Synthesis of Highly Functionalised Dispiropyrrolidine Derivatives as Novel Acetylcholinesterase Inhibitors

Ang      Chee Wei; Mohamed      Ashraf Ali; Yeong      Keng Yoon; Rusli      Ismail; Tan      Soo Choon; Kooi-Yeong      Khaw; Vikneswaran      Murugaiyah; Venu      Sanjeevi Lakshmipathi

Abstract

In the effort of finding novel acetyl cholinesterase (AChE) inhibitors to improve the efficacy of Alzheimer’s disease (AD) treatment, series of substituted aryl-1´-methyldispiro[indan-2,2´ pyrrolidine-3´,2-indan]-1,3,1-trione and substituted 7´-aryl-5´,6´,7´,7a´-tetrahydrodispiro-[indane-2,5´-pyrrolo[1,2-c][1,3]thiazole-6´,2-indan]-1,3,1-trione analogues were synthesized using [3+2]-cycloaddition reactions. These newly synthesized pyrrolidine compounds were assayed for their biological activity using Ellman’s method. The structural elucidation of the compounds was performed by using ¹H-NMR, ¹³C-NMR, ESI-MS spectra and elemental analyses. Eight out of twenty synthesized compounds showed more than 50% inhibition at concentration of 10 µM. Compound 2e, 2i and 3e were among the most active one, giving IC₅₀ value as 3.3 M for 2e, 3.7 µM for 2i and 5.5 µM for 3e, respectively. Lineweaver-Burk plot indicated that 2i inhibits AChE in a competitive manner. Molecular modelling study was performed to disclose the binding interaction of these compounds with the active site of AChE.

Keywords: Acetyl cholinesterase inhibitors, Alzheimer’s disease, Cycloaddition, Ellman’s method, Lineweaver-Burk plot, Pyrrolidine, Molecular modeling.

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