Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors
Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors
复制标题
N-(3-(1H-四唑-1-基)苯基)异烟酰胺衍生物作为新型黄嘌呤氧化酶抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2019.111717
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发表时间：
2019
影响因子：
6.7
通讯作者：
Meng Fan-hao
中科院分区：
文献类型：
--
作者：
Zhang Ting-jian;Zhang Yi;Tu Shun;Wu Yu-hang;Zhang Zhen-hao;Meng Fan-hao
In our previous study, we reported a series ofN-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identifiedN-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound1) as the most potent one with an IC50value of 0.312 μM. To further optimize the structure and improve the potency, a structure-based drug design (SBDD) strategy was performed to construct the missing H-bond between the small molecule and the Asn768 residue of XO. We introduced a tetrazole moiety at the 3′-position of the phenyl to serve as an H-bond acceptor and obtained a series ofN-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives (2a-tand6–8). Besides, to investigate the influence of the amide-reversal, someN-(pyridin-4-yl)-3-(1H-tetrazol-1-yl)benzamide derivatives (3c,3e,3i,3kand3u) were also synthesized and evaluated. Biological evaluation and structure-activity relationship analysis demonstrated that the 3′-(1H-tetrazol-1-yl) moiety was an excellent fragment for theN-phenylisonicotinamide scaffold; a substituted benzyloxy, especially, anm-cyanobenzyloxy (e.g.,2s), linking at the 4′-position was welcome for the potency; and the amide-reversal could damage the potency, so maintenance of theN-phenylisonicotinamide scaffold was essential. In summary, starting from compound1, the SBDD effort successfully identified a promising XO inhibitor2s(IC50= 0.031 μM), with a 10-fold gain in potency. Its potency was very close to the positive control topiroxostat (IC50= 0.021 μM). A Lineweaver-Burk plot indicated that compound2sacted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics simulations revealed that the tetrazole moiety could occupy the Asn768-sub-pocket with N-4 atom accepting an H-bond from the Asn768 residue, as expected.
