Open AccessDesign, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities
Author(s) -
Lin Sun,
Alexej Dick,
Megan E. Meuser,
Tianguang Huang,
Waleed A. Zalloum,
Chin Ho Chen,
Srinivasulu Cherukupalli,
Peng Zhan,
Xiao Ding,
Ping Gao,
Dongwei Kang,
Erik De Clercq,
Christophe Pannecouque,
Chantal Simon,
KuoHsiung Lee,
Xinyong Liu,
Peng Zhan
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00015
Subject(s) - chemistry , capsid , mechanism of action , moiety , phenylalanine , stereochemistry , context (archaeology) , structure–activity relationship , human immunodeficiency virus (hiv) , chemical synthesis , in vitro , pharmacology , biochemistry , virology , amino acid , biology , gene , paleontology
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 PF-74 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 11l , which exhibited anti-HIV-1 NL4-3 activity 5.78-fold better than PF-74 . Interestingly, 11l also showed anti-HIV-2 ROD activity (EC 50 = 31 nM), with almost 120 times increased potency over PF-74 . 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 11l was 6.25 times more potent as compared to PF-74 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 PF-74 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 11l . Additionally, 11l exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to PF-74 , 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.