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.

Age-dependent formation of insoluble protein aggregates is a hallmark of many neurodegenerative diseases. We are interested in the cell chemistry that drives the aggregation of polyQ-expanded mutant Huntingtin (mHtt) protein into insoluble inclusion bodies (IBs). Using an inducible cell model of Huntington's disease, we show that a transient cold shock (CS) at 4 °C followed by recovery incubation at temperatures of 25−37 °C strongly and rapidly induces the compaction of diffuse polyQexpanded Huntingtin Exon1 -enhanced green fluorescent protein chimera protein (mHtt) into round, micron size, cytosolic IBs. This transient CS-induced mHtt IB formation is independent of microtubule integrity or de novo protein synthesis. The addition of millimolar concentrations of sodium chloride accelerates, whereas urea suppresses this transient CS-induced mHtt IB formation. These results suggest that the low temperature of CS constrains the conformation dynamics of the intrinsically disordered mHtt into labile intermediate structures to facilitate de-solvation and hydrophobic interaction for IB formation at the higher recovery temperature. This work, along with our previous observation of the effects of heat shock protein chaperones and osmolytes in driving mHtt IB formation, underscores the primacy of mHtt structuring and rigidification for H-bond-mediated cross-linking in a two-step mechanism of mHtt IB formation in living cells.

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