A Facile Regio‐ and Stereoselective Synthesis and Cholinesterase Inhibitory Activity of New Oxobenzothiophene Grafted Spiropyrrolidine/Pyrrolizidine Hybrids Employing Multicomponent 1,3‐Dipolar Cycloaddition Methodology

Abstract

AbstractA stereo‐, regio‐ and chemoselective synthesis of a series of structurally diverse novel oxobenzothiophene embedded spirooxindolopyrrolidine/pyrrolizidine hybrid heterocycles were achieved in excellent yields by multicomponent 1,3‐dipolar cycloaddition reaction process. The 1,3‐dipole component employed was generated in situ from isatin and N‐methylglycine/L‐proline while the dipolarophile, ethyl 2‐(3‐oxobenzo[b]thiophen‐2(3H)‐ylidene)acetate was prepared from thiophenol in two good yielding steps. The formation of spiroheterocyclic hybrids occurred through the formation of two C=C and one C−N bonds in a single synthetic transformation. The compounds formed consists of three adjacent stereocenters, out of which two are spirocarbons. The synthesized spiro compounds were assayed for their AChE/BChE inhibitory activity and most of the spirocompounds showed promising cholinesterase inhibitory activity. Among them, spiropyrrolidine that substituted with chlorine atom on the oxindole ring displayed significant activity (4.16±0.09 μM) with respect to standard drug, galantamine (2.09±0.11 μM). Molecular modelling simulation was explored for the most potent compound that revealed interesting binding templates to the active site of enzyme.