Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 116, Issue -, Pages 200-209Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.03.077
Keywords
Tacrine; Multi-target-directed ligands; Alzheimer's disease; Cholinesterase inhibitors; Self-induced A beta aggregation
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Funding
- Foundation of Educational Commission of Guangdong Province of China [2013KJCX0151, 2014KTSCX096]
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A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced beta-amyloid (A beta) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of A beta aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity. (C) 2016 Elsevier Masson SAS. All rights reserved.
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