Exploiting the hydrophobic channel of the NNIBP: Discovery of novel diarylpyrimidines as HIV-1 NNRTIs against wild-type and K103N mutant viruses

Abstract

To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC₅₀ values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC₅₀ values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC_50(IIIB) = 16 nM, EC_50(K103N) = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization.