Zongkai Huang, Xupeng Gou, Xudong Hang, Ting Shi, Jiaxing Yang, Yan Liu, Xinlian He, Jin Li, Keao Quan, Hongkai Bi* and Youfu Luo*,
{"title":"作为金黄色葡萄球菌新型 DHFR 抑制剂的 5-(5-碘-2-异丙基-4-甲氧基苯氧基)嘧啶-2,4-二胺 (AF-353) 衍生物的设计、合成和生物学评价。","authors":"Zongkai Huang, Xupeng Gou, Xudong Hang, Ting Shi, Jiaxing Yang, Yan Liu, Xinlian He, Jin Li, Keao Quan, Hongkai Bi* and Youfu Luo*, ","doi":"10.1021/acs.jmedchem.3c02355","DOIUrl":null,"url":null,"abstract":"<p >The high lethality of <i>Staphylococcus aureus</i> infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound <b>h1</b> (<b>AF-353</b>) as a novel <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of <b>h1</b> and performed a comprehensive structure–activity relationship (SAR) assay based on <b>h1</b>. The representative compound <b>j9</b> exhibited potent antibacterial activity against <i>S. aureus</i> without cross-resistance to other antimicrobial classes. Multiple genetic and biochemical approaches showed that <b>j9</b> directly binds to <i>Sa</i>DHFR, resulting in strong inhibition of its enzymatic activity (IC<sub>50</sub> = 0.97 nM). Additionally, <b>j9</b> had an acceptable <i>in vivo</i> safety profile and oral bioavailability (<i>F</i> = 40.7%) and also showed favorable efficacy in a mouse model of methicillin-resistant <i>S. aureus</i> (MRSA) skin infection. Collectively, these findings identified <b>j9</b> as a novel <i>Sa</i>DHFR inhibitor with the potential to combat drug-resistant <i>S. aureus</i> infections.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 6","pages":"4757–4781"},"PeriodicalIF":6.8000,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Biological Evaluation of 5-(5-Iodo-2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (AF-353) Derivatives as Novel DHFR Inhibitors against Staphylococcus aureus\",\"authors\":\"Zongkai Huang, Xupeng Gou, Xudong Hang, Ting Shi, Jiaxing Yang, Yan Liu, Xinlian He, Jin Li, Keao Quan, Hongkai Bi* and Youfu Luo*, \",\"doi\":\"10.1021/acs.jmedchem.3c02355\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The high lethality of <i>Staphylococcus aureus</i> infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound <b>h1</b> (<b>AF-353</b>) as a novel <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of <b>h1</b> and performed a comprehensive structure–activity relationship (SAR) assay based on <b>h1</b>. The representative compound <b>j9</b> exhibited potent antibacterial activity against <i>S. aureus</i> without cross-resistance to other antimicrobial classes. Multiple genetic and biochemical approaches showed that <b>j9</b> directly binds to <i>Sa</i>DHFR, resulting in strong inhibition of its enzymatic activity (IC<sub>50</sub> = 0.97 nM). Additionally, <b>j9</b> had an acceptable <i>in vivo</i> safety profile and oral bioavailability (<i>F</i> = 40.7%) and also showed favorable efficacy in a mouse model of methicillin-resistant <i>S. aureus</i> (MRSA) skin infection. Collectively, these findings identified <b>j9</b> as a novel <i>Sa</i>DHFR inhibitor with the potential to combat drug-resistant <i>S. aureus</i> infections.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"67 6\",\"pages\":\"4757–4781\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-03-11\",\"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.3c02355\",\"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.3c02355","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design, Synthesis, and Biological Evaluation of 5-(5-Iodo-2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (AF-353) Derivatives as Novel DHFR Inhibitors against Staphylococcus aureus
The high lethality of Staphylococcus aureus infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound h1 (AF-353) as a novel Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of h1 and performed a comprehensive structure–activity relationship (SAR) assay based on h1. The representative compound j9 exhibited potent antibacterial activity against S. aureus without cross-resistance to other antimicrobial classes. Multiple genetic and biochemical approaches showed that j9 directly binds to SaDHFR, resulting in strong inhibition of its enzymatic activity (IC50 = 0.97 nM). Additionally, j9 had an acceptable in vivo safety profile and oral bioavailability (F = 40.7%) and also showed favorable efficacy in a mouse model of methicillin-resistant S. aureus (MRSA) skin infection. Collectively, these findings identified j9 as a novel SaDHFR inhibitor with the potential to combat drug-resistant S. aureus infections.
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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