Citation: Bairu Meng, Zongji Zhuo, Han Yu, Sining Tao, Zixuan Chen, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu. Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs[J]. Chinese Chemical Letters, ;2024, 35(6): 108827. doi: 10.1016/j.cclet.2023.108827 shu

Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs

Bairu Meng ^a ,
Zongji Zhuo ^a ,
Han Yu ^a ,
Sining Tao ^a ,
Zixuan Chen ^a ,
Erik De Clercq ^b ,
Christophe Pannecouque ^b ,
Dongwei Kang ^{a, c, *,} ,
Peng Zhan ^{a, c, *,} ,
Xinyong Liu ^{a, c, *,}

a.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China
b.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Leuven B-3000, Belgium
c.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan 250012, China

kangdongwei@126.com

zhanpeng1982@sdu.edu.cn

xinyongl@sdu.edu.cn

Received Date: 7 June 2023
Revised Date: 18 July 2023
Accepted Date: 19 July 2023
Available Online: 24 July 2023

Figures(5)

Inspired by our previous studies to discover novel human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) by targeting the tolerant region II of the NNRTIs binding pocket (NNIBP), a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs. The results showed that compound 16b was the most active inhibitor, exhibiting 50% effective concentration (EC₅₀) values from 0.021 µmol/L to 0.298 µmol/L against wild-type (WT) and a panel of NNRTIs-resistant HIV-1 strains. Moreover, 16b was demonstrated with a significantly low 50% cytotoxicity concentration (CC₅₀) value (> 200 µmol/L) and high selectivity index (SI) values. In addition, 16b yielded moderate reverse transcriptase (RT) enzyme inhibition with a 50% inhibition concentration (IC₅₀) value of 0.183 µmol/L, which demonstrated that it acted as HIV-1 NNRTIs. The binding mode of 16b with RT was also illustrated via molecular docking. Overall, this work provided a novel lead compound for developing potent HIV-1 NNRTIs.
- HIV-1,
- NNRTIs,
- DAPYs,
- Tolerant region II,
- Drug design
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