publication . Article . Other literature type . 2015

synthesis and pharmacokinetic evaluation of siderophore biosynthesis inhibitors for mycobacterium tuberculosis

Nelson, Kathryn M.; Viswanathan, Kishore; Dawadi, Surendra; Duckworth, Benjamin P.; Boshoff, Helena I.; Barry, Clifton E.; Aldrich, Courtney C.;
Open Access
  • Published: 09 Jul 2015 Journal: Journal of Medicinal Chemistry, volume 58, pages 5,459-5,475 (issn: 0022-2623, eissn: 1520-4804, Copyright policy)
  • Publisher: American Chemical Society (ACS)
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 sub-optimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pKa of...
Subjects
free text keywords: Molecular Medicine, Drug Discovery, Structure–activity relationship, Drug development, Mycobacterium tuberculosis, biology.organism_classification, biology, Pharmacology, Lipophilicity, Bioavailability, Chemistry, Prodrug, Biochemistry, Nucleoside, Pharmacokinetics, Article
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publication . Article . Other literature type . 2015

synthesis and pharmacokinetic evaluation of siderophore biosynthesis inhibitors for mycobacterium tuberculosis

Nelson, Kathryn M.; Viswanathan, Kishore; Dawadi, Surendra; Duckworth, Benjamin P.; Boshoff, Helena I.; Barry, Clifton E.; Aldrich, Courtney C.;