Title : Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase - Zhou_2020_Eur.J.Med.Chem_200_112415 |
Author(s) : Zhou B , Li H , Cui Z , Li D , Geng H , Gao J , Zhou L |
Ref : Eur Journal of Medicinal Chemistry , 200 :112415 , 2020 |
Abstract :
As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of =0.72 muM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the pi-pi action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents. |
PubMedSearch : Zhou_2020_Eur.J.Med.Chem_200_112415 |
PubMedID: 32454229 |
Zhou B, Li H, Cui Z, Li D, Geng H, Gao J, Zhou L (2020)
Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase
Eur Journal of Medicinal Chemistry
200 :112415
Zhou B, Li H, Cui Z, Li D, Geng H, Gao J, Zhou L (2020)
Eur Journal of Medicinal Chemistry
200 :112415