5‘-O-[(N-Acyl)sulfamoyl]adenosines as Antitubercular Agents that Inhibit MbtA:  An Adenylation Enzyme Required for Siderophore Biosynthesis of the Mycobactins

• Published in: Journal of medicinal chemistry 2007-11, Vol.50 (24), p.6080-6094
• Main Authors: Qiao, Chunhua, Gupte, Amol, Boshoff, Helena I, Wilson, Daniel J, Bennett, Eric M, Somu, Ravindranadh V, Barry, Clifton E, Aldrich, Courtney C
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biological and medical sciences; Ligases - antagonists & inhibitors; Medical sciences; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Oxazoles - metabolism; Peptide Synthases - antagonists & inhibitors; Pharmacology. Drug treatments; Siderophores - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070905o

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 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.