Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors.,European Journal of Medicinal Chemistry

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Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-09-18 , DOI: 10.1016/j.ejmech.2019.111717
Ting-Jian Zhang ₁ , Yi Zhang ₁ , Shun Tu ₁ , Yu-Hang Wu ₁ , Zhen-Hao Zhang ₁ , Fan-Hao Meng ₁

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In our previous study, we reported a series of N-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identified N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound 1) as the most potent one with an IC50 value 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 of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives (2a-t and 6-8). Besides, to investigate the influence of the amide-reversal, some N-(pyridin-4-yl)-3-(1H-tetrazol-1-yl)benzamide derivatives (3c, 3e, 3i, 3k and 3u) 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 the N-phenylisonicotinamide scaffold; a substituted benzyloxy, especially, an m-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 the N-phenylisonicotinamide scaffold was essential. In summary, starting from compound 1, the SBDD effort successfully identified a promising XO inhibitor 2s (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 compound 2s acted 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.

中文翻译：

N-（3-（1H-四唑-1-基）苯基）异烟酰胺衍生物作为黄嘌呤氧化酶抑制剂的设计，合成及生物学评价。

在我们先前的研究中，我们报道了一系列N-苯基异烟酰胺衍生物作为新型黄嘌呤氧化酶（XO）抑制剂，并确定了N-（3-氰基-4-（（2-氰基苄氧基）氧基）苯基）异烟酰胺（化合物1）是最有效的一种，IC50值为0.312μM。为了进一步优化结构并提高效能，进行了基于结构的药物设计（SBDD）策略，以构建小分子与XO的Asn768残基之间缺失的H键。我们在苯基的3'位引入一个四唑部分作为H键受体，并获得了一系列N-（3-（1H-四唑-1-基）苯基）异烟酰胺衍生物（2a-t和6-8）。此外，为了研究酰胺逆转的影响，还合成了一些N-（吡啶-4-基）-3-（1H-四唑-1-基）苯甲酰胺衍生物（3c，3e，3i，3k和3u）。并进行评估。生物学评估和结构-活性关系分析表明，3'-（1H-四唑-1-基）部分是N-苯基异烟酰胺骨架的极好片段。为了效力，欢迎在4′-位连接的取代的苄氧基，特别是间-氰基苄氧基（例如2s）；而且酰胺的逆转可能会破坏药效，因此维持N-苯基异烟酰胺支架是必不可少的。总而言之，从化合物1开始，SBDD的努力成功鉴定出了有希望的XO抑制剂2s（IC50 = 0.031μM），效力提高了10倍。它的效力非常接近于阳性对照托吡司他（IC50 = 0.021μM）。Lineweaver-Burk图表明化合物2s充当了混合型XO抑制剂。

更新日期：2019-09-18

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