Synthesis and bioevaluation of 2-phenyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acid/carbohydrazide derivatives as potent xanthine oxidase inhibitors

Abstract

A series of 2-phenyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acids/carbohydrazides as analogues of febuxostat were synthesized and evaluated for their in vitro xanthine oxidase (XO) inhibitory activity.

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

“…Variation in the position of the three nitrogen atoms within the central five‐membered ring was reported by Shi et al. in their work on 2‐aryl‐5‐methyl‐2 H ‐1,2,3‐triazole‐4‐carboxylic acids 139 and carbohydrazide derivatives 140 . The carbohydrazide derivatives showed no activity at a concentration of 10 μ m , while among the carboxylic acid derivatives, those with a cyano group were generally more active than those with a nitro group.…”

A multiscale screening strategy for the identification of novel xanthine oxidase inhibitors based on the pharmacological features of febuxostat analogues

“…23 In comparison with allopurinol, non-purine XOIs like febuxostat and topiroxostat exhibit more outstanding inhibitory activity and lower toxicity, indicating that there is still an urgent need for novel non-purine alternatives with favorable toxicology profile. 1,7,8,16,24,25 As for in silico studies of XOIs, many experiments have been performed to explore the structure-activity relationship (SAR) of febuxostat analogues, topiroxostat analogues and natural compounds, and to design novel compounds. [26][27][28] However, few studies have reported pharmacophore-based virtual screening for XOIs.…”

“…2), including pyrazole (3), selenazole (4), imidazole ( 5), isoxazole (6), triazole (8), and pyrimidine (9). 1,7,8,13,16,25 This study focused on the in silico exploration of new XOI scaffolds, which might provide important information for designing novel XOI candidates. The pharmacophore models were constructed to extract the common structural features of febuxostat (1), topiroxostat (2), Y-700 (3), and some aforementioned XOI candidates (4-10).…”

Cu-Mediated Expeditious Annulation of Alkyl 3-Aminoacrylates with Aryldiazonium Salts: Access to Alkyl N2-Aryl 1,2,3-Triazole-carboxylates for Druglike Molecular Synthesis

“…Particularly, trisubstituted N -aryl 1,2,3-triazoles are important scaffolds found in numerous druglike and biologically active molecules, such as c-Met kinase and xanthine oxidase inhibitors, as well as antibacterial, anti-influenza, and other anticancer agents (Scheme a). These functionalized molecules are commonly synthesized from the corresponding substituted alkyl N -aryl 1,2,3-triazole-carboxylates as precursors. − Most of these triazole precursors are in turn accessed via multiple steps, especially involving the coupling reactions between aryldiazonium salts and sodium azide. ,− In contrast to the multistep synthesis of such N -aryl 1,2,3-triazole motifs originated from aryldiazonium salts and nitrogen-based synthons, the single-step synthesis based on aryldiazonium salts and other suitable amino-containing reaction partners is exceptionally desirable. Moreover, among these alkyl triazole-carboxylate moieties, drug discovery based on N 2 -aryl triazoles remains hitherto elusive compared with the N 1 -aryl counterparts.…”

“…N itrogen heterocyclic compounds are ubiquitous structural motifs in the pharmaceutical industry. 1 Particularly, trisubstituted N-aryl 1,2,3-triazoles are important scaffolds found in numerous druglike and biologically active molecules, such as c-Met kinase 2 and xanthine oxidase inhibitors, 3 as well as antibacterial, 4 anti-influenza, 5 and other anticancer agents 6 (Scheme 1a). These functionalized molecules are commonly synthesized from the corresponding substituted alkyl N-aryl 1,2,3-triazole-carboxylates as precursors.…”