A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C-4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)-1 in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC50 values in the range of 1.7-13.2 nm. Of these compounds, 2-bromophenyl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazone (9k) displayed the most potent anti-HIV-1 activity (EC50=1.7 +/- 0.6 nm), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4-methyl phenyl analogue 9d (EC50=2.4 +/- 0.2 nm, SI=18461) showed broad spectrum HIV inhibitory activity, with EC50 values of 2.4 +/- 0.2 nm against wild-type HIV-1, 5.3 +/- 0.4 mu m against HIV-1 double-mutated strain RES056 (K103N+Y181C), and 5.5 mu m against HIV-2 ROD strain. Furthermore, structure-activity relationship (SAR) data and molecular modeling results for these compounds are also discussed.