title: Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis.
abstract: MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5'-O-[N-(Salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from suboptimal drug disposition properties resulting in a short half-life (t(1/2)), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pK(a) of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t(1/2) and AUC. Increasing the pK(a) of the acyl-sulfonyl linker yielded incremental enhancements, while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters.
authors.affiliation: †Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Nelson
authors.affiliation: ‡Department of Medicinal Chemistry, University of Minnesota, 8-174 WDH, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Kishore
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: ‡Department of Medicinal Chemistry, University of Minnesota, 8-174 WDH, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dawadi
authors.affiliation: †Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Duckworth
authors.affiliation: §Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: §Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: †Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.|‡Department of Medicinal Chemistry, University of Minnesota, 8-174 WDH, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008025:Ligases / Q000037:antagonists & inhibitors; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017262:Siderophores / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000995:Antitubercular Agents; D011355:Prodrugs; D017262:Siderophores; D008025:Ligases; C526815:salicyl-AMP ligase, Mycobacterium tuberculosis