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 EC values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC = 16 nM, EC = 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.Copyright © 2021 Elsevier Ltd. All rights reserved.
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Erik De Clercq