2-Aryl-8-aza-3-deazaadenosine analogues of 5'-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis.
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 Ki values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM.
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
Anna
A
Krajczyk
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
Joanna
J
Zeidler
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
Piotr
P
Januszczyk
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Surendra
S
Dawadi
Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Helena I
HI
Boshoff
Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Clifton E
CE
Barry
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland. Electronic address: tostr@ibch.poznan.pl.
Tomasz
T
Ostrowski
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: aldri015@umn.edu.
Courtney C
CC
Aldrich
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D017262:Siderophores / Q000096:biosynthesis*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000737:chemistry*
D000995:Antitubercular Agents; D017262:Siderophores; C018258:3-deazaadenosine; D014372:Tubercidin
8-Aza-3-deazaadenosine; Adenylation inhibitor; Modified nucleoside; Siderophore biosynthesis; Tuberculosis