2. Academic Validation
  3. Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

  • J Med Chem. 2021 Apr 22;64(8):5067-5081. doi: 10.1021/acs.jmedchem.1c00128.
Li Ding 1 2 3,  Christophe Pannecouque 4,  Erik De Clercq 4,  Chunlin Zhuang 2 3,  Fen-Er Chen 1 2 3 5
Affiliations

Affiliations

  • 1 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 2 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 3 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 4 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
  • 5 Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, 310014 Hangzhou, China.
PMID: 33851529 DOI: 10.1021/acs.jmedchem.1c00128
Abstract

Considering the nonideal metabolic stability of the difluoro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted alkyl groups on the linker region to block the potential metabolic sensitive sites generated 22 derivatives. Among them, compound 12a with an N-methyl group displayed excellent anti-HIV-1 activity and selectivity. The methyl group was hopped to the central pyrimidine to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved anti-HIV-1 activity, much lower cytotoxicity, and nanomolar activity toward multiple mutants. In addition, 16y has a better stability in human liver microsomes than 4. Moreover, no apparent in vivo acute toxicity was observed in 16y-treated female, especially pregnant mice. This series of alkylated compounds with highly potency and safety represent a promising lead template for future discovery.

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