title: A therapeutic approach to cerebrovascular diseases based on indole substituted hydrazides and hydrazines able to interact with human vascular adhesion protein-1, monoamine oxidases (A and B), AChE and BuChE.
abstract: Herein, we report the biological evaluation of a series of indole substituted hydrazides and hydrazines throughout the assessment of their multipotent inhibitory potency towards monoamine oxidase (MAO) A and B, semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), and the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Hydrazine JL72 (3-(3-hydrazinylpropyl)-1H-indole) showed a potent, reversible and non-time-dependent inhibition of MAO-A, which suggests its capacity in restoring serotoninergic neurotransmission being devoid of the side effects observed for classic MAO-A inhibitors. In addition, JL72 behaved as a moderate BuChE inhibitor. Finally, both hydrazines and hydrazides derivatives showed high affinity towards SSAO/VAP-1. Among them, JL72 behaved as a noncompetitive and the most potent inhibitor (IC50 = 0.19 ± 0.04 μM), possessing also a significant anti-inflammatory activity. The combined inhibition of SSAO/VAP-1, MAO (A and B), AChE and BuChE appear as an important therapeutic target to be considered in the treatment of cerebrovascular and neurological disorders such as Alzheimer's disease.
authors.affiliation: Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Esteban
authors.forename: Irene
authors.initials: I
authors.lastname: Bolea
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Montse
authors.initials: M
authors.lastname: Solé
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002461:Cell Line, Transformed; D002561:Cerebrovascular Disorders / Q000201:enzymology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014162:Transfection
chemical_list: D015815:Cell Adhesion Molecules; D006834:Hydrazines; D007211:Indoles; C030374:indole; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase