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
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.