Journal article
Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities
Journal of medicinal chemistry, v 63(9), pp 4790-4810
14 May 2020
PMID: 32298111
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of
to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound
, which exhibited anti-HIV-1
activity 5.78-fold better than
. Interestingly,
also showed anti-HIV-2
activity (EC
= 31 nM), with almost 120 times increased potency over
. However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound
was 6.25 times more potent as compared to
but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as
with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of
. Additionally,
exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to
, as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors.
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Details
- Title
- Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities
- Creators
- Lin Sun - Shandong UniversityAlexej Dick - Drexel UniversityMegan E Meuser - Drexel UniversityTianguang Huang - Shandong UniversityWaleed A Zalloum - American University of MadabaChin-Ho Chen - Duke UniversitySrinivasulu Cherukupalli - Shandong UniversityShujing Xu - Shandong UniversityXiao Ding - Shandong UniversityPing Gao - Shandong UniversityDongwei Kang - Shandong UniversityErik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchSimon Cocklin - Drexel UniversityKuo-Hsiung Lee - University of North Carolina at Chapel HillXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- Journal of medicinal chemistry, v 63(9), pp 4790-4810
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R01 GM125396 / NIGMS NIH HHS R01 AI150491 / NIAID NIH HHS T32 MH079785 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000535279800025
- Scopus ID
- 2-s2.0-85084694244
- Other Identifier
- 991019168697404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal