There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead <b>K-5a2</b> led to the identification of a potent inhibitor <b>16c</b>. <b>16c</b> yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of <b>16c</b> toward the NNRTI-adjacent site as a lead development strategy. Furthermore, <b>16c</b> demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of <b>16c</b> as a promising anti-HIV-1 drug candidate.