title: Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors.
abstract: The spacer structure of homobivalent quinazolinimes acting as potent acetyl-(AChE)- and butyrylcholinesterase (BChE) inhibitors was chemically modified introducing tertiary amine and acyl-amide moieties, and the activities at both ChEs were evaluated. Molecular docking was applied to explain the data and probe the capacity of the mid-gorge site of both ChEs. The novel spacer structures considerably alter the biological profile of bivalent quinazolinimines with regard to both inhibitory activity and selectivity. Mutual interaction of binding to the various sites of the enzymes was further investigated by applying also different spacer lengths and ring sizes of the alicycle of the tricyclic quinazolinimines. In order to achieve selectivity toward BChE and to improve inhibitory activities, the spacer structure was optimized and identified a highly potent and selective BChE inhibitor.
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D055598:Chemical Phenomena; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism; D003124:Colorimetry; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C560454:4-methyl-N-(4-(8,9,10,11-tetrahydro-6H-azocino(2,1-b)quinazolin-13(7H)-ylideneamino)butyl)-N-(3-(8,9,10,11-tetrahydro-6H-azocino(2,1-b)quinazolin-13(7H)-ylideneamino)propyl)pentanamide; D002800:Cholinesterase Inhibitors; D011799:Quinazolines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases