Synthesis and Biological Evaluation of 6-Substituted 5-Alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as Potent HIV-1 NNRTIs

A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-4(3H)-ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti-HIV activity in MT-4 cells. Most of these new congeners exhibited moderate to good activities against the wild-type virus, with EC(50) values in the range of 1.40-0.19 mu m. Among them, 2-[(4-cyanophenylamino)carbonylmethylthio]- 6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-one 4b6 is one of the compounds endowed with the highest broad-spectrum HIV-1 inhibitory activity, with EC(50) values of .19 +/- 0.005 mu m against the wild-type virus, 1.05 +/- 0.24 mu m (twofold resistance) against the E138K strain, and 2.38 +/- 0.13 mu m (4.5-fold resistance) against the Y181C strain. Furthermore, reverse transcriptase (RT) inhibition assays against wildtype HIV-1 RT were performed with selected derivatives, confirming that the main target of these compounds is HIV-1 RT and that these new S-DABO analogues act as non-nucleoside RT inhibitors (NNRTIs). Structure-activity relationship and molecular modeling analyses of these new congeners are also discussed.