Kathryn M Nelson1, Kishore Viswanathan2, Surendra Dawadi2, Benjamin P Duckworth1, Helena I Boshoff3, Clifton E Barry3, Courtney C Aldrich1,2. 1. †Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States. 2. ‡Department of Medicinal Chemistry, University of Minnesota, 8-174 WDH, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States. 3. §Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
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.
MbtA catalyzes the first committed biosynthetic step of the n class="Chemical">mycobactins, which are important virulence factors associated with iron acquisition inMycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5'-O-[N-(Salicyl)sulfamoyl]adenosine (1) is a bisubstrateinhibitor 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 fluorineinto 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: Ravindranadh V Somu; Helena Boshoff; Chunhua Qiao; Eric M Bennett; Clifton E Barry; Courtney C Aldrich Journal: J Med Chem Date: 2006-01-12 Impact factor: 7.446
Authors: Sivagami Sundaram Chavadi; Karen L Stirrett; Uthamaphani R Edupuganti; Olivia Vergnolle; Gigani Sadhanandan; Emily Marchiano; Che Martin; Wei-Gang Qiu; Clifford E Soll; Luis E N Quadri Journal: J Bacteriol Date: 2011-08-26 Impact factor: 3.490
Authors: Alexandra Manos-Turvey; Esther M M Bulloch; Peter J Rutledge; Edward N Baker; J Shaun Lott; Richard J Payne Journal: ChemMedChem Date: 2010-07-05 Impact factor: 3.466
Authors: Helen M Baldan; Helene J De Rosa; Iguatemy L Brunetti; Valdecir F Ximenes; Rosângela G P Machado Journal: Biopharm Drug Dispos Date: 2007-11 Impact factor: 1.627
Authors: Surendra Dawadi; Helena I M Boshoff; Sae Woong Park; Dirk Schnappinger; Courtney C Aldrich Journal: ACS Med Chem Lett Date: 2018-03-16 Impact factor: 4.345
Authors: Surendra Dawadi; Kishore Viswanathan; Helena I Boshoff; Clifton E Barry; Courtney C Aldrich Journal: J Org Chem Date: 2015-04-30 Impact factor: 4.354
Authors: Olivia Vergnolle; Hua Xu; JoAnn M Tufariello; Lorenza Favrot; Adel A Malek; William R Jacobs; John S Blanchard Journal: J Biol Chem Date: 2016-08-26 Impact factor: 5.157
Authors: Catherine L Shelton; Kathleen M Meneely; Trey A Ronnebaum; Annemarie S Chilton; Andrew P Riley; Thomas E Prisinzano; Audrey L Lamb Journal: J Biol Inorg Chem Date: 2022-05-05 Impact factor: 3.862