Structure-Based design of Marine-derived Meridianin C derivatives as glycogen synthase kinase 3尾 inhibitors with improved oral bioavailability: From aminopyrimidyl-indoles to the sulfonyl analogues was written by Han, Shuwen;Zhou, Wei;Zhuang, Chunlin;Chen, Fener. And the article was included in Bioorganic Chemistry in 2022.Category: indole-building-block This article mentions the following:
Glycogen synthase kinase 3尾 (GSK-3尾) has become an attractive target for the treatment of diabetes. Compound I is an indole-based GSK-3尾 inhibitor designed from the Meridianin C, a marine natural product (MNP) isolated from Aplidium聽meridianum. However, this compound has a moderate inhibitory activity toward GSK-3尾 (IC50 = 24.4 渭M), moderate glucose uptake (38%), and especially, a low oral bioavailability (F = 11.4%). In the present study, applying the structure-based design strategy, a series of derivatives modified on the indole moiety were synthesized based on the lead compound I, followed by evaluating their cytotoxic activity, antihyperglycemic activity, and kinase inhibitory activity. Among this series, compound 6x with a sulfonyl group displayed the highest glucose uptake (83.5%) in muscle L6 cells, showing much higher inhibitory activity against GSK-3尾 (IC50 = 5.25 渭M). Mol. docking indicated that compound 6x was properly inserted into the ATP-binding binding pocket of GSK-3尾 with a higher docking score (-8.145 kcal/mol) compared with that of compound I (-6.950 kcal/mol), interpreting the higher kinase inhibitory activity toward GSK-3尾. Remarkably, compound 6x showed favorable drug-like properties, including significantly better oral bioavailability (F = 47.4%) and no two-week acute toxicity at a dose of 1g/kg. Our findings suggest that these MNP-derived sulfonyl indole derivatives could be used as lead compounds for the development of anti-hyperglycemic drugs. In the experiment, the researchers used many compounds, for example, 4-Nitroindole (cas: 4769-97-5Category: indole-building-block).
4-Nitroindole (cas: 4769-97-5) belongs to indole derivatives. Indole, first isolated in 1866, and it is commonly synthesized from phenylhydrazine and pyruvic acid, although several other procedures have been discovered. Indole plays a fundamental role for QS in E. coli, being one of the signal molecules responsible for the transcription of a variety of genes (gabT, and tnaB ASTD). Category: indole-building-block
Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles