5'-O-[(N-acyl)sulfamoyl]adenosines as antitubercular agents that inhibit MbtA: an adenylation enzyme required for siderophore biosynthesis of the mycobactins.
A study of the structure-activity relationships of 5'-O-[N-(salicyl)sulfamoyl]adenosine (6), a potent inhibitor of the bifunctional enzyme salicyl-AMP ligase (MbtA, encoded by the gene Rv2384) in Mycobacterium tuberculosis, is described, targeting the salicyl moiety. A systematic series of analogues was prepared exploring the importance of substitution at the C-2 position revealing that a hydroxy group is required for optimal activity. Examination of a series of substituted salicyl derivatives indicated that substitution at C-4 was tolerated. Consequently, a series of analogues at this position provided 4-fluoro derivative, which displayed an impressive MIC99 of 0.098 microM against whole-cell M. tuberculosis under iron-limiting conditions. Examination of other heterocyclic, cycloalkyl, alkyl, and aminoacyl replacements of the salicyl moiety demonstrated that these nonconservative modifications were poorly tolerated, a result consistent with the fairly strict substrate specificities of related non-ribosomal peptide synthetase adenylation enzymes.
Qiao
Chunhua
C
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Gupte
Amol
A
Boshoff
Helena I
HI
Wilson
Daniel J
DJ
Bennett
Eric M
EM
Somu
Ravindranadh V
RV
Barry
Clifton E
CE
Aldrich
Courtney C
CC
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008025:Ligases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010080:Oxazoles / Q000378:metabolism*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D017262:Siderophores / Q000378:metabolism*; D013329:Structure-Activity Relationship
C526816:5'-O-(N-(salicyl)sulfamoyl)adenosine; D000995:Antitubercular Agents; D010080:Oxazoles; D017262:Siderophores; C018608:mycobactins; D008025:Ligases; C526815:salicyl-AMP ligase, Mycobacterium tuberculosis; D010453:Peptide Synthases; D000241:Adenosine