New amyloid beta-disaggregating agents: synthesis, pharmacological evaluation, crystal structure and molecular docking ofN-(4-((7-chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines

MedChemComm
2018.0

Abstract

In the journey towards the development of potent multi-targeted ligands for the treatment of Alzheimer's disease, a series of Aβ aggregation inhibitors having quinoline scaffold were designed utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations <i>via</i> ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aβ self-aggregation inhibition. Molecules <b>5g</b> and <b>5a</b> showed the highest inhibitory potential, 53.73% and 53.63% at 50 μM respectively; higher than the standard Aβ disaggregating agent, curcumin. Molecules <b>5g</b> and <b>5a</b> disaggregated AChE-induced (58.26%, 47.36%) Aβ aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu<sup>2+</sup>-induced Aβ aggregation. A docking study significantly showed their interaction with key residues of Aβ and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (<b>5a</b>, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (ii)-<b>5a</b> and Cu(ii)-<b>5g</b> complexes were found by Job's method (0.5 : 1 for <b>5a</b> and 0.8 : 1 for <b>5g</b>). <i>In silico</i> ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aβ aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.

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