A new series of tacrine-flavonoid hybrids (13a-u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ₁₋₄₂) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ₁₋₄₂ aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.
Keywords: ASNDIIUXKSSGTR-UHFFFAOYSA-N; Alzheimer's disease; CCSIEQWILAQNOJ-UHFFFAOYSA-N; CFTXWMALZMFVFR-UHFFFAOYSA-N; Cholinesterase; DAQOTHBGIZARGM-UHFFFAOYSA-N; DDOHQRNJXWAFAL-UHFFFAOYSA-N; FYFPJPCNMIMCSI-UHFFFAOYSA-N; Flavonoid; JBVVLTRVHVGZEU-UHFFFAOYSA-N; JBXYRSPJNIZSAT-UHFFFAOYSA-N; JFGPPVAZTXRZDC-UHFFFAOYSA-N; JWCIYSMFMZTUME-UHFFFAOYSA-N; LESFBJPJZADQHL-UHFFFAOYSA-N; MDVLYACOLMKYAL-UHFFFAOYSA-N; Metal chelator; NHRHUIFWROFHGI-UHFFFAOYSA-N; NYSKQVVKHYVKTB-UHFFFAOYSA-N; OXTPOGAMUKLJIJ-UHFFFAOYSA-N; PDCBHYYTMYMYBE-UHFFFAOYSA-N; PGHRDQIVQWNEGD-UHFFFAOYSA-N; RQWXJZZQVBAPHB-UHFFFAOYSA-N; SXDGSJQISGFVLK-UHFFFAOYSA-N; TZWXGPOBAFCOHW-UHFFFAOYSA-N; Tacrine; VBAJECZQEAYMJO-UHFFFAOYSA-N; β-Amyloid aggregation.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.