title: Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: structure-activity relationships of the nucleobase domain of 5'-O-[N-(salicyl)sulfamoyl]adenosine.
abstract: 5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 microM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Labello
authors.forename: Ravindranadh V
authors.initials: RV
authors.lastname: Somu
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Jagadeshwar
authors.initials: J
authors.lastname: Vannada
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D017262:Siderophores / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: C526816:5'-O-(N-(salicyl)sulfamoyl)adenosine; D000995:Antitubercular Agents; D009705:Nucleosides; D017262:Siderophores; D000241:Adenosine