Synthesis of new harmine isoxazoles and evaluation of their potential anti-Alzheimer, anti-inflammatory, and anticancer activities

Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by ¹H NMR, ¹³C NMR and HRMS. The evaluation of their anti-Acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3±1.9% at 100 -M). Compound 2 exhibited the best anti-AChE activity (IC₅₀=1.9±1.5 μM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC₅₀=5.0±0.3 μM (3a) and IC₅₀=6.3±0.4 μM (3b) against HCT 116 cells, IC₅₀=5.0±1.0 μM (3d) against MCF7 cells).