Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl) methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1, 6c6, and 6b1 (EC(50) = 0.24 +/- 0.05, 0.38 +/- 0.13, 0.39 +/- 0.05 mu M, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50) = 0.21 mu M) and delavirdine (DLV) (EC(50) = 0.32 mu M). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies. (C) 2011 Elsevier Ltd. All rights reserved.