Structure-based discovery of novel diarylpyrimidines as potent and selective Non-Nucleoside reverse transcriptase inhibitors: From CH(CN)-Biphenyl-Diarylpyrimidines to CNNH2-Biphenyl-Diarylpyrimidines

Xiao-Mei Chen; Christophe Pannecouque; Erik De Clercq; Yu-Xuan Lian; Angela Corona; Laura Dettori; Enzo Tramontano; Shuai Wang; Fen-Er Chen

doi:10.1016/j.ejmech.2025.117271

Structure-based discovery of novel diarylpyrimidines as potent and selective Non-Nucleoside reverse transcriptase inhibitors: From CH(CN)-Biphenyl-Diarylpyrimidines to CNNH₂-Biphenyl-Diarylpyrimidines

Eur J Med Chem. 2025 Jan 12:285:117271. doi: 10.1016/j.ejmech.2025.117271. Online ahead of print.

Authors

Xiao-Mei Chen¹, Christophe Pannecouque², Erik De Clercq², Yu-Xuan Lian¹, Angela Corona³, Laura Dettori³, Enzo Tramontano³, Shuai Wang⁴, Fen-Er Chen⁵

Affiliations

¹ Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
² Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
³ Dept Appl Sci Biosyst, University of Cagliari, I-09042 Monserrato, Italy.
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].
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 Flow Chemistry and Engineering, School of Chemistry and Materials, Jiangxi Normal University, Nanchang, 330022, China. Electronic address: [email protected].

PMID: 39813776
DOI: 10.1016/j.ejmech.2025.117271

Abstract

In order to enhance the anti-HIV-1 potency and selectivity of the previously reported compound 3 (EC₅₀ = 27 nM, SI = 1361), a series of novel biphenyl-diarylpyrimidine derivatives were developed by employing structure-based drug design strategy. Among these derivatives, compound M44 demonstrated the most potent inhibitory activity against wild-type (WT) HIV-1 as well as five drug-resistant mutants (EC₅₀ = 5-148 nM), which were 5-173 times more potent than that of 3 (EC₅₀ = 27-9810 nM). Furthermore, this analogue exhibited approximately 11-fold lower cytotoxicity (CC₅₀ = 54 μM) than that of etravirine and rilpivirine. Concurrently, it possessed an improved selectivity index (SI) of 10995. Additionally, compound M44 was characterized by favorable metabolic stability in human plasma and human liver microsomes. No acute toxicity or organ damage was observed at a dose of 2 g/kg. Overall, M44 represents a highly promising lead compound that warrants further optimization efforts to identify potential anti-HIV-1 drug candidates.

Keywords: AIDS; DAPYs; HIV-1; NNRTIs.