Discovery of novel diarylpyrimidine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors: Design,...

Our previous efforts have led to the development of potent NNRTI K-5a2, but it suffered from poor metabolic stability and aqueous solubility. Another work resulted in compounds XJ2-56 and XJ2-90 with reduced activity against the Y188L mutant strain. In this work, 24 novel DAPY derivatives were designed based on a fragment hybridization strategy. The anti-HIV-1 activity in MT-4 cells demonstrated that 29 was the most potent inhibitor for HIV-1 IIIB, with an EC₅₀ of 1.38 nM. Moreover, it also exhibited excellent potency against a panel of mutant HIV-1 strains with EC₅₀ ranging from 1.61 to 119 nM. The enzyme inhibition assay showed that these compounds acted as HIV-1 NNRTIs. In addition, the aqueous solubility of 29 (S = 3.35 μg/mL) was greatly improved. Molecular docking was also conducted to clarify the binding mode of the newly designed compounds with RT.