Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors
| Autor: | Bao-Le Zhang, Stephen D. Weeks, Arthur Van Aerschot, Manesh Nautiyal, Steff De Graef, Sergei V. Strelkov, L. Pang, Eveline Lescrinier, Jef Rozenski, Bharat Gadakh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Purine
Benzimidazole sugar-base condensation Protein Conformation Stereochemistry Pharmaceutical Science Crystallography X-Ray 01 natural sciences Article Analytical Chemistry Amino Acyl-tRNA Synthetases lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry Drug Discovery Humans Structure–activity relationship aminoacyl sulfamoylated nucleosides Hydroxymethyl Enzyme Inhibitors Physical and Theoretical Chemistry aaRS inhibition 030304 developmental biology chemistry.chemical_classification 0303 health sciences 010405 organic chemistry Aminoacyl tRNA synthetase structure-activity relationship Organic Chemistry heterocycle glycosylation Ribonucleoside Neisseria gonorrhoeae 0104 chemical sciences Amino acid chemistry Chemistry (miscellaneous) Molecular Medicine Benzimidazoles Ribonucleosides Isoleucine |
| Zdroj: | Molecules, Vol 25, Iss 4751, p 4751 (2020) Molecules Volume 25 Issue 20 'Molecules ', vol: 25, pages: 4751-1-4751-24 (2020) |
| ISSN: | 1420-3049 |
| Popis: | Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N1-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N9-position, we obtained the N3-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N7-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these &ldquo base-flipped&rdquo analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N3-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N1 and the N6-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis. |
| Databáze: | OpenAIRE |
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