Luke R. Churchman , James R. Beckett , Lendl Tan , Kyra Woods , Daniel Z. Doherty , Amna Ghith , Paul V. Bernhardt , Stephen G. Bell , Nicholas P. West , James J. De Voss
{"title":"合成类固醇结核分枝杆菌抑制剂。","authors":"Luke R. Churchman , James R. Beckett , Lendl Tan , Kyra Woods , Daniel Z. Doherty , Amna Ghith , Paul V. Bernhardt , Stephen G. Bell , Nicholas P. West , James J. De Voss","doi":"10.1016/j.jsbmb.2024.106479","DOIUrl":null,"url":null,"abstract":"<div><p>Oxidised derivatives of cholesterol have been shown to inhibit the growth of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). The bacteriostatic activity of these compounds has been attributed to their inhibition of CYP125A1 and CYP142A1, two metabolically critical cytochromes P450 that initiate degradation of the sterol side chain. Here, we synthesise and characterise an extensive library of 28 cholesterol derivatives to develop a structure-activity relationship for this class of inhibitors. The candidate compounds were evaluated for MIC with virulent <em>Mtb</em> and in binding studies with CYP125A1 and CYP142A1 from <em>Mtb.</em></p></div>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis of steroidal inhibitors for Mycobacterium tuberculosis\",\"authors\":\"Luke R. Churchman , James R. Beckett , Lendl Tan , Kyra Woods , Daniel Z. Doherty , Amna Ghith , Paul V. Bernhardt , Stephen G. Bell , Nicholas P. West , James J. De Voss\",\"doi\":\"10.1016/j.jsbmb.2024.106479\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Oxidised derivatives of cholesterol have been shown to inhibit the growth of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). The bacteriostatic activity of these compounds has been attributed to their inhibition of CYP125A1 and CYP142A1, two metabolically critical cytochromes P450 that initiate degradation of the sterol side chain. Here, we synthesise and characterise an extensive library of 28 cholesterol derivatives to develop a structure-activity relationship for this class of inhibitors. The candidate compounds were evaluated for MIC with virulent <em>Mtb</em> and in binding studies with CYP125A1 and CYP142A1 from <em>Mtb.</em></p></div>\",\"PeriodicalId\":2,\"journal\":{\"name\":\"ACS Applied Bio Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-02-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Bio Materials\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S096007602400027X\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, BIOMATERIALS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096007602400027X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
Synthesis of steroidal inhibitors for Mycobacterium tuberculosis
Oxidised derivatives of cholesterol have been shown to inhibit the growth of Mycobacterium tuberculosis (Mtb). The bacteriostatic activity of these compounds has been attributed to their inhibition of CYP125A1 and CYP142A1, two metabolically critical cytochromes P450 that initiate degradation of the sterol side chain. Here, we synthesise and characterise an extensive library of 28 cholesterol derivatives to develop a structure-activity relationship for this class of inhibitors. The candidate compounds were evaluated for MIC with virulent Mtb and in binding studies with CYP125A1 and CYP142A1 from Mtb.
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