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Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non\u2010nucleoside 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 <jats:bold>11h<\/jats:bold> bearing the cyano\u2010substituted benzyl moiety proved to be the most effective inhibitor against HIV\u20101 wild\u2010type and mutant strains (EC<jats:sub>50<\/jats:sub>\u2009=\u20090.0039\u20130.338\u2009\u03bcM), being far more potent than or comparable to etravirine and doravirine. Besides, <jats:bold>11h<\/jats:bold> did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of <jats:bold>11h<\/jats:bold> was further confirmed to be reverse transcriptase (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.055\u2009\u03bcM). Preliminary structure\u2013activity 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\u2010likeness assessment indicated that <jats:bold>11h<\/jats:bold> possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for <jats:bold>11h<\/jats:bold>. Notably, <jats:bold>11h<\/jats:bold> was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half\u2010lives in human plasma and liver microsomes. Overall, <jats:bold>11h<\/jats:bold> holds great promise as an ideal Anti\u2010HIV\u20101 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug\u2010like profiles.<\/jats:p>","DOI":"10.1002\/jmv.29830","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T10:20:01Z","timestamp":1722248401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structure\u2010based design, synthesis, and biological characterization of indolylarylsulfone derivatives as novel human immunodeficiency virus type 1 inhibitors with potent antiviral activities and favorable drug\u2010like profiles"],"prefix":"10.1002","volume":"96","author":[{"given":"Zhao","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"},{"name":"China\u2010Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province  Jinan Shandong China"},{"name":"Suzhou Research Institute of Shandong University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huizhan","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik\u00a0De","family":"Clercq","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy Rega Institute for Medical Research, K.U. Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy Rega Institute for Medical Research, K.U. Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin\u2010Ho","family":"Chen","sequence":"additional","affiliation":[{"name":"Surgical Oncology Research Facility, Duke University Medical Center  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9232-953X","authenticated-orcid":false,"given":"Dongwei","family":"Kang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"},{"name":"China\u2010Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"},{"name":"China\u2010Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University  Jinan Shandong China"},{"name":"China\u2010Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1916753"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28973"},{"key":"e_1_2_9_4_1","unstructured":"The Joint United Nations Programme on HIV\/AIDS. 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