Inhibition of Siderophore Biosynthesis by 2-Triazole Substituted Analogues of 5′-O-[N-(Salicyl)sulfamoyl]adenosine: Antibacterial Nucleosides Effective against Mycobacterium tuberculosis

Abstract

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.

Functional and Structural Analysis of the Siderophore Synthetase AsbB through Reconstitution of the Petrobactin Biosynthetic Pathway from Bacillus anthracis

“…Because abrogation of petrobactin production or uptake has been shown to severely attenuate B. anthracis virulence (6,10,15), enzymes in the biosynthetic pathway remain attractive targets for identification of new antimicrobials. Gaining deeper insights into the details of NIS-associated enzyme function might provide access to mechanism-based inhibitors, as have been demonstrated for nonribosomal peptide synthetase-derived siderophore adenylation domains (13,65,66). Moreover, development of the chemoenzymatic approach described in this work toward creating new siderophore analogs could be applied to generate a class of "Trojan horse" antibiotics, bearing improved target effects and IC 50 values compared with conventional chemotherapeutics (67,68).…”

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

“…[100] Structure-activity relationships revealed remarkable ability to tolerate a wide range of substituents at the 4-position of the triazole moiety, and the majority of the compounds possessed subnanomolar activity.…”

The Synthesis and X-ray Studies of 6-pyrrolidinyl-2-triazolyl Purine Arabinonucleoside

“…Then it was cooled to ambient temperature and ethanol (1 mL) was added and the mixture was stirred for 15 min at the same temperature followed by evaporation under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL) washed with saturated aqueous solution of NaHCO 3 (15 mL) and water (15 mL (8) 3 A solution of NaN 3 (5.16 g; 0.079 mol) in water (60 mL) was added to a solution of 9-(2',3',4'-tri-O-acetyl-α-Darabinopyranosyl)-2,6-di-chloropurine (7) (8.88 g; 0.020 mol) in EtOH (250 mL). The resulting mixture was stirred at 40 °C for 1 h and controlled by TLC (EtOAc/DCM = 1 : 1; R f = 0.64).…”

“…For example, the groups of Van Calenbergh [2], Aldrich [3] and Lakshman [4] develop approaches to the synthesis of 2-triazolyl derivatives. On the other hand, 6-triazolyl derivatives have been studied by Lakshman and co-workers [5] and by the groups of Guieu and Parrain [6].…”