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

A 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 & PLUSMN;0.09 & mu;M) with respect to standard drug, galantamine (2.09 & PLUSMN;0.11 & mu;M). Molecular modelling simulation was explored for the most potent compound that revealed interesting binding templates to the active site of enzyme.