In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structureactivity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication at the lower micromolar concentration range (EC50: 0.046- 5.46µM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with EC50 value of 0.046µM, CC50 of 99.9µM and the viral selectivity index amounted up to 2149. These values were much better than those of NVP (EC50= 0.09 µM) and DDC (EC50= 1.04 µM). Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC50 value of 4.06 µM, which was at the same order of magnitude as that of NVP (2.74 µM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.