2. Academic Validation
  3. Halogenation-Driven Discovery of Halomethylene-Biphenyl-Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Safety and PK Profiles

Halogenation-Driven Discovery of Halomethylene-Biphenyl-Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Safety and PK Profiles

  • J Med Chem. 2025 Aug 14;68(15):15358-15371. doi: 10.1021/acs.jmedchem.4c02237.
Xiao-Mei Chen 1,  Qian Xu 2 3,  Christophe Pannecouque 4,  Erik De Clercq 4,  Enzo Tramontano 5,  Phuong-Thao Tran 6,  Shuai Wang 2 3,  Fen-Er Chen 1 7 2 3
Affiliations

Affiliations

  • 1 Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, 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, Leuven B-3000, Belgium.
  • 5 Dept Appl Sci Biosyst, University of Cagliari, I-09042 Monserrato, Italy.
  • 6 Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam.
  • 7 Institute of Flow Chemistry and Engineering, School of Chemistry and Materials, Jiangxi Normal University, Nanchang 330022, China.
PMID: 40808526 DOI: 10.1021/acs.jmedchem.4c02237
Abstract

To improve the safety and PK profiles of our previously established (S)-4a, a series of halomethylene-linked biphenyl-DAPYs were developed. Enantioselectivity studies of the most promising 5m suggested that the (S)-enantiomer was more potent than its (R)-counterpart and racemate. The optimal (S)-5m exhibited remarkable Antiviral activity toward wild-type HIV-1 and single mutant strains (EC50 = 3.7-231 nM). Notably, this compound possessed 32-fold lower cytotoxicity and a 13-fold higher selectivity index (CC50 > 288 μM, SI > 78,125) than those of (S)-4a. In vitro metabolic stability assays demonstrated that (S)-5m had good stability in human plasma and human liver microsomes. Besides, no apparent inhibition of CYP or hERG was observed. More importantly, (S)-5m was characterized by favorable in vivo safety properties (LD50 > 2 g/kg) and significantly improved PK profiles (F = 49.5%, T1/2 = 13.86 h). These findings provided insights for the design of novel NNRTIs for HIV treatment.

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