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

[摘要] 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.

[发布机构] Stellenbosch University