Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl/butyryl cholinesterase

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• 作者：Marco Catto^a ; Andrey A. Berezin^b ; Daniele Lo Re^b ; Georgia Loizou^b ; Marina Demetriades^b ; Angelo De Stradis^c ; Francesco Campagna^a ; Panayiotis A. Koutentis^b ; Angelo Carotti^a ; ^{angelo.carotti@uniba.it} ; ^{carotti_angelo@hotmail.com}
• 关键词：Benzotriazinones ; Triazafluoranthenones ; Alzheimer's disease ; ¦Â-Amyloid aggregation inhibitors ; Cholinesterase inhibitors ; Multitarget-directed ligands
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：58
• 期：Complete
• 页码：84-97
• 全文大小：1903 K

文摘

Alzheimer's disease (AD) onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target. Two new chemical entities, the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (benzotriazinone I) and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one (triazafluoranthenone II), were explored for their multitarget-directed inhibition of beta-amyloid (A¦Â) fibrillization and acetyl- (AChE) and/or butyryl- (BChE) cholinesterase, three valuable targets for AD therapy. Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II, respectively, allowed the preparation of a series of compounds that were tested as A¦Â_1-40 aggregation and cholinesterase inhibitors. Potent inhibitors of A¦Â self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC₅₀ equal to 0.37?¦ÌM. Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors. In particular, benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity, the former displaying IC₅₀ values of 1.4, 1.5 and 1.9?¦ÌM on A¦Â aggregation and AChE and BChE inhibition, respectively, and the latter showing IC₅₀ values of 1.4 and an outstanding 0.025?¦ÌM in the A¦Â aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and A¦Â aggregation inhibition, were submitted to a time course kinetic assay followed with thioflavin T (ThT) spectrofluorimetry, circular dichroism (CD) and transmission electron microscopy (TEM). Experimental data indicated that 24 acted at a low concentration ratio (10?¦ÌM 24 vs. 50?¦ÌM A¦Â), stabilizing the unstructured A¦Â peptide and inhibiting fibrillogenesis, and that 29 also acted as fibrillization inhibitor, but likely enhancing and stabilizing the ¦Â-sheet arrangement of A¦Â to yield protofibrillar species as detected by TEM.