2-Aryl-8-aza-3-deazaadenosine analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis

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• 作者：Anna Krajczyk^a ; Joanna Zeidler^a ; Piotr Januszczyk^a ; Surendra Dawadi^b ; Helena I. Boshoff^c ; Clifton E. Barry III^c ; Tomasz Ostrowski^a ; ^{tostr@ibch.poznan.pl" class="auth_mail" title="E-mail the corresponding author} ; Courtney C. Aldrich^b ; ^{aldri015@umn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：8-Aza-3-deazaadenosine ; Modified nucleoside ; Tuberculosis ; Siderophore biosynthesis ; Adenylation inhibitor
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：24
• 期：14
• 页码：3133-3143
• 全文大小：1135 K

文摘

A series of 5′-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa–Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent K_i values ranging from 6.1 to 25 nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50 μM.