A Series of Compounds Bearing a Dipyrido-Pyrimidine Scaffold Acting as Novel Human and Insect Pest Chitinase Inhibitors

文献类型： 外文期刊

第一作者： Kumar, Ashutosh

作者： Kumar, Ashutosh;Zhang, Kam Y. J.;Yang, Qing;Jiang, Xi;Liu, Tian;Yang, Qing;Motomura, Yasutaka;Motomura, Yasutaka;Moro, Kazuyo;Zhou, Yong;Moro, Kazuyo

作者机构：

期刊名称：JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：7.446； 五年影响因子：7.319 ）

ISSN： 0022-2623

年卷期： 2020 年 63 卷 3 期

页码：

收录情况： SCI

摘要： Chitinases not only play vital roles in the human innate immune system but are also essential for the development of pathogenic fungi and pests. Chitinase inhibitors are efficient tools to investigate the elusive role of human chitinases and to control pathogens and pests. Via hierarchical virtual screening, we have discovered a series of chitinase inhibitors with a novel scaffold that have high inhibitory activities and selectivities against human and insect chitinases. The most potent human chitotriosidase inhibitor, compound 40, exhibited a K-i of 49 nM, and the most potent inhibitor of the insect pest chitinase Of Chi-h, compound 53, exhibited a K-i of 9 nM. The binding of these two most potent inhibitors was confirmed by X-ray crystallography. In a murine model of bleomycin-induced pulmonary fibrosis, compound 40 was found to suppress the chitotriosidase activity by 60%, leading to a significant increase in inflammatory cells and suggesting that chitotriosidase played a protective role.

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