Background:The interaction between methionine and aromatic residues in protein complexes is poorly understood. Results: The Met-aromatic motif is prevalent in known protein structures and stabilizes TNF ligand-receptor binding interactions. Conclusion:The Met sulfur-aromatic binding motif provides additional stabilization over purely hydrophobic interactions and at longer distances. Significance: This motif is prevalent and may be associated with a number of mutation-and age-associated diseases.

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 structureactivity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC 99 under irondeficient conditions of 0.049 µM 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 arylcapped siderphores for virulence.

The synthesis, biochemical, and biological evaluation of a systematic series of 2-triazole derivatives of 5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) are described as inhibitors of aryl acid adenylating enzymes (AAAE) involved in siderophore biosynthesis by Mycobacterium tuberculosis. Structure activity relationships revealed a remarkable ability to tolerate a wide range of substituents at the 4-position of the triazole moiety and a majority of the compounds possessed subnanomolar apparent inhibition constants. However, the in vitro potency did not always translate into whole cell biological activity against M. tuberculosis, suggesting intrinsic resistance, due to limited permeability, plays an important role in the observed activities. Additionally, the well-known valence tautomerism between 2-azidopurines and their fused tetrazole counterparts led to an unexpected facile acylation of the purine N-6 amino group.