Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase

Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targe ting the nonnucleoside inhibitor (NNI) binding site of human immunodeficien cy virus (HIV) reverse transcriptase (RT) have been designed based on the s tructure of the NNI binding pocket and tested for anti-HIV activity. Our le ad DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrim idin-4-(1H)-one, elicited potent inhibitory activity against purified recom binant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) bu t showed no detectable cytotoxicity at concentrations as high as 100 mu M.