In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with novel structures, we have employed a scaffold hopping strategy to explore the chemically diversed space of bioactive compounds. The original arylazolylthioacetanilide platform was replaced with different imidazopyridinylthioacetanilide scaffolds to yield the optimal pharmacophore moieties in order to generate novel NNRTIs with desirable potency. Some of the new compounds proved able to inhibit HIV-1 replication in the low micromolar range. In particular, compound 5b16 displayed the most potent anti-HIV-1 activity (EC(50) = 0.21 ± 0.06 μM), inhibiting HIV-1 IIIB replication in MT-4 cells more effectively than dideoxycytidine (EC(50) = 1.4 ± 0.1 μM) and similarly with nevirapine (EC(50) = 0.20 ± 0.10 μM). Preliminary structure-activity relationship (SAR) of the newly synthesized congeners is discussed, and molecular modeling study is performed to rationalize the SAR conclusions.