Atefeh Garzan, S. Kaleem Ahmed, Nicole N. Haese, Gauthami Sulgey, Samuel Medica, Jessica L. Smith, Sixue Zhang, Fahim Ahmad, Shuklendu Karyakarte, Lynn Rasmussen, Victor DeFilippis, Babu Tekwani, Robert Bostwick, Mark J. Suto, Alec J. Hirsch, Thomas E. Morrison, Mark T. Heise, Corinne E. Augelli-Szafran, Daniel N. Streblow, Ashish K. Pathak and Omar Moukha-Chafiq*,
{"title":"4-取代-2-噻唑酰胺作为甲病毒复制抑制剂的研究","authors":"Atefeh Garzan, S. Kaleem Ahmed, Nicole N. Haese, Gauthami Sulgey, Samuel Medica, Jessica L. Smith, Sixue Zhang, Fahim Ahmad, Shuklendu Karyakarte, Lynn Rasmussen, Victor DeFilippis, Babu Tekwani, Robert Bostwick, Mark J. Suto, Alec J. Hirsch, Thomas E. Morrison, Mark T. Heise, Corinne E. Augelli-Szafran, Daniel N. Streblow, Ashish K. Pathak and Omar Moukha-Chafiq*, ","doi":"10.1021/acs.jmedchem.4c0107310.1021/acs.jmedchem.4c01073","DOIUrl":null,"url":null,"abstract":"<p >2-(Methylthio)-<i>N</i>-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide <b>1</b> was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC<sub>50</sub> = 0.6 μM; EC<sub>90</sub> = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC<sub>50</sub> = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure–activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of <b>1</b> led to the discovery of a new potent inhibitor <i>N</i>-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide <b>26</b>, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC<sub>90</sub> of 0.45 μM with considerably improved MLM stability (<i>t</i><sub>1/2</sub> = 74 min) as compared to <b>1</b>. Mechanism of action studies show that <b>26</b> inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The <i>in vivo</i> efficacy studies of compound <b>26</b> on CHIKV infection in mice are reported.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20858–20878 20858–20878"},"PeriodicalIF":6.8000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses\",\"authors\":\"Atefeh Garzan, S. Kaleem Ahmed, Nicole N. Haese, Gauthami Sulgey, Samuel Medica, Jessica L. Smith, Sixue Zhang, Fahim Ahmad, Shuklendu Karyakarte, Lynn Rasmussen, Victor DeFilippis, Babu Tekwani, Robert Bostwick, Mark J. Suto, Alec J. Hirsch, Thomas E. Morrison, Mark T. Heise, Corinne E. Augelli-Szafran, Daniel N. Streblow, Ashish K. Pathak and Omar Moukha-Chafiq*, \",\"doi\":\"10.1021/acs.jmedchem.4c0107310.1021/acs.jmedchem.4c01073\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >2-(Methylthio)-<i>N</i>-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide <b>1</b> was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC<sub>50</sub> = 0.6 μM; EC<sub>90</sub> = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC<sub>50</sub> = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure–activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of <b>1</b> led to the discovery of a new potent inhibitor <i>N</i>-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide <b>26</b>, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC<sub>90</sub> of 0.45 μM with considerably improved MLM stability (<i>t</i><sub>1/2</sub> = 74 min) as compared to <b>1</b>. Mechanism of action studies show that <b>26</b> inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The <i>in vivo</i> efficacy studies of compound <b>26</b> on CHIKV infection in mice are reported.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"67 23\",\"pages\":\"20858–20878 20858–20878\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01073\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01073","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses
2-(Methylthio)-N-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC50 = 0.6 μM; EC90 = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC50 = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure–activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of 1 led to the discovery of a new potent inhibitor N-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC90 of 0.45 μM with considerably improved MLM stability (t1/2 = 74 min) as compared to 1. Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV infection in mice are reported.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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