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Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor

Brigg, Siobhan Ernan (2017-12)

Thesis (MSc)--Stellenbosch University, 2017.

Thesis

ENGLISH ABSTRACT: HIV-1 remains the worst pandemic faced by mankind since its discovery as the causative agent of AIDS in the early 1980s. An enormous amount of research has been done to find a cure, but to date there has been no success and resistance is widespread among the available treatment. This project focused on the development of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a rational design approach. The lead compound, ethyl 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole-2-carboxylate, was shown to have low nano-molar potency against HIV-1 (IC50 = 16 nM), however it had two main shortcomings which needed to be addressed; poor resistance profile and poor acid stability. Previous research had shown the resistance profile could be improved by introducing meta substitution on the phenyl moiety which interacts with Tyr181 of the NNRTI binding pocket (NNIBP). We were successful in synthesising several meta substituted phenyl derivatives of the lead compound and these were shown to be equally as potent as the lead compound. Their activity against resistant strains is yet to be determined as we are awaiting the results from biological testing. The presence of an acid labile methyl ether functionality on the molecule which was susceptible to an acid catalysed indole mediated SN1 substitution in aqueous acidic medium meant that the lead compound could never be considered as a candidate for an orally available drug. The methyl ether moiety was exchanged for a sulfide moiety and several of these derivatives were successfully synthesised. Acid stability tests showed that we were successful in our endeavour to improve the acid stability, offering an advantage over the lead compound despite a slight reduction in potency. However to completely eliminate the possibility of substitution, we replaced the methyl ether moiety for an ethyl group, successfully synthesising ethyl 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxylate and 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxamide and we are currently awaiting the results from biological testing to determine whether this derivative is active against HIV-1. The functionality in the 2-position of the indole was also investigated through the synthesis of 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole and 5-chloro-3-((methylthio)(phenyl)methyl)-1H-indole. These derivatives lacking a group in the 2-position of the indole showed significant reduction in potency. Replacement of the ethyl ester for an isobutyl ester to give isobutyl 5-chloro-3-((3,5-dimethylphenyl)(methylthio)methyl)-1H-indole-2-carboxylate, showed some maintenance of potency, however the larger side chain was not well accommodated in the NNIBP. The presence of a chiral centre on the lead compound, and all derivatives synthesised in the project, resulted in our final aim; we set out to develop a method for resolving these enantiomers. Unfortunately, although we employed a variety of different strategies, including the use of chiral auxiliaries and the classical resolution method of attempting to make diastereomeric salts, we were not successful in achieving this aim.

AFRIKAANSE OPSOMMING: MIV-1 bly die ergste pandemie wat die mensdom sedert die ontdekking van die oorsaak van VIGS in die vroeë 1980s. ‘n Enorme hoeveelheid navorsing is al onderneem om ‘n kuur te ontdek, maar daar was tot op hede geen sukses nie. Hierdie projek het gefokus op die ontwikkeling van nuwe nie-nukleosied trutranskriptase inhibeerders (NNRTIs) met gebruik van ‘n rasioniële ontwerpbenadering. Die loodverbinding, etiel-5-chloor-3- (metoksiel (fenyl) metiel) -1H-indool-2-karboksilaat, het getoon dat dit 'n lae nano-molêre sterkte teen MIV-1 (IC50 = 16 nM) het, maar dit het twee hoof tekortkominge wat aangespreek moes word; swak weerstandsprofiel en swak suur stabiliteit. Vorige navorsing het getoon dat die weerstandsprofiel verbeter kan word deur die meta-substitusie op die fenielgroep in te voer wat met Tyr181 van die NNRTI-bindingsak (NNIBP) in wisselwerking tree. Ons was suksesvol om verskeie meta-gesubstitueerde fenielederivate van die hoofverbinding te sintetiseer en dit is getoon dat dit ewe sterk as die hoofverbinding is. Hul aktiwiteit teen weerstandbiedende stamme moet nog nie bepaal word nie, aangesien ons die resultate van biologiese toetse afwag. Die teenwoordigheid van 'n suur labiele metiel eter funksie op die molekule wat vatbaar was vir 'n suur gekataliseerde indool gemedieerde SN1 substitusie in waterige suur medium beteken dat die lood verbinding nooit beskou kan word as 'n kandidaat vir 'n mondelinge beskikbare geneesmiddel. Die metiel-etergroep is vir 'n sulfieddeel uitgeruil en verskeie van hierdie afgeleides is suksesvol gesintetiseer. Suur stabiliteit toetse het getoon dat ons suksesvol was in ons strewe om die suur stabiliteit te verbeter, wat 'n voorsprong bo die hoofverbindings bied ten spyte van 'n effense vermindering in sterkte. Om die moontlikheid van vervanging egter heeltemal uit te skakel, het ons die metiel-etergroep vervang vir 'n etielgroep, met die suksesvolle sintetisering van etiel 5-chloor-3- (1-fenylpropyl) -1H-indool-2-karboksilaat en 5-chloor-3- 1-fenylpropyl) -1H-indool-2-karboksamied en wag tans op die resultate van biologiese toetsing om vas te stel of hierdie afgeleide teen MIV-1 aktief is. Die funksionaliteit in die 2-posisie van die indool is ook ondersoek deur die sintese van 5-chloor-3- (metoksiel (fenyl) metiel) -1H-indool en 5-chloor-3 -((metielthio) (feniel) metiel) -1H-indool. Hierdie afgeleides wat 'n groep in die 2-posisie van die indool het, het aansienlike vermindering in sterkte getoon. Vervanging van die etiel ester vir 'n isobutiel ester om isobutiel 5-chloor-3 - ((3,5-dimetylfenyl) (metielthio) metiel) -1H-indool-2-karboksilaat te gee, het 'n mate van instandhouding van sterkte getoon, maar die groter kant ketting is nie goed geakkommodeer in die NNIBP nie. Die teenwoordigheid van 'n chirale sentrum op die loodverband, en al die afgeleides wat in die projek gesintetiseer is, het tot ons finale doel gelei; Ons het 'n metode ontwikkel om hierdie enantiomere op te los. Ongelukkig het ons ongelukkig nie geslaag om hierdie doelwit te bereik nie, alhoewel ons 'n verskeidenheid verskillende strategieë gehad het, insluitende die gebruik van chirale hulpmiddels en die klassieke resolusie metode om diastereomere soute te maak.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/102766
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