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Design, synthesis, and mechanistic investigations of phenylalanine derivatives containing a benzothiazole moiety as HIV-1 capsid inhibitors with improved metabolic stability
Journal article   Open access   Peer reviewed

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

Shujing Xu, Lin Sun, Alexej Dick, Waleed A. Zalloum, Tianguang Huang, Megan E. Meuser, Xujie Zhang, Yucen Tao, Srinivasulu Cherukupalli, Dang Ding, …
European journal of medicinal chemistry, v 227, 113903
05 Jan 2022
DOI: https://doi.org/10.1016/j.ejmech.2021.113903
PMID: 34653770
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119080View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Benzothiazole Capsid inhibitor HIV-1 Metabolic stability Phenylalanine
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 (t1/2) 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. [Display omitted] •Novel phenylalanine derivatives containing a benzothiazole moiety are identified as HIV-1 capsid inhibitors.•Compound 7u displayed greater metabolic stability in human liver microsomes with half-life (t1/2) 109-fold that of PF74.•The newly synthesized compounds exhibited better antiviral activity than PF74 against HIV-2.•The anti-HIV-2 activity of 7m was almost 5 times higher than that of PF74.

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25 citations in Web of Science
24 citations in Scopus

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Medicinal
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