Hybridization‐based design of novel anticholinesterase indanone–carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies

Abstract

Inspired by the structures of donepezil and rivastigmine, a novel series of indanone–carbamate hybrids was synthesized using the pharmacophore hybridization‐based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 μM; compound 4b: IC50 = 4.64 μM). Moreover, the results of the Aβ1–40 aggregation assay revealed that compound 4b is a potent Aβ1–40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype‐selective enzyme inhibitors. The presented indanone–carbamate scaffold can be structurally modified and optimized through medicinal chemistry‐based approaches for designing novel multitargeted anti‐Alzheimer agents.

Developing novel indanone-chalcone hybrids bearing ester group with potential anti-Alzheimer effects by combining molecular hybridization and bioisosteric replacement drug design approaches

“…The synthetic route employed to produce the new target compounds was illustrated in Scheme 1. Initially, the reaction of 2,3-dihydro-5,6-dimethoxyinden-1-one 9 with 4-hydroxybenzaldehyde 10 or 3hydroxybenzaldehydein 11 in butanol at re ux temperature produced derivatives 12a-b, which chemical characterization was reported previously [20,21]. Based on different studies, it has been known that the chemical shift values for the vinyl proton adjacent to a carbonyl group could be above and below 7.0 ppm for E and Z isomers, respectively [24].…”

“…Also, compound 8l showed the highest activity in meta series of compounds 8i-n (IC 50 value of 26.7 on AChE). The compounds introduced in the current study are designed based on bioisoesteric replacement of carbmate group attached to indanone-chalcone core of perviously reported active compound 5 [20,21]. In order to better evaluate the effects of such bioisoesteric replacement, the AChE inhibitory activities for substituted indanone chalcone hybrids including previously reported carbamate compounds 5a-l are listed in Table 2.…”

“…In order to better evaluate the effects of such bioisoesteric replacement, the AChE inhibitory activities for substituted indanone chalcone hybrids including previously reported carbamate compounds 5a-l are listed in Table 2. The most active compounds with carbamate moiety substituted at para and meta positions of indanone-chalcone hybrid structures were compound 5a (IC 50 value of 13.09 ± 12.14 µM on AChE) and 5i (IC 50 values of 20.70 ± 6.50 on AChE), respectively [20,21]. In comparison, the most active para and meta substituted indanonechalcone structures with ester functional group (8e and 8l, prepared in this study with IC 50 values of 18.7 ± 2.76 and 26.7 ± 5.8, respectively) showed relatively less AChE inhibitory activities.…”

“…Based on different studies, it has been known that the chemical shift values for the vinyl proton adjacent to a carbonyl group could be above and below 7.0 ppm for E and Z isomers, respectively [24]. According to this mostly accepted rule, the presence of a single peak at 7.30 ppm for the vinyl proton in 1 HNMR spectrum of intermediate compound 12a [20,21] is most likely indicative of E isomer for the intermediate compound and all other compounds prepared from that. However, we are aware that for unequivocal assignment of the geometry of the vinyl group, one may need to acquire single crystal X-ray or NOESY NMR data for 12a or any of the nal derivatives.…”

“…Compound 7 with aromatic ester moiety was reported with dual inhibitory potency against acetylcholinesterase and Aβ 1−42 aggregation. In current study, inspired by our previous studies [20][21][22][23] a series of dual AChE inhibitors were designed to ful ll interaction with CAS, PAS and gorge regions of AChE through esteric, indanonic and chalcone moieties of the designed molecules, respectively.…”