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

Anna Krajczyk, Joanna Zeidler, Piotr Januszczyk, Surendra Dawadi, Helena I. Boshoff, Clifton E. Barry, Tomasz Ostrowski, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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 Kivalues 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.

Original languageEnglish (US)
Pages (from-to)3133-3143
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number14
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported by the Polish Ministry of Science and Higher Education grant no. N N405 2516 33 (J.Z.), under statutory financing, and under the KNOW program. It was also supported by a grant from the NIH ( AI070219 to C.C.A.) and the Intramural Research Program of the NIAID , NIH (C.E.B.). We wish to thank Dr. Lukasz Marczak and Dr. Barbara Swarcewicz for MS spectra measurements.

Keywords

  • 8-Aza-3-deazaadenosine
  • Adenylation inhibitor
  • Modified nucleoside
  • Siderophore biosynthesis
  • Tuberculosis

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