Development of triazine non-nucleoside reverse transcriptase inhibitors for microbicidal applications

Abstract

Background In search of antiretrovirals with microbicide potential, we have synthesized a library of non-nucleoside reverse transcriptase inhibitors (NNRTIs), encompassing 71 triazine analogues. We present data on the anti-HIV activity and toxicity using a broad armamentarium of in vitro assays and models. Materials and methods In a primary screen, the anti-HIV activity against the laboratory strain Ba-L and against a primary subtype C isolate was determined in the TZM-bl cell line. Cellular toxicity on TZM-bl cells was evaluated using WST-1. Subsequently, a selection o f1 7 compounds was further evaluated for anti-HIV activity in different primary cells, including peripheral blood mononuclear cells, dendritic cells and CD4+ T lymphocytes. In addition, the activity against NNRTI-resistantviruses (V106A, Y181C, L100I/ K103N) was tested. The toxicity profile was further investigated using blood cells and epithelial cells originating from the female genital tract (FGT) and in a dual chamber assay modeling the FGT and underlying mucosae. Finally, toxicity towards vaginal flora (reference strains of L.vaginalis, L. iners, L. jensenii, L. gasseri, L. crispatus ,A vaginae, G. vaginalis) was measured for the lead molecules UAMC00838 and UAMC01009. Dapivirine (TMC120) was used as a bench mark throughout the study. Results