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Maalej E.,University of Sfax | Chabchoub F.,University of Sfax | Samadi A.,Laboratorio Of Radicales Libres Y Quimica Computacional | De Los Rios C.,University of Alcalá | Marco-Contelles J.,Laboratorio Of Radicales Libres Y Quimica Computacional
Bioorganic and Medicinal Chemistry Letters | Year: 2011

The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines (19-28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzo[f] chromene-2-carbonitriles (10-18) with suitable cycloalkanones is described. These molecules are potent, in the nanomolar range [IC 50 (EeAChE) = 7-101 nM], and selective inhibitors of acetylcholinesterase (AChE). The most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3- b]quinolin-14-yl)phenol (20) [IC 50 (EeAChE) = 7 ± 2 nM] is four-fold more active than tacrine. Kinetic studies on compound 20 showed that this is a mixed-type inhibitor of EeAChE with a K i of 5.00 nM. However, racemic 20 was unable to displace propidium iodide, suggesting that the inhibitor does not strongly bind to the peripheral anionic site (PAS) of AChE. Docking, molecular dynamics stimulations, and MM-GBSA calculations agree well with this behavior. © 2011 Elsevier Ltd. All rights reserved.


Sucunza D.,Laboratorio Of Radicales Libres Y Quimica Computacional | Samadi A.,Laboratorio Of Radicales Libres Y Quimica Computacional | Chioua M.,Laboratorio Of Radicales Libres Y Quimica Computacional | Silva D.B.,Laboratorio Of Radicales Libres Y Quimica Computacional | And 6 more authors.
Chemical Communications | Year: 2011

The Sandmeyer reaction of differently C-2 substituted N-(prop-2-yn-1- ylamino)pyridines is an efficient, mild, new and practical method for the stereospecific synthesis of (E)-exo-halomethylene bicyclic pyridones bearing the imidazo[1,2-a]pyridine heterocyclic ring system. © 2011 The Royal Society of Chemistry.


Da Silva D.B.,Laboratorio Of Radicales Libres Y Quimica Computacional | Da Silva D.B.,University of Lisbon | Samadi A.,Laboratorio Of Radicales Libres Y Quimica Computacional | Infantes L.,CSIC - Institute of Physical Chemistry "Rocasolano" | And 2 more authors.
Tetrahedron Letters | Year: 2010

An unexpected, but simple method for the efficient synthesis of new 2.2′-azopyridine dyes, such as (E)-diethyl 6,6′-(diazene-1,2-diyl) bis(5-cyano-2-methyl-4-phenylnicotinates) (2, 4, 6, 8, 10, and 12), based on the treatment of ethyl 6-amino-5-cyano-2-methyl-4-arylnicotinates (1, 3, 5, 7, 9, and 11) with NBS/benzoyl peroxide, is described. The X-ray diffraction analysis and the UV-vis absorption spectra of dye 2 are reported and discussed. © 2010 Elsevier Ltd. All rights reserved.


Bolea I.,Institute Of Neurociencies | Juarez-Jimenez J.,Institute Of Biomedicina Ibub | De Los Rios C.,Laboratorio Of Radicales Libres Y Quimica Computacional | Chioua M.,Hospital Universitario Of La Princesa | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2- yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented) © 2011 American Chemical Society.


Leon R.,University of Cambridge | Leon R.,Instituto Teofilo Hernando | Leon R.,Laboratorio Of Radicales Libres Y Quimica Computacional | Marco-Contelles J.,Laboratorio Of Radicales Libres Y Quimica Computacional
Current Medicinal Chemistry | Year: 2011

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting mainly elderly people. The reasons why AD occurs are complex and multifactorial and several biochemical targets are thought to play a key role in its progress and development. This fact has led to the development of a multitarget-directed ligand strategy as a logical approach for designing a suitable therapy. Currently, most prescribed drugs for treating AD are acetylcholinesterase inhibitors (AChEI), although these inhibitors represent solely palliative treatment. This account will summarize our current therapeutic approach for the design of multitarget drugs primarily aimed at inhibiting AChE using the key features of tacrine, which was the first approved drug for AD treatment. Secondly, as calcium homeostasis is directly related to the cell death-survival equilibrium, suitable therapy might include an action that regulates calcium homeostasis by means of targeting voltage dependent calcium channels. It is, therefore, hoped that targeting calcium homeostasis will lead directly to the development of potential neuroprotective agents. Thus, 1,4-dihydropyridines, well-known voltage-dependent calcium channel (VDCC) ligands, will be incorporated into the new molecules as a second structural feature in order to bring about this action. As a result of this development, herein, we describe the synthetic and pharmacological profile of new [1,8]-naphthyridine analogues, which are hybrids of tacrine and 1,4-dihydropyridines. Some of our molecules have shown improved inhibitory action against cholinesterases, whilst maintaining their VDCC modulating activity, and have good characteristics as neuroprotective agents. Based on kinetic analysis of the AChE inhibition experiments, it has been shown that many of the compounds bind at the peripheral anionic site (PAS). Since the AChE PAS is linked to β-amyloid aggregation, this would give a third biological target for further preclinical development, making these molecules highly interesting targets in the search to obtain better treatments for AD. © 2011 Bentham Science Publishers Ltd.


PubMed | Laboratorio Of Radicales Libres Y Quimica Computacional
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2011

The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)--aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.

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