Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents

Abstract

The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aβ) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer's disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1-22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman's colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aβ aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC values of 1.08 and 1.09 μM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aβ aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.

Profiling donepezil template into multipotent hybrids with antioxidant properties

“…All the compounds revealed selective AChE inhibition potency ranging from 0.08 to 0.92 µM concentrations observing that higher activity is bound to EWG-containing substituents on aromatic moiety. The latter is consistent with previous studies 118 , 119 . The highest inhibition activity reached p- fluoro substituted benzamide 31 being mixed-type AChE inhibitor ( 31 : Ee AChE IC 50 = 80 nM; eq BChE IC 50 = 3.21 µM; SI for AChE = 40; Figure 6 ).…”

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

“…Binding of an inhibitor to two sites on the target can also result in a considerable enhancement of affinity as a result of the chelate effect [ 212 ]. Examples of multiple points of binding resulting in increased affinity can be seen, for example, in [ 213 , 214 , 215 , 216 ]. Since galantamine and rivastigmine also inhibit BChE, whereas donepezil does not, further evidence would be necessary, before it would be possible to evaluate the possible benefits of inhibiting that enzyme.…”

Medicinal Chemistry of Indane and Its Analogues: A Mini Review

“…The in silico investigations suggested hydrogen bonding and π‐π stacking interactions of test derivatives with the active sit residues of target enzymes. The test derivatives displayed superior potency to inhibit the aggregation of Aβ‐peptides, unlike donepezil [77] . Further modifications led to the development of derivatives 83 a – f (Figure 20) as multi‐target‐directed ligands against Alzheimer′s disease.…”