Synthesis and Biological Evaluation of 5-benzyl-3-pyridyl-1H-1,2,4-triazole Derivatives as Xanthine Oxidase Inhibitors

Abstract

Background: Topiroxostat is an excellent xanthine oxidase (XO) inhibitor, possessing a specific 3,5-diaryl-1,2,4-triazole framework.

Objective: The present work was aimed to investigate the preliminary structure-activity relationship (SAR) of 2-cyanopyridine-4-yl-like fragments of topiroxostat analogues.

Methods: A series of 5-benzyl-3-pyridyl-1H-1,2,4-triazole derivatives (1a-j and 2a-j) were designed and synthesized by replacement of the 2-cyanopyridine-4-yl moiety with substituted benzyl groups. XO inhibitory activity in vitro was evaluated. Furthermore, molecular modeling simulations were performed to predict the possible interactions between the synthesized compounds and XO binding pocket.

Results: The SARs analysis demonstrated that 3,5-diaryl-1,2,4-triazole framework is not essential; in spite of its lower potency, 5-benzyl-3-pyridyl-1H-1,2,4-triazole is an acceptable scaffold for XO inhibitory activity to some extent. A 3'-nitro and a 4'-sec-butoxy group link to the benzyl moiety will be welcome. Furthermore, the most promising compound, 1h, was identified with an IC50 value of 0.16 μM, and the basis of XO inhibition by 1h was rationalized through the aid of molecular modelling studies.

Conclusion: Compound 1h could be a lead compound for further investigation and the present work may provide some insight into the search for more structurally diverse XO inhibitors with topiroxostat as a prototype.

Keywords: 1,2,4-triazole; Topiroxostat; gout; pyrazoles; selenazoles; xanthine oxidase..