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

Publication ,  Journal Article
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 in: Eur J Med Chem
February 5, 2021

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.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

February 5, 2021

Volume

211

Start / End Page

113063

Location

France

Related Subject Headings

  • Structure-Activity Relationship
  • Pyrimidines
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV Reverse Transcriptase
  • Drug Design
  • Anti-HIV Agents
  • 3405 Organic chemistry
 

Citation

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Feng, D., Zuo, X., Jing, L., Chen, C.-H., Olotu, F. A., Lin, H., … Zhan, P. (2021). Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase. Eur J Med Chem, 211, 113063. https://doi.org/10.1016/j.ejmech.2020.113063
Feng, Da, Xiaofang Zuo, Lanlan Jing, Chin-Ho Chen, Fisayo A. Olotu, Hao Lin, Mahmoud Soliman, et al. “Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.Eur J Med Chem 211 (February 5, 2021): 113063. https://doi.org/10.1016/j.ejmech.2020.113063.
Feng, Da, et al. “Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.Eur J Med Chem, vol. 211, Feb. 2021, p. 113063. Pubmed, doi:10.1016/j.ejmech.2020.113063.
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. Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase. Eur J Med Chem. 2021 Feb 5;211:113063.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

February 5, 2021

Volume

211

Start / End Page

113063

Location

France

Related Subject Headings

  • Structure-Activity Relationship
  • Pyrimidines
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV Reverse Transcriptase
  • Drug Design
  • Anti-HIV Agents
  • 3405 Organic chemistry