Synthesis of Highly Functionalised Dispiropyrrolidine Derivatives as Novel Acetylcholinesterase Inhibitors

Author(s): Ang Chee Wei, Mohamed Ashraf Ali, Yeong Keng Yoon, Rusli Ismail, Tan Soo Choon, Kooi-Yeong Khaw, Vikneswaran Murugaiyah, Venu Sanjeevi Lakshmipathi.

Journal Name: Letters in Drug Design & Discovery

Volume 11 , Issue 2 , 2014

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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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Article Details

Year: 2014
Page: [156 - 161]
Pages: 6
DOI: 10.2174/15701808113109990038
Price: $65

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