Design, synthesis, and biological evaluation of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives as xanthine oxidase inhibitors.

A series of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives (1a-p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC values of 8.1 and 6.7 μm, respectively. The Lineweaver-Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X position is not as effective as a nitrogen atom, and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.