheads positioned to interact with the thiol of cysteine in the Y181C mutant strain of the virus. These compounds, however, proved to be toxic and thus ineffective as NNRTIs. Finally, molecular modelling was used to design flexible diaryl ether NNRTIs with the ability to form desirable interactions with residues in the binding pocket. We sought to achieve an improved resistance profile through π-π stacking interactions with conserved amino acid residues Trp229 and Tyr318 and additional interactions with Tyr188 and Lys101. Three proof-of-concept compounds were then synthesised, of which 3-(3-amino-2-methoxyphenoxy)-5-chlorobenzonitrile proved to be highly effective with an inhibition activity (IC50 value) of 5 nM against wild-type HIV-1.