Citation: Yin-Xiang Zhang, Christophe Pannecouque, Erik De Clercq, Enzo Tramontano, Angela Corona, Laura Dettori, Phuong-Thao Tran, Xu-Dong Li, Shuo Su, Shuai Wang, Fen-Er Chen. Discovery of novel and potent non-nucleoside reverse transcriptase inhibitors through structure-based drug design for HIV treatment[J]. Chinese Chemical Letters, ;2026, 37(8): 112448. doi: 10.1016/j.cclet.2026.112448 shu

Discovery of novel and potent non-nucleoside reverse transcriptase inhibitors through structure-based drug design for HIV treatment

a.
Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, State Key Laboratory of Green Chemical Synthesis and Conversion, Fudan University, Shanghai 200043, China
b.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
c.
Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200032, China
d.
School of Data Science, Fudan University, Shanghai 200043, China
e.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium
f.
Dept Appl Sci Biosyst, University of Cagliari, Monserrato I-09042, Italy
g.
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Cua Nam, Hanoi 10000, Vietnam

shuaiwang@fudan.edu.cn

rfchen@fudan.edu.cn

Received Date: 1 October 2025
Revised Date: 21 January 2026
Accepted Date: 22 January 2026
Available Online: 23 January 2026

Figures(5)

In this work, a series of novel non-nucleoside reverse transcriptase inhibitors featuring pyridine-difluoro/dimethylaniline fragment and 4-aminepiperidine moiety were synthesized based on structure-based design strategy. Among these, the dimethyl-substituted analogue 20m, characterized by a larger dihedral angle, emerged as the most potent inhibitor against wild-type (WT) human immunodeficiency virus-1 (HIV-1) as well as multiple resistant strains. Compound 20m exhibited remarkable antiviral activity with median effect concentration (EC₅₀) values of 0.003 µmol/L (WT), 0.011 µmol/L (L100I), 0.001 µmol/L (K103N), 0.006 µmol/L (Y181C), 0.108 µmol/L (Y188L), 0.008 µmol/L (E138K), 0.196 µmol/L (F227L + V106A), and 0.032 µmol/L (Y181C + K103N), consistently outperforming efavirenz (EFV). Notably, 20m also demonstrated dramatically enhanced aqueous solubility, reaching >3954.5 µg/mL in phosphate buffer at pH 4.5 and >7380.6 µg/mL at pH 2.0, far exceeding that of etravirine (ETR). Collectively, these findings lay a robust foundation for the future optimization and development of next-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- HIV-1,
- NNRTIs,
- RT,
- Dihedral angle,
- Aqueous solubility
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1.
沈阳化工大学材料科学与工程学院沈阳 110142