Structure-based design, synthesis, and biological characterization of indolylarylsulfone derivatives as novel human immunodeficiency virus type 1 inhibitors with potent antiviral activities and favorable drug-like profiles

被引:0
作者
Wang, Zhao [1 ,2 ,3 ]
Wang, Wenbo [1 ]
Gao, Zhen [1 ]
Gao, Huizhan [1 ]
Clercq, Erik De [4 ]
Pannecouque, Christophe [4 ]
Chen, Chin-Ho [5 ]
Kang, Dongwei [1 ,2 ]
Zhan, Peng [1 ,2 ]
Liu, Xinyong [1 ,2 ]
机构
[1] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ,Cheeloo Coll Med, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China
[2] China Belgium Collaborat Res Ctr Innovat Antiviral, Jinan, Shandong, Peoples R China
[3] Shandong Univ, Suzhou Res Inst, Suzhou, Jiangsu, Peoples R China
[4] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, Leuven, Belgium
[5] Duke Univ, Med Ctr, Surg Oncol Res Facil, Durham, NC 27710 USA
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
biological evaluation; HIV-1; indolylarylsulfone derivatives; molecular dynamics simulation; structure-based design; REVERSE-TRANSCRIPTASE INHIBITORS; CRYSTAL-STRUCTURES; RESISTANCE; RILPIVIRINE; MECHANISMS; DISCOVERY; CHANNEL;
D O I
10.1002/jmv.29830
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 mu M), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 mu M). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
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页数:20
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