Background: Novel carboxamides and thioureas of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-
4-yl)methyl) inden-1-one were synthesized and their potential anticholinesterase activities were evaluated.
The inhibition potency of the compounds 17a-j and 19a-j against AChE was measured and evaluated
using Ellman’s spectrophotometric method. Among carboxamides series, compound 17f, 17i, 17j
and among thiourea series, compound 19a, 19b were found to be the most active.
Methods: The scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl) inden-1-one 16, key intermediate
of drug donepezil has been synthesised in three steps and derivatised as carboxamides and
thioureas for SAR studies. Compounds 17a-j and 19a-j were characterised by 1H NMR and LCMS. The
inhibitory activity and antiamnesic effect were studied using different sources such as electric eel
AChE, human serum AChE and rat brain homogenate AChE.
Results: The results of bioassays indicated that among all the synthesized compounds tested, five compounds
17f, 17i, 17j, 19a and 19b shows IC50 at a dose of 67, 42, 64, 52 and 63 nM respectively against
electric eel, human serum and rat brain homogenate, which lead to the suggestion that compound 17i
might be considered to be a potent AChE inhibitor.
Conclusion: Derivatives of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one with
different substitutions were synthesised and tested for their AChE activity. The order of potency is
17i>17j>17f and 19a>19b. The other compounds screened failed to elicit any inhibition of acetyl cholinesterase
from rat brain homogenate. It may be concluded from this study that, for effective binding
and blocking the AChE activity, molecule needs to bind with peripheral site and active site of the enzyme.
Therefore, it can be summarized that by changing the functional group and substitution in the
scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one needs to be studied for better
AChE inhibitory activity in future research.