LTHIOMETHYL)THIO]-6-(BENZYL)-PYRIMIDIN-4-(1H)-ONES AS POTENT NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS OF S-DABO SERIES

Novel dihydroalkoxybenzyloxopyrimidine (S-DABO) derivatives targeting the non-nucleoside inhibitor (NNI) binding site of human immunodeficie ncy virus (HIV) reverse transcriptase (RT) have been synthesized using a novel computer model for the NNI binding pocket and tested for thei r RT inhibitory activity in cell-free assays using purified recombinan t HIV RT as well as for their anti-HIV activity in HTLVIIIB-infected p eripheral blood mononuclear cells. Our computational approach allowed the identification of several ligand derivatization sites for the gene ration of more potent S-DABO derivatives. Our lead S-DABO derivative, 2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4- (1H)-one (compound 3), elicited potent anti-HIV activity with an IC50 value of less than 1nM for inhibition of HIV replication without any evidence of cytotoxi city and an unprecedented selectivity index of >100,000. (C) 1998 Else vier Science Ltd. All rights reserved.