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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.
Eur J Med Chem. 2012 Dec; 58:84-97.EJ

Abstract

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 (Aβ) 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 Aβ(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Aβ self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 μM. 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 IC(50) values of 1.4, 1.5 and 1.9 μM on Aβ aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 μM in the Aβ aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Aβ 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 μM 24 vs. 50 μM Aβ), stabilizing the unstructured Aβ peptide and inhibiting fibrillogenesis, and that 29 also acted as fibrillization inhibitor, but likely enhancing and stabilizing the β-sheet arrangement of Aβ to yield protofibrillar species as detected by TEM.

Authors+Show Affiliations

Dipartimento di Farmacia, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23108363

Citation

Catto, Marco, et al. "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." European Journal of Medicinal Chemistry, vol. 58, 2012, pp. 84-97.
Catto M, Berezin AA, Lo Re D, et al. 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. Eur J Med Chem. 2012;58:84-97.
Catto, M., Berezin, A. A., Lo Re, D., Loizou, G., Demetriades, M., De Stradis, A., Campagna, F., Koutentis, P. A., & Carotti, A. (2012). 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. European Journal of Medicinal Chemistry, 58, 84-97. https://doi.org/10.1016/j.ejmech.2012.10.003
Catto M, et al. 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. Eur J Med Chem. 2012;58:84-97. PubMed PMID: 23108363.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Catto,Marco, AU - Berezin,Andrey A, AU - Lo Re,Daniele, AU - Loizou,Georgia, AU - Demetriades,Marina, AU - De Stradis,Angelo, AU - Campagna,Francesco, AU - Koutentis,Panayiotis A, AU - Carotti,Angelo, Y1 - 2012/10/11/ PY - 2012/07/23/received PY - 2012/09/27/revised PY - 2012/10/03/accepted PY - 2012/10/31/entrez PY - 2012/10/31/pubmed PY - 2013/5/17/medline SP - 84 EP - 97 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 58 N2 - 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 (Aβ) 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 Aβ(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Aβ self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 μM. 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 IC(50) values of 1.4, 1.5 and 1.9 μM on Aβ aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 μM in the Aβ aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Aβ 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 μM 24 vs. 50 μM Aβ), stabilizing the unstructured Aβ peptide and inhibiting fibrillogenesis, and that 29 also acted as fibrillization inhibitor, but likely enhancing and stabilizing the β-sheet arrangement of Aβ to yield protofibrillar species as detected by TEM. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/23108363/Design_synthesis_and_biological_evaluation_of_benzo[e][124]triazin_7_1H__one_and_[124]_triazino[561_jk]carbazol_6_one_derivatives_as_dual_inhibitors_of_beta_amyloid_aggregation_and_acetyl/butyryl_cholinesterase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(12)00606-X DB - PRIME DP - Unbound Medicine ER -