TY - JOUR
T1 - 5′-O-[(N-acyl)sulfamoyl]adenosines as antitubercular agents that inhibit MbtA
T2 - An adenylation enzyme required for siderophore biosynthesis of the mycobactins
AU - Qiao, Chunhua
AU - Gupte, Amol
AU - Boshoff, Helena I.
AU - Wilson, Daniel J.
AU - Bennett, Eric M.
AU - Somu, Ravindranadh V.
AU - Barry, Clifton E.
AU - Aldrich, Courtney C.
PY - 2007/11/29
Y1 - 2007/11/29
N2 - 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 MIC 99 of 0.098 μM 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 nonconserative modifications were poorly tolerated, a result consistent with the fairly strict substrate specificities of related non-ribosomal peptide synthetase adenylation enzymes.
AB - 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 MIC 99 of 0.098 μM 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 nonconserative modifications were poorly tolerated, a result consistent with the fairly strict substrate specificities of related non-ribosomal peptide synthetase adenylation enzymes.
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U2 - 10.1021/jm070905o
DO - 10.1021/jm070905o
M3 - Article
C2 - 17967002
AN - SCOPUS:37849036789
SN - 0022-2623
VL - 50
SP - 6080
EP - 6094
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 24
ER -