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366 results on '"Marco-Contelles J."'

2. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

Author

Bautista-Aguilera OM, Esteban G, Chioua M, Nikolic K, Agbaba D, Moraleda I, Iriepa I, Soriano E, Samadi A, Unzeta M, and Marco-Contelles J

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC]), Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO) (IQOG, CSIC), Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13–15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD. Keywords: donepezil-pyridyl hybrids, ChE, MAO, 3D-QSAR, molecular modeling, ADMET

Published
2014

3. The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents

Author

Keuler, T., Lemke, C., Elsinghorst, P. W., Iriepa, I., Chioua, M., Martínez-Grau, M. A., Beadle, C. D., Vetman, T., López-Muñoz, F., Wille, T., Bartz, U., (0000-0003-3168-3062) Deuther-Conrad, W., (0000-0003-0690-0328) Marco-Contelles, J., (0000-0002-9376-7897) Gütschow, M., Keuler, T., Lemke, C., Elsinghorst, P. W., Iriepa, I., Chioua, M., Martínez-Grau, M. A., Beadle, C. D., Vetman, T., López-Muñoz, F., Wille, T., Bartz, U., (0000-0003-3168-3062) Deuther-Conrad, W., (0000-0003-0690-0328) Marco-Contelles, J., and (0000-0002-9376-7897) Gütschow, M.

Abstract

The multifactorial nature of Alzheimer’s disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the 1 and 2 receptor. Our study provides a framework for the development of further chromanone-based multineurotarget agents.

Published
2022

5. Studies on the affinity of 6-[(: N -(cyclo)aminoalkyl)oxy]-4 H -chromen-4-ones for sigma 1/2 receptors

Author

(0000-0003-3168-3062) Deuther-Conrad, W., Diez-Iriepa, D., Iriepa, I., López-Muñoz, F., Martínez-Grau, A. M., (0000-0002-9376-7897) Gütschow, M., (0000-0003-0690-0328) Marco-Contelles, J., (0000-0003-3168-3062) Deuther-Conrad, W., Diez-Iriepa, D., Iriepa, I., López-Muñoz, F., Martínez-Grau, A. M., (0000-0002-9376-7897) Gütschow, M., and (0000-0003-0690-0328) Marco-Contelles, J.

Abstract

Sigma represent attractive targets for the development of potential agents for the treatment of neurodegenerative disorders. In search of multitarget small molecules (MSMs) against Morbus Alzheimer and related diseases, we have discovered that 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, exhibited S1/S2 receptor modulatory activity. A further chromenone, 6-((5-morpholinopentyl)oxy)-4H-chromen-4-one (12), was identified to be almost equipotent to S1RA, an established 1 receptor antagonist.

Published
2021

8. Contilisant, a Tetratarget Small Molecule for Alzheimer’s Disease Therapy Combining Cholinesterase, Monoamine Oxidase Inhibition and H3R Antagonism with Sigma 1R Agonism Profile

Author

Bautista-Aguilera, O. M., Budni, J., Mina, F., Medeiros, E. B., Deuther-Conrad, W., Entrena, J. M., Moraleda, I., Iriepa, I., López-Muñoz, F., and Marco-Contelles, J.

Subjects
ASS234, rVAChT modulator, Cognitive impairment, ChE inhibitor, hSigma 1R agonist, Y-maze test, Molecular modeling, Radial arm-maze test, Alzheimer’s disease, H3R antagonist, MAO inhibitor, Aβ, Contilisant
Abstract

Contilisant, a permeable, antioxidant and neuroprotectant agent, showing high nM affinity at H3R, excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, Contilisant significantly restores the cognitive deficit induced by Aβ1-42 in the radial maze assay in an in vivo Alzheimer’s disease test, comparing very favorably with donepezil.

Published
2018

9. Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

Author

Bautista‐Aguilera, O.M., Hagenow, S., Palomino‐Antolin, A., Farré‐Alins, V., Ismaili, L., Joffrin, P.-L., Jimeno, M.L., Soukup, O., Janocková, J., Kalinowsky, L., Proschak, E., Iriepa, I., Moraleda, I., Schwed, J.S., Martínez, A.R., López‐Muñoz, F., Chioua, M., Egea, J., Ramsay, R.R., Marco‐Contelles, J., Stark, H., and Publica

Abstract

The therapy of complex neurodegenerative diseases requires the development of multitarget‐directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small‐molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide‐induced cognitive deficits.

Published
2017

10. Rational design of dimebon bivalent ligands against Alzheimer’s disease

Author

Simoni, Elena, MICHELA ROSINI, Manuela Bartolini, VINCENZA ANDRISANO, Soriano, E., Marco Contelles, J., Melchiorre, Carlo, Maria Laura Bolognesi, Simoni E., Rosini M., Bartolini M., Andrisano V., Soriano E., Marco-Contelles J., Melchiorre C., and Bolognesi M.L.

Subjects
bivalent ligands, dimebon, Alzheimer's disease
Published
2012

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