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Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors.

Authors
  • Chen, Xiaomei1
  • Ding, Li2
  • Tao, Yuan2
  • Pannecouque, Christophe3
  • De Clercq, Erik3
  • Zhuang, Chunlin4
  • Chen, Fen-Er5
  • 1 Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. , (China)
  • 2 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. , (China)
  • 3 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium. , (Belgium)
  • 4 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: [email protected] , (China)
  • 5 Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, 310014, Hangzhou, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
European journal of medicinal chemistry
Publication Date
Sep 15, 2020
Volume
202
Pages
112549–112549
Identifiers
DOI: 10.1016/j.ejmech.2020.112549
PMID: 32712537
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The single enantiomers of seven hydroxyl-substituted biphenyl-diarylpyrimidines were designed and synthesized by a bioisosterism strategy as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The cellular and enzymatic assays indicated that the novel obtained compounds had significant activities and relatively low cytotoxicity. The supercritical fluid chromatography (SFC) enantioseparations of the racemic compounds and the enantiomeric profiling resulted that the (S) forms were generally more potent than the (R) counterparts. Among all the chiral derivatives, (S)-(-)-12a showed the best potency with the antiviral activities against wild-type (WT) and single mutant strains (L100I, K103 N, Y181C, E138K; especially Y188L), and RT enzyme in the low nanomolar concentration range. Toward double mutant virus strains (F227L + V106A, RES056), (S)-(-)-12a possessed submicromolar antiviral activities. In addition, (S)-(-)-12a showed a high cell-based selectivity index (SI WT = 5822) and no apparent toxicity was observed in the in vivo acute toxicity assay and electrocardiogram. The molecular docking studies predicted the binding modes of the compounds with RT and explained the activity differences for the enantiomers. Although the rat pharmacokinetic assay indicated a poor oral metabolism of the hydroxyl compound, the promising antiviral activity of the chiral hydroxyl-substituted biphenyl-diarylpyrimidines provided valuable lead compounds for further anti-HIV drug design. Copyright © 2020 Elsevier Masson SAS. All rights reserved.

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