Synthesis and biological evaluation of novel 2-(substituted phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs

A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC50 ranging from 4.48 μM to 0.18 μM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-5-methylpyrimidin-4(3H)-one 4b3 was identified as the most promising compound (EC50 = 0.18 ± 0.06 μM, CC50 >243.56 μM, SI >1326). The structure–activity relationship (SAR) of these new congeners is discussed.

The compound 4b3 was docked into the NNRTIs binding pocket (NNIBP) of HIV-1 RT (PDB code: 1RT2) using Autodock Vina [http://vina.scripps.edu]. The docking result of 4b3 is showed by PyMOL [http://pymol.sourceforge.net].Figure optionsDownload as PowerPoint slide