A versatile synthetic approach to various 5-alkynyl modified isatin derivatives: Cytotoxicity, acetylcholinesterase inhibition activity and molecular modeling study

Abstract

Isatin derivatives have been of great interest in drug development research. 5-Alkynyl substituted isatin derivatives with anticancer potential and acetylcholinesterase inhibition (AChE) activity are designed and synthesized. The copper(I) catalyzed one-pot three-component reaction (AChauhan et al. (2021)³-coupling) of new 3-(1,3-dioxolane)-5-(ethynyl)isatins with formaldehyde and secondary amines or the Sonogashira cross-coupling reaction of C-3 protected iodoisatins with fluoro-N-(prop-2-ynyl)benzamide and prop-2-ynyl 4-fluorobenzoate were the main approaches for the synthesis of 5-(3-X-prop-1-yn-1-yl) substituted isatin derivatives (yield 53–87 %). 1-Benzyl-5-(prop-1-yn-1-yl)indoline-2,3-diones are smoothly formed by refluxing of 3-(1,3-dioxolane)-5-(propynyl)isatins in hydrochloric acid/MeOH (1:9, v/v). Results of in vitro biological assays (MTT-test) revealed that new 3-(1,3-dioxolane)-5-(3-X-prop-1-yn-1-yl)-1-benzylisatin derivatives are exhibited remarkable cytotoxicity against human cervical (C 33 A and CaSki), breast (MCF-7), prostate (DU-145) and glioblastoma (SNB-19 and T98G) cancer cell lines within low micromolar GI₅₀ values. Additionally, all new compounds demonstrated relatively low cytotoxicity against the normal epithelial VERO cells (GI₅₀ > 70 μM), indicating good selectivity. Moreover, the appropriate isatin derivatives displayed good and moderate acetylcholinesterase inhibition activity in vitro (Ellman’ s method) with IC₅₀ up to 1.0–3.7 μM comparable to that for clinically used galantamine. Based on the results of in silico experiments the isatin derivatives bearing 5-(prop-1-yn-1-yl) substituents are promising for further search of acetylcholinesterase inhibitors in this series of compounds.