Synthesis and evaluation of tetrahydrobenzo[cd]indole derivatives as glycogen phosphorylase inhibitors

IF 3.1 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2025-02-08 DOI:10.1007/s00044-025-03384-7

Panarat Arunrattiyakorn, Chanitha Juiprasert, Symeon M. Koulas, Pornthip Boonsri, Thammarat Aree, Maho Yagi-Utsumi, Koichi Kato, Demetres D. Leonidas

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Abstract

A series of tetrahydrobenzo[cd]indole derivatives was synthesized by condensation of a fungal metabolite hyphodermin A, a naphtho[1,2-c]furan-3,9-dione derivative, and various anilines in methanol. Using this approach, ten analogs (3a–3j) were synthesized and tested as inhibitors against glycogen phosphorylase (GP). While compounds 3e and 3i bearing hydrophobic bromo and trifluoromethyl groups showed moderated inhibition (K_i = 32.3–57.4 μΜ), compound 3g with hydroxy group had the most potent activity with a K_i value of 7.9 ± 0.7 μΜ against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb-3g complexes revealed that this inhibitor binds at a subsite within the indole binding site of GP which has not been previously observed to bind ligands.

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四氢苯并[cd]吲哚衍生物糖原磷酸化酶抑制剂的合成及评价

以真菌代谢物牛皮素A、萘[1,2-c]呋喃-3,9-二酮衍生物和多种苯胺为原料，在甲醇中缩合合成了一系列四氢苯并[cd]吲哚衍生物。利用这种方法，合成了10个类似物（3a-3j），并测试了它们作为糖原磷酸化酶（GP）的抑制剂。含疏水溴基和三氟甲基的化合物3e和3i对人肝脏GPa的抑制作用较弱（Ki = 32.3-57.4 μΜ），含羟基的化合物3g对人肝脏GPa的抑制作用最强，Ki值为7.9±0.7 μΜ。对兔肌肉GPb-3g复合物的x射线晶体学研究显示，这种抑制剂结合在GP的吲哚结合位点内的一个亚位点上，该亚位点以前没有观察到与配体的结合。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.