Synthesis and biological evaluation of N-acyl diaryl pyrimidines (NDAPYs) as novel reverse transcriptase inhibitors.

Diaryl pyrimidines (DAPYs) are privileged structures for Non-Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs), and they are considered as one of the fundamental scaffolds of existing anti-HIV agents. In this study, we designed novel molecules by the addition of a N-acyl group to the C4-position of Rilpivirine/Etravirine basic scaffold, a well-known class of DAPYs, in order to provide more interactions with K103 and E138 in Reverse Transcriptase. This was leading, as expected, to better in vitro RT inhibition, and the compounds 12c (56 %) and 12 k (49 %) demonstrated three-fold higher potency than Doravirine (17 %). Additionally, compound 12c was identified as a strong and 12k as a moderate HIV reverse transcriptase enzyme inhibitor in the in vitro experiments. DAPYs are also crucial in the development of novel anti-cancer agents targeting several kinases, and our compounds, 12d and 12j, exhibited moderate cytotoxicity with IC values of 14.21 and 10.16 μM, respectively, against PC-3 cells and caused cell cycle arrest at G2/M checkpoint. The compound 12d induced apoptosis and reduced angiogenesis in PC-3 cells. Additionally, preliminary kinase screening against a panel of eight human kinases demonstrated only low PIM1 inhibition. However, the absence of correlation with cytotoxicity advocates an alternative mode of action that ought to be determined. Altogether, these studies indicate that the C4-position of diaryl pyrimidines could be important and warrants further investigated towards optimization of potential reverse transcriptase inhibitors.