A convenient one-pot approach to the synthesis of novel pyrazino[1,2-a]indoles fused to heterocyclic systems and evaluation of their biological activity as acetylcholinesterase inhibitors

Abstract

Pyrazino[1,2-a]indoles fused with various heterocycles, such as oxazolidine, oxazinane, imidazolidine, hexahydropyrimidine and benzimidazole, were synthesized transition metal-free by domino reactions which involved the condensation of 1-(2-bromoethyl)-3-chloro-1H-indole-2-carbaldehydes 28–31 with various nucleophilic amines, resulting in the formation of two new interesting fused heterocycles. The anticholinesterase, antioxidant and antibacterial activities of the compounds were evaluated. Acetylcholinesterase (AChE) inhibitory activities were tested by Ellman’s assay, antioxidant activities were detected using the 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS•+) free-radical scavenging method and antibacterial activities were determined by agar diffusion tests. The oxazolo-pyrazino[1,2-a]indoles (8, 10), the oxazino-pyrazino[1,2-a]indoles (16, 18, 19), the pyrimido-pyrazino[1,2-a]indole (22), and the benzoimidazo-pyrazino[1,2-a]indole (27) possessed the highest inhibitory activity against AChE with IC50 values in the range 20–40 μg mL−1. The oxazolo-pyrazino[1,2-a]indoles (8, 9), the imidazo-pyrazino[1,2-a]indoles (12, 13), and the benzoimidazo-pyrazino[1,2-a]indole (24) revealed the highest antioxidant values with IC50 values less than 300 μg mL−1. However, the oxazolo-pyrazino[1,2-a]indole (11) and imidazo-pyrazino[1,2-a]indoles (12, 13) exhibited weak to moderate bioactivities against all tested Gram-positive bacteria, namely Staphylococcus aureus, Bacillus subtilis and Bacillus cereus.