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

Journal Article (Journal Article)

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 EC50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50 = 10.6 nM), being comparable with ETR (EC50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50 = 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.

Full Text

Duke Authors

Cited Authors

  • Feng, D; Zuo, X; Jing, L; Chen, C-H; Olotu, FA; Lin, H; Soliman, M; De Clercq, E; Pannecouque, C; Lee, K-H; Kang, D; Liu, X; Zhan, P

Published Date

  • February 5, 2021

Published In

Volume / Issue

  • 211 /

Start / End Page

  • 113063 -

PubMed ID

  • 33340914

Electronic International Standard Serial Number (EISSN)

  • 1768-3254

Digital Object Identifier (DOI)

  • 10.1016/j.ejmech.2020.113063


  • eng

Conference Location

  • France