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• 362-75-4 2',3'-isopropylidene adenosine 
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• 69-72-7 salicylic acid 

Relevant academic research and scientific papers

Integrated Target-Based and Phenotypic Screening Approaches for the Identification of Anti-Tubercular Agents That Bind to the Mycobacterial Adenylating Enzyme MbtA

Iron is essential for the pathogenicity and virulence of Mycobacterium tuberculosis, which synthesises salicyl-capped siderophores (mycobactins) to acquire this element from the host. MbtA is the adenylating enzyme that catalyses the initial reaction of mycobactin biosynthesis and is solely expressed by mycobacteria. A 3200-member library comprised of lead-like, structurally diverse compounds was screened against M. tuberculosis for whole-cell inhibitory activity. A set of 846 compounds that inhibited the tubercle bacilli growth were then tested for their ability to bind to MbtA using a fluorescence-based thermal shift assay and NMR-based Water-LOGSY and saturation transfer difference (STD) experiments. We identified an attractive hit molecule, 5-hydroxyindol-3-ethylamino-(2-nitro-4-trifluoromethyl)benzene (5), that bound with high affinity to MbtA and produced a MIC90 value of 13 μm. The ligand was docked into the MbtA crystal structure and displayed an excellent fit within the MbtA active pocket, adopting a binding mode different from that of the established MbtA inhibitor Sal-AMS.

Structure-activity relationship of adenosine 5′-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: Rational design of antagonists

Adenosine 5′-diphosphoribose (ADPR) activates TRPM2, a Ca 2+, Na+, and K+ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2′-deoxy-ADPR (86, IC50 = 3 μM), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca2+ signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.

ANTI-MICROBIAL AGENTS AND USES THEREOF

Many pathogens, including Mycobacterium tuberculosis and Yersinia pestis, rely on an iron acquisition system based on siderophores, secreted iron-chelating compounds with extremely high Fe(III) affinity. The compounds of the invention are inhibitors of domain salicylation enzymes, which catalyze the salicylation of an aroyl carrier protein (ArCP) domain to form a salicyl-ArCP domain thioester intermediate via a two-step reaction. The compounds include the intermediate mimic 5 '-O- [N- (salicyl)sulfamoyl] -adenosine (salicyl-AMS) and analogs thereof. These compounds are inhibitors of the salicylate activity of MbtA, YbtE, PchD, and other domain salicylation enzymes involved in the biosynthesis of siderophores. Therefore, these compounds may be used in the treatment of infection caused by microorganisms which rely on siderphore-based iron acquisition systems. Pharmaceutical composition and methods of using these compounds to treat or prevent infection are also provided as well as methods of preparing the inventive compounds.