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The rational design and synthesis of novel HIV non-nucleoside reverse transcriptase inhibitors

Muller, Ronel (2013-12)

Thesis (MSc)--Stellenbosch University, 2013.


ENGLISH ABSTRACT: With a cure for HIV and AIDS still absent, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a major role in the current antiretroviral treatments used, which have shown to improve and prolong the lives of HIV patients significantly. However, with rapid mutations of the HI virus, the use of these drugs is becoming limited, thereby highlighting the need for the development of new NNRTIs. Previous work by our research team has led to the development of a cyclopropyl-containing indole-based compound with an inhibition activity (IC50 value) of 0.1 μM, as determined in an in vitro single-cycle, non-replicative phenotypic assay. Therefore, in this project, we focussed on enhancing the intermolecular interactions of our compound to three major areas in the NNRTI binding pocket, namely the Tyr181, the Val179, and the Lys101 binding pockets. Hereby we were able to obtain both improved and lower potencies, with our most active compound having an inhibition activity (IC50 value) of 1 nM. For the interaction to the Tyr181 binding pocket, we were thus unable to synthesise a heterocyclic ring system onto our molecule as opposed to the previously used phenyl ring. Secondly, for the interaction to the Lys101 binding pocket we were able to synthesise a tetrazole ring system and an amide functionality onto the 2-position of the indole. Lastly, in our quest to synthesise the cyclopropyl moiety onto our compound for the interaction in the Val179 binding pocket, we were able to investigate the full inhibition effect of this interaction by synthesising a similar compound with no interaction in this binding pocket. Moreover, we were able to synthesise a new compound with a methoxy moiety for this interaction with an inhibition activity (IC50 value) of 1 nM. With this compound only being submitted for efficacy evaluation as a racemic compound mixture, this opened a new door for research possibilities for our team.

AFRIKAANSE OPSOMMING: In die awesigheid van 'n geneesmiddel vir MIV en VIGS, speel nie-nukleosied omkeerbare transkripsie inhibitore ("NNRTIs")'n groot rol in die huidige antiretrovirale behandeling. Ongelukkig ondergaan die MI virus mutasies, wat dus die gebruik van hierdie antiretrovirale middels beperk. Hierdie beklemtoon dus die noodsaaklikheid vir die ontwikkeling van nuwe "NNRTIs". Vorige werk wat deur ons navorsings groep verrig is, het gelei tot die ontwikkeling van "n siklopropiel bevattende indol verbinding, met "n inhibisie aktiwiteit ("IC50" waarde) van 0.1 μM. Gevolglik, het ons in hierdie projek gefokus om die intermolekulêre interaksies van hierdie verbinding in drie hoof areas in die "NNRTI" bindings ruimte te verbeter, genaamd die Tyr181, die Val179, en die Lys101 bindings ruimtes. Hierdie projek het dus beide verbeterde en ook laer inhibisie aktiwiteits resultate gelewer, waar die mees aktiewe verbinding 'n inhibisie aktiwiteit ("IC50" waarde) van 1 nM behaal het. Vir die interaksie na die Tyr181 bindings ruimte, was ons dus onsuksesvol om 'n heteroaromatiese ring te sintetiseer as plaasvervanger vir die oorspronklike feniel ring. Tweedens, vir die interaksie na die Lys101 bindings ruimte, was ons in staat om 'n tetrazol ring en 'n amied funksionaliteit aan die 2-posisie van die indol te sintetiseer. In ons stryd om die siklopropiel ring aan ons verbinding te sintetiseer vir die interaksie in die Val179 bindings ruimte, was ons in staat om die volledige effek van hierdie interaksie te bepaal deur 'n soortgelykke verbinding te sintetiseer met geen interaksie in die Val179 bindings ruimte nie. Daarenbowe, het ons 'n verbining gesintetiseer met 'n inhibisie aktiwiet ("IC50" waarde) van 1 nM, waarvan die aktiwitiet van slegs die rasemiese mengsel van die verbinding bepaal is. Hierdie vinding het dus 'n nuwe navorsings deur vir ons groep geopen.

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