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Deuterated-biphenyl-DAPY derivatives as potent and low-cytotoxicity non-nucleoside reverse transcriptase inhibitors: design, synthesis and anti-HIV-1 evaluation
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Kun ZHANG1, 2, Yue-yue BU1, 2, Christophe Pannecouque3, Erik De Clercq3, Enzo Tramontano4, Phuong-Thao Tran5, Shuai WANG1, 2, *, Fen-er CHEN1, 2, *
Acta Pharmaceutica Sinica | 2025, 60(8) : 2545 - 2554
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Acta Pharmaceutica Sinica | 2025, 60(8): 2545-2554
• Original Articles •
Deuterated-biphenyl-DAPY derivatives as potent and low-cytotoxicity non-nucleoside reverse transcriptase inhibitors: design, synthesis and anti-HIV-1 evaluation
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Kun ZHANG1, 2, Yue-yue BU1, 2, Christophe Pannecouque3, Erik De Clercq3, Enzo Tramontano4, Phuong-Thao Tran5, Shuai WANG1, 2, *, Fen-er CHEN1, 2, *
Affiliations
  • 1Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
  • 2Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
  • 3Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
  • 4Dept Appl Sci Biosyst, University of Cagliari, Monserrato Ⅰ-09042, Italy
  • 5Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 008404, Vietnam
Published: 2025-08-12 doi: 10.16438/j.0513-4870.2025-0653
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in AIDS treatment. Diarylpyrimidine derivatives (DAPYs) represent one of the most important classes of NNRTIs. The previously reported ZK-4a showed high cytotoxicity (CC50 = 5.98 μmol·L-1), significantly limiting its therapeutic potential. To resolve this issue, we adopted a two-pronged strategy: replacing the NH fragment with an O atom and modifying the C-5 position of the pyrimidine core. These modifications enabled the design and synthesis of 27 novel deuterated-biphenyl-DAPY analogues. Fortunately, all deuterated-biphenyl-DAPYs exhibited broad and highly efficient antiviral activity, as well as obviously decreased cytotoxicity (CC50 = 18.02- > 297.27 μmol·L-1). Among them, compound 8s achieved an EC50 value of 8.88 nmol·L-1 while showing negligible cytotoxicity (CC50 > 287.68 μmol·L-1). Compound 8s also displayed exceptional resistance profiles with EC50 values of 7.54 nmol·L-1 (L100I), 8.57 nmol·L-1 (K103N), 24.28 nmol·L-1 (Y181C), 62.71 nmol·L-1 (Y188L) and 14.38 nmol·L-1 (E138K). Additionally, the target of deuterated-biphenyl-DAPYs was verified by reverse transcriptase enzyme inhibition assays.

acquired immunodeficiency syndrome  /  human immunodeficiency virus-1  /  antiviral  /  non-nucleoside reverse transcriptase inhibitor  /  deuterated-biphenyl-DAPY
张坤, 卜悦悦, Christophe Pannecouque, Erik De Clercq, Enzo Tramontano, Phuong-Thao Tran, 王帅, 陈芬儿. 氘代-联苯-DAPYs衍生物作为高效低毒非核苷类逆转录酶抑制剂的设计、合成及抗HIV-1病毒活性研究. 药学学报, 2025 , 60 (8) : 2545 -2554 . DOI: 10.16438/j.0513-4870.2025-0653
Kun ZHANG, Yue-yue BU, Christophe Pannecouque, Erik De Clercq, Enzo Tramontano, Phuong-Thao Tran, Shuai WANG, Fen-er CHEN. Deuterated-biphenyl-DAPY derivatives as potent and low-cytotoxicity non-nucleoside reverse transcriptase inhibitors: design, synthesis and anti-HIV-1 evaluation[J]. Acta Pharmaceutica Sinica, 2025 , 60 (8) : 2545 -2554 . DOI: 10.16438/j.0513-4870.2025-0653
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Year 2025 volume 60 Issue 8
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Article Info
doi: 10.16438/j.0513-4870.2025-0653
  • Receive Date：2025-06-11
  • Online Date：2026-09-20
  • Published：2025-08-12
Article Data
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History
  • Received：2025-06-11
  • Revised：2025-07-03
Affiliations
    1Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
    2Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
    3Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
    4Dept Appl Sci Biosyst, University of Cagliari, Monserrato Ⅰ-09042, Italy
    5Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 008404, Vietnam
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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