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

IF 2.6 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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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.