Letters in Drug Design & Discovery

Atta-ur-Rahman  , FRS
Honorary Life Fellow
Kings College
University of Cambridge
Email: lddd@benthamscience.org


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 and Venu Sanjeevi Lakshmipathi

Affiliation: Institute for Research in Molecular Medicine Universiti Sains Malaysia Minden 11800 Penang Malaysia.


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

Page: [156 - 161]
Pages: 6
DOI: 10.2174/15701808113109990038