Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti -HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC 50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC 50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC 50 = 10.6 nM), being comparable with ETR (EC 50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC 50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC 50 = 0.0589 μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti -HIV-1 agents. Image 1 • A series of "dual-site" binding diarylpyrimidine derivatives were discovered. • Trans -double bond with spatial orientation advantage was introduced. • 14c turned out to be potent inhibitor against single mutation strain E138K. • 14c acted as classical NNRT inhibitors with high affinity for WT HIV-1 RT. • 14c and 17l are proposed as promising inhibitors by MD simulation. [ABSTRACT FROM AUTHOR]