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New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical approaches regarding these molecules. Our interest was focused on the detailed analysis of (i) new pharmacological options for selective hMAO inhibitors; (ii) innovative analytical procedures to discover/screen hMAO inhibitors, and (iii) the recent possibility of using labeled hMAO inhibitors to unravel neurodegenerative diseases and drug distribution. All these three aspects could open new scenarios stimulating the interest of researchers in this field.

Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.

Although there are clinical trials and in vivo studies in literature regarding the anxiolytic and antidepressant activities of the components of Crocus sativus L., their effects on the human monoamine oxidases (hMAO-A and hMAO-B), enzymes which are involved in mental disorders and neurodegenerative diseases, have not yet been investigated. We have thus examined the hMAO inhibitory activities of crocin and safranal (the most important active principles in saffron) and, subsequently, designed a series of safranal derivatives to evaluate which chemical modifications confer enhanced inhibition of the hMAO isoforms. Docking simulations were performed in order to identify key molecular recognitions of these inhibitors with both isoforms of hMAO. In this regard, different mechanisms of action were revealed. This study concludes that safranal and crocin represent useful leads for the discovery of novel hMAO inhibitors for the clinical management of psychiatric and neurodegenerative disorders., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted CN bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A new scaffold of hydrazothiazoles has been designed as monoamine oxidase (MAO) inhibitors combining the hydrazine moiety of iproniazid and the thiazole nucleus of glitazones, a class of peroxisome proliferator-activated receptor (PPAR)γ agonists recently co-crystallized with human MAO-B. The resulting derivatives were synthesized and assayed to evaluate their in vitro activity against both the A and B isoforms of hMAO. All compounds were shown to be selective hMAO-B inhibitors with IC(50) values in the low micromolar/high nanomolar range. Such results suggest that the hydrazothiazole scaffold could be considered as an interesting pharmacophore for the future design of new lead compounds as coadjuvants for the treatment of neurodegenerative diseases., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)