As a continuation of our efforts to discover and develop "me-better" drugs of DAPYs, novel diarylpyridine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. The majority of these compounds showed high activity against wild-type HIV-1 strain (IIIB) with EC50 values in the range of 0.04-4.41 μM. Among them, compound 5b2 (EC50 = 0.04 μM, SI = 3963) was the most potent. This compound showed anti-HIV-1IIIB activity superior than of Nevirapine but still inferior than of Etravirine. Selected compounds were also evaluated for the activity against reverse transcriptase (RT), and most of the compounds exhibited submicromolar IC50 values indicating they are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.