Phuong Nguyen Hoai Huynh, Phatcharin Khamplong, Minh-Hoang Phan, Thanh-Phuc Nguyen, Phuong Ngoc Lan Vu, Quang-Vinh Tang, Phumin Chamsodsai, Supaphorn Seetaha, Truong Lam Tuong, Thien Y. Vu, Duc-Duy Vo, Kiattawee Choowongkomon and Cam-Van T. Vo
{"title":"作为 SARS-CoV-2 主要蛋白酶抑制剂的不对称咪唑-4,5-二甲酰胺衍生物:设计、合成和生物学评价。","authors":"Phuong Nguyen Hoai Huynh, Phatcharin Khamplong, Minh-Hoang Phan, Thanh-Phuc Nguyen, Phuong Ngoc Lan Vu, Quang-Vinh Tang, Phumin Chamsodsai, Supaphorn Seetaha, Truong Lam Tuong, Thien Y. Vu, Duc-Duy Vo, Kiattawee Choowongkomon and Cam-Van T. Vo","doi":"10.1039/D4MD00414K","DOIUrl":null,"url":null,"abstract":"<p >The SARS-CoV-2 main protease, a vital enzyme for virus replication, is a potential target for developing drugs in COVID-19 treatment. Until now, three SARS-CoV-2 main protease inhibitors have been approved for COVID-19 treatment. This study explored the inhibitory potency of asymmetric imidazole-4,5-dicarboxamide derivatives against the SARS-CoV-2 main protease. Fourteen derivatives were designed based on the structure of the SARS-CoV-2 main protease active site, the hydrolysis mechanism, and the experience gained from the reported inhibitor structures. They were synthesized through a four-step procedure from benzimidazole and 2-methylbenzimidazole. SARS-CoV-2 main protease inhibition was evaluated <em>in vitro</em> by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. <em>N</em>-(4-Chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1<em>H</em>-imidazole-5-carboxamide (<strong>5a2</strong>) exhibited the highest potency against the SARS-CoV-2 main protease with an IC<small><sub>50</sub></small> of 4.79 ± 1.37 μM relative to ebselen with an IC<small><sub>50</sub></small> of 0.04 ± 0.013 μM. Enzyme kinetic and molecular docking studies were carried out to clarify the inhibitory mechanism and to prove that the compound interacts at the active site. We also performed cytotoxicity assay to confirm that these compounds are not toxic to human cells.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 11","pages":" 3880-3888"},"PeriodicalIF":4.1000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Asymmetric imidazole-4,5-dicarboxamide derivatives as SARS-CoV-2 main protease inhibitors: design, synthesis and biological evaluation†\",\"authors\":\"Phuong Nguyen Hoai Huynh, Phatcharin Khamplong, Minh-Hoang Phan, Thanh-Phuc Nguyen, Phuong Ngoc Lan Vu, Quang-Vinh Tang, Phumin Chamsodsai, Supaphorn Seetaha, Truong Lam Tuong, Thien Y. Vu, Duc-Duy Vo, Kiattawee Choowongkomon and Cam-Van T. Vo\",\"doi\":\"10.1039/D4MD00414K\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The SARS-CoV-2 main protease, a vital enzyme for virus replication, is a potential target for developing drugs in COVID-19 treatment. Until now, three SARS-CoV-2 main protease inhibitors have been approved for COVID-19 treatment. This study explored the inhibitory potency of asymmetric imidazole-4,5-dicarboxamide derivatives against the SARS-CoV-2 main protease. Fourteen derivatives were designed based on the structure of the SARS-CoV-2 main protease active site, the hydrolysis mechanism, and the experience gained from the reported inhibitor structures. They were synthesized through a four-step procedure from benzimidazole and 2-methylbenzimidazole. SARS-CoV-2 main protease inhibition was evaluated <em>in vitro</em> by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. <em>N</em>-(4-Chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1<em>H</em>-imidazole-5-carboxamide (<strong>5a2</strong>) exhibited the highest potency against the SARS-CoV-2 main protease with an IC<small><sub>50</sub></small> of 4.79 ± 1.37 μM relative to ebselen with an IC<small><sub>50</sub></small> of 0.04 ± 0.013 μM. Enzyme kinetic and molecular docking studies were carried out to clarify the inhibitory mechanism and to prove that the compound interacts at the active site. We also performed cytotoxicity assay to confirm that these compounds are not toxic to human cells.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":\" 11\",\"pages\":\" 3880-3888\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00414k\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00414k","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Asymmetric imidazole-4,5-dicarboxamide derivatives as SARS-CoV-2 main protease inhibitors: design, synthesis and biological evaluation†
The SARS-CoV-2 main protease, a vital enzyme for virus replication, is a potential target for developing drugs in COVID-19 treatment. Until now, three SARS-CoV-2 main protease inhibitors have been approved for COVID-19 treatment. This study explored the inhibitory potency of asymmetric imidazole-4,5-dicarboxamide derivatives against the SARS-CoV-2 main protease. Fourteen derivatives were designed based on the structure of the SARS-CoV-2 main protease active site, the hydrolysis mechanism, and the experience gained from the reported inhibitor structures. They were synthesized through a four-step procedure from benzimidazole and 2-methylbenzimidazole. SARS-CoV-2 main protease inhibition was evaluated in vitro by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. N-(4-Chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1H-imidazole-5-carboxamide (5a2) exhibited the highest potency against the SARS-CoV-2 main protease with an IC50 of 4.79 ± 1.37 μM relative to ebselen with an IC50 of 0.04 ± 0.013 μM. Enzyme kinetic and molecular docking studies were carried out to clarify the inhibitory mechanism and to prove that the compound interacts at the active site. We also performed cytotoxicity assay to confirm that these compounds are not toxic to human cells.