Design, synthesis, and mechanistic investigations of phenylalanine derivatives containing a benzothiazole moiety as HIV-1 capsid inhibitors with improved metabolic stability

Eur J Med Chem. 2022 Jan 5:227:113903. doi: 10.1016/j.ejmech.2021.113903.

Shujing Xu ¹, Lin Sun ¹, Alexej Dick ², Waleed A Zalloum ³, Tianguang Huang ¹, Megan E Meuser ², Xujie Zhang ¹, Yucen Tao ¹, Srinivasulu Cherukupalli ¹, Dang Ding ¹, Xiao Ding ¹, Shenghua Gao ¹, Xiangyi Jiang ¹, Dongwei Kang ¹, Erik De Clercq ⁴, Christophe Pannecouque ⁵, Simon Cocklin ⁶, Xinyong Liu ⁷, Peng Zhan ⁸

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
2 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, PA, 19102, USA.
3 Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
5 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@kuleuven.be.
6 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, PA, 19102, USA. Electronic address: sc349@drexel.edu.
7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.

PMID: 34653770 DOI: 10.1016/j.ejmech.2021.113903

Abstract

Further clinical development of PF74, a lead compound targeting HIV-1 capsid, is impeded by low Antiviral activity and inferior metabolic stability. By modifying the benzene (region I) and indole of PF74, we identified two potent compounds (7m and 7u) with significantly improved metabolic stability. Compared to PF74, 7u displayed greater metabolic stability in human liver microsomes (HLMs) with half-life (t_1/2) 109-fold that of PF74. Moreover, mechanism of action (MOA) studies demonstrated that 7m and 7u effectively mirrored the MOA of compounds that interact within the PF74 interprotomer pocket, showing direct and robust interactions with recombinant CA, and 7u displaying Antiviral effects in both the early and late stages of HIV-1 replication. Furthermore, MD simulation corroborated that 7u was bound to the PF74 binding site, and the results of the online molinspiration software predicted that 7m and 7u had desirable physicochemical properties. Unexpectedly, this series of compounds exhibited better Antiviral activity than PF74 against HIV-2, represented by compound 7m whose anti-HIV-2 activity was almost 5 times increased potency over PF74. Therefore, we have rationally redesigned the PF74 chemotype to inhibitors with novel structures and enhanced metabolic stability in this study. We hope that these new compounds can serve as a blueprint for developing a new generation of HIV treatment regimens.

Keywords

Benzothiazole; Capsid inhibitor; HIV-1; Metabolic stability; Phenylalanine.

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