| Autor: |
Neres J; Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA., Labello NP, Somu RV, Boshoff HI, Wilson DJ, Vannada J, Chen L, Barry CE 3rd, Bennett EM, Aldrich CC |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2008 Sep 11; Vol. 51 (17), pp. 5349-70. Date of Electronic Publication: 2008 Aug 09. |
| DOI: |
10.1021/jm800567v |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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