Citation: Kun Zhang, Li-Min Zhao, Tianhao Xing, Yueyue Bu, Qingyun Wang, Christophe Pannecouque, Erik De Clercq, Angela Corona, Laura Dettori, Enzo Tramontano, Shuai Wang, Fen-Er Chen. Rational structure-based design and optimization of next-generation biphenyl-piperidine-triazine derivatives as potent non-nucleoside reverse transcriptase inhibitors[J]. Chinese Chemical Letters, ;2026, 37(1): 111283. doi: 10.1016/j.cclet.2025.111283 shu

Rational structure-based design and optimization of next-generation biphenyl-piperidine-triazine derivatives as potent non-nucleoside reverse transcriptase inhibitors

Kun Zhang ^{a, c, d, 1} ,
Li-Min Zhao ^{c, d, 1} ,
Tianhao Xing ^{a, c, d} ,
Yueyue Bu ^{a, c, d} ,
Qingyun Wang ^{a, c, d} ,
Christophe Pannecouque ^e ,
Erik De Clercq ^e ,
Angela Corona ^f ,
Laura Dettori ^f ,
Enzo Tramontano ^f ,
Shuai Wang ^{b, c, d, *,} ,
Fen-Er Chen ^{a, c, d, *,}

a.
Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
b.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
c.
Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China
d.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
e.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
f.
Department of Life and Environmental Sciences, University of Cagliari, Monserrato I-09042, Italy

shuaiwang@fudan.edu.cn

rfchen@fudan.edu.cn

Received Date: 5 March 2025
Revised Date: 29 April 2025
Accepted Date: 30 April 2025
Available Online: 21 May 2025

Figures(3)

To enhance the anti-resistance efficacy of our previously disclosed naphthyl-triazine 5, structure-based drug design strategy was rationally conducted to design a series of novel biphenyl-piperidine-triazine-containing non-nucleoside reverse transcriptase inhibitors. Remarkably, several of these compounds demonstrated single-digit nanomolar antiviral potency against both wild-type (WT) human immunodeficiency virus-1 (HIV-1) and five clinically relevant mutant strains. Among these, compound 11s emerged as the most potent inhibitor, showing remarkable efficacy against WT HIV-1 (50% effective concentration (EC₅₀) = 2 nmol/L) and five mutant strains (EC₅₀ = 0.003–0.073 µmol/L), which was significantly superior to that of compound 5. This optimized derivative demonstrated substantially improved pharmacological properties compared to existing drugs etravirine (ETR) and rilpivirine (RPV), showing a 4-fold reduction in cytotoxicity alongside 6-fold enhancement in selectivity index (50% cytotoxic concentration (CC₅₀) = 19.69 µmol/L, selectivity index (SI) = 7438). The compound’s metabolic profile revealed exceptional stability, with an elimination half-life (t_1/2 = 41.4 min) more than double that of RPV (t_1/2 = 16.03 min). Comprehensive safety evaluation indicated minimal cytochrome P450 (CYP) enzymes interference, low cardiac ion channel activity, and no observable acute toxicity, collectively suggesting a reduced risk profile for therapeutic applications. These promising characteristics significantly advance the development potential of biphenyl-piperidine-triazine derivatives as next-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs), offering enhanced efficacy, improved safety, and favorable pharmacokinetic properties for antiretroviral therapy.
- AIDS,
- HIV-1,
- NNRTIs,
- Biphenyl-piperidine-triazines,
- Anti-resistance efficacy
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