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35 results on '"Munoz-Torrero D."'

2. Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-7

Author

Gutschow, M, Eynde, J, Jampilek, J, Kang, C, Mangoni, A, Fossa, P, Karaman, R, Trabocchi, A, Scott, P, Reynisson, J, Rapposelli, S, Galdier, S, Winum, J, Brullo, C, Prokai-Tatrai, K, Sharma, A, Schapira, M, Azuma, Y, Cerchia, L, Spete, M, Torri, G, Collina, S, Geronikaki, A, Garcia-Sosa, A, Helena Vasconcelos, M, Sousa, M, Kosalec, I, Tuccinardi, T, Duarte, I, Salvador, J, Bertinaria, M, Pellecchia, M, Amato, J, Rastelli, G, Gomes, P, Guedes, R, Sabatier, J, Estevez-Braun, A, Pagano, B, Mangani, S, Ragno, R, Kokotos, G, Brindisi, M, Gonzalez, F, Borges, F, Miloso, M, Rautio, J, Munoz-Torrero, D, Gutschow M., Eynde J. J. V., Jampilek J., Kang C., Mangoni A. A., Fossa P., Karaman R., Trabocchi A., Scott P. J. H., Reynisson J., Rapposelli S., Galdier S., Winum J. -Y., Brullo C., Prokai-Tatrai K., Sharma A. K., Schapira M., Azuma Y. -T., Cerchia L., Spete M., Torri G., Collina S., Geronikaki A., Garcia-Sosa A. T., Helena Vasconcelos M., Sousa M. E., Kosalec I., Tuccinardi T., Duarte I. F., Salvador J. A. R., Bertinaria M., Pellecchia M., Amato J., Rastelli G., Gomes P. A. C., Guedes R. C., Sabatier J. -M., Estevez-Braun A., Pagano B., Mangani S., Ragno R., Kokotos G., Brindisi M., Gonzalez F. V., Borges F., Miloso M., Rautio J., Munoz-Torrero D., Gutschow, M, Eynde, J, Jampilek, J, Kang, C, Mangoni, A, Fossa, P, Karaman, R, Trabocchi, A, Scott, P, Reynisson, J, Rapposelli, S, Galdier, S, Winum, J, Brullo, C, Prokai-Tatrai, K, Sharma, A, Schapira, M, Azuma, Y, Cerchia, L, Spete, M, Torri, G, Collina, S, Geronikaki, A, Garcia-Sosa, A, Helena Vasconcelos, M, Sousa, M, Kosalec, I, Tuccinardi, T, Duarte, I, Salvador, J, Bertinaria, M, Pellecchia, M, Amato, J, Rastelli, G, Gomes, P, Guedes, R, Sabatier, J, Estevez-Braun, A, Pagano, B, Mangani, S, Ragno, R, Kokotos, G, Brindisi, M, Gonzalez, F, Borges, F, Miloso, M, Rautio, J, Munoz-Torrero, D, Gutschow M., Eynde J. J. V., Jampilek J., Kang C., Mangoni A. A., Fossa P., Karaman R., Trabocchi A., Scott P. J. H., Reynisson J., Rapposelli S., Galdier S., Winum J. -Y., Brullo C., Prokai-Tatrai K., Sharma A. K., Schapira M., Azuma Y. -T., Cerchia L., Spete M., Torri G., Collina S., Geronikaki A., Garcia-Sosa A. T., Helena Vasconcelos M., Sousa M. E., Kosalec I., Tuccinardi T., Duarte I. F., Salvador J. A. R., Bertinaria M., Pellecchia M., Amato J., Rastelli G., Gomes P. A. C., Guedes R. C., Sabatier J. -M., Estevez-Braun A., Pagano B., Mangani S., Ragno R., Kokotos G., Brindisi M., Gonzalez F. V., Borges F., Miloso M., Rautio J., and Munoz-Torrero D.

Published
2020

5. 3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 angstrom resolution: kinetic and molecular dynamic correlates

Author

Dvir, H., Wong, D.M., Harel, M., Barril, X., Orozco, M., Luque, F.J., Munoz-Torrero, D., Camps, P., Rosenberry, T.L., Silman, I., and Sussman, J.L.

Subjects
Acetylcholinesterase -- Research, Enzyme inhibitors -- Analysis, Binding sites (Biochemistry) -- Analysis, Molecular structure -- Analysis, Structure-activity relationships (Biochemistry) -- Analysis, Biological sciences, Chemistry
Abstract

The kinetics of the binding of huprine X inhibitor to the Torpedo californica acetylcholinesterase reveal that it binds to the anionic site and obstructs access to the esteratic site as shown by molecular dynamics simulation of the huprine X inhibitor/enzyme complex crystal structure.

Published
2002

18. ChemInform Abstract: Synthesis and Evaluation of Tacrine‐Related Compounds for the Treatment of Alzheimer′s Disease.

Author

AGUADO, F., primary, BADIA, A., additional, BANOS, J. E., additional, BOSCH, F., additional, BOZZO, C., additional, CAMPS, P., additional, CONTRERAS, J., additional, DIERSSEN, M., additional, ESCOLANO, C., additional, GOERBIG, D. M., additional, MUNOZ‐TORRERO, D., additional, PUJOL, M. D., additional, SIMON, M., additional, VAZQUEZ, M. T., additional, and VIVAS, N. M., additional

Published
1994
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19. Dimeric and Hybrid Anti-Alzheimer Drug Candidates

Author

Munoz-Torrero, D. and Camps, P.

Abstract

In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimers disease. As a consequence of their capability to simultaneously interact with two binding sites of the same biological target (the enzyme acetylcholinesterase in most cases), to expand their interaction in the main binding site of the target molecule, or to interact with two different biological targets of interest in the pathogenesis of the disease, these dimeric or hybrid compounds exhibit an improved pharmacological profile including high affinity interactions, additional non conventional actions or complementary actions, what makes them potential drug candidates for the treatment of Alzheimers disease. Herein, we review from a structural point of view the main classes of dimeric or hybrid compounds developed for the treatment of Alzheimers disease, along with the pharmacological profile of the most active compounds.

Published
2006

20. Synthesis and Pharmacological Evaluation of Huprine−Tacrine Heterodimers:  Subnanomolar Dual Binding Site Acetylcholinesterase Inhibitors

Author

Camps, P., Formosa, X., Munoz-Torrero, D., Petrignet, J., Badia, A., and Clos, M. V.

Abstract

A series of huprine−tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC50 values in the subnanomolar and low nanomolar range, respectively.

Published
2005

21. Synthesis, in Vitro Pharmacology, and Molecular Modeling of syn-Huprines as Acetylcholinesterase Inhibitors

Author

Camps, P., Gomez, E., Munoz-Torrero, D., Badia, A., Vivas, N. M., Barril, X., Orozco, M., and Luque, F. J.

Abstract

Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (±)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.

Published
2001

24. New Tacrine−Huperzine A Hybrids (Huprines):  Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

Author

Camps, P., Achab, R. El, Morral, J., Munoz-Torrero, D., Badia, A., Banos, J. E., Vivas, N. M., Barril, X., Orozco, M., and Luque, F. J.

Abstract

Several new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives (tacrine−huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (−)-20, rac-26, (−)-26, rac-30, (−)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (−)-20, (−)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438−871-fold higher than for BChE. Several hybrid compounds, specially (−)-20 and (−)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme−inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (−)-20 and (−)-30 and showed their ability to cross the blood−brain barrier. Molecular modeling simulations of the AChE−inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.

Published
2000

25. Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Author

Camps, P., Achab, R. El, Gorbig, D. M., Morral, J., Munoz-Torrero, D., Badia, A., Banos, J. E., Vivas, N. M., Barril, X., Orozco, M., and Luque, F. J.

Abstract

Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)−huperzine A hybrids, rac-21−31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (−)-huperzine A]. The activity of some THA−huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27−31, (−)-28, and (−)-30], which are more active than (−)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (−)-huperzine A. Most of the tested compounds 19−31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA−huperzine A hybrids:  the 4-aminoquinoline subunit of (−)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (−)-huperzine A, in agreement with the absolute configurations of (−)-19 and (−)-huperzine A.

Published
1999

29. Breakthroughs in medicinal chemistry: new targets and mechanisms, new drugs, new hopes-7

Author

Gütschow, Michael, Eynde, Jean Jacques Vanden, Jampilek, Josef, Kang, CongBao, Mangoni, Arduino, Fossa, Paola, Karaman, Rafik, Trabocchi, Andrea, Scott, Peter, Reynisson, Jóhannes, Rapposelli, Simona, Galdiero, Stefania, Winum, Jean-Yves, Brullo, Chiara, Prokai-Tatrai, Katalin, Sharma, Arun, Schapira, Matthieu, Azuma, Yasu-Taka, Cerchia, Laura, Spetea, Mariana, Torri, Giangiacomo, Collina, Simona, Geronikaki, Athina, García-Sosa, Alfonso, Vasconcelos, M Helena, Sousa, Maria Emília, Kosalec, Ivan, Tuccinardi, Tiziano, Duarte, Iola, Salvador, Jorge, Bertinaria, Massimo, Pellecchia, Maurizio, Amato, Jussara, Rastelli, Giulio, Gomes, Paula, Guedes, Rita, Sabatier, Jean-Marc, Estévez-Braun, Ana, Pagano, Bruno, Mangani, Stefano, Ragno, Rino, Kokotos, George, Brindisi, Margherita, González, Florenci, Borges, Fernanda, Miloso, Mariarosaria, Rautio, Jarkko, Muñoz-Torrero, Diego, Vanden Eynde, Jean Jacques, Vasconcelos, M. Helena, Gutschow, M., Eynde, J. J. V., Jampilek, J., Kang, C., Mangoni, A. A., Fossa, P., Karaman, R., Trabocchi, A., Scott, P. J. H., Reynisson, J., Rapposelli, S., Galdiero, S., Winum, J. -Y., Brullo, C., Prokai-Tatrai, K., Sharma, A. K., Schapira, M., Azuma, Y. -T., Cerchia, L., Spete, M., Torri, G., Collina, S., Geronikaki, A., Garcia-Sosa, A. T., Helena Vasconcelos, M., Sousa, M. E., Kosalec, I., Tuccinardi, T., Duarte, I. F., Salvador, J. A. R., Bertinaria, M., Pellecchia, M., Amato, J., Rastelli, G., Gomes, P. A. C., Guedes, R. C., Sabatier, J. -M., Estevez-Braun, A., Pagano, B., Mangani, S., Ragno, R., Kokotos, G., Brindisi, M., Gonzalez, F. V., Borges, F., Miloso, M., Rautio, J., Munoz-Torrero, D., Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Gutschow, M, Eynde, J, Jampilek, J, Kang, C, Mangoni, A, Fossa, P, Karaman, R, Trabocchi, A, Scott, P, Reynisson, J, Rapposelli, S, Galdier, S, Winum, J, Brullo, C, Prokai-Tatrai, K, Sharma, A, Schapira, M, Azuma, Y, Cerchia, L, Spete, M, Torri, G, Collina, S, Geronikaki, A, Garcia-Sosa, A, Helena Vasconcelos, M, Sousa, M, Kosalec, I, Tuccinardi, T, Duarte, I, Salvador, J, Bertinaria, M, Pellecchia, M, Amato, J, Rastelli, G, Gomes, P, Guedes, R, Sabatier, J, Estevez-Braun, A, Pagano, B, Mangani, S, Ragno, R, Kokotos, G, Brindisi, M, Gonzalez, F, Borges, F, Miloso, M, Rautio, J, and Munoz-Torrero, D

Subjects
RM, Pharmaceutical research, molecular targeted therapy, Chemistry, Pharmaceutical, MESH: Pharmaceutical Preparations, [SDV]Life Sciences [q-bio], Pharmaceutical Science, animals, chemistry, pharmaceutical, drug discovery, humans, pharmaceutical preparations, structure-activity relationship, Q1, chemistry, 01 natural sciences, Clinical chemistry, Analytical Chemistry, lcsh:QD241-441, 03 medical and health sciences, MESH: Chemistry, Pharmaceutical, Química clínica, MESH: Structure-Activity Relationship, lcsh:Organic chemistry, MESH: Drug Discovery, CHIM/06 - CHIMICA ORGANICA, MESH: Molecular Targeted Therapy, pharmaceutical, MESH: Animals, RM695, Investigació farmacèutica, Physical and Theoretical Chemistry, 030304 developmental biology, 0303 health sciences, MESH: Humans, 010405 organic chemistry, Medicinal Chemistry, New Targets, New Mechanisms, New Drugs, Organic Chemistry, R735, R1, 3. Good health, 0104 chemical sciences, Editorial, n/a, Chemistry (miscellaneous), Molecular Medicine, Breakthroughs, Medicinal Chemistry, medicinal chemistry, targets, drugs, molecules, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs.

Published
2020
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30. From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Author

Matthias Scheiner, Elsa M. Arce, María Isabel Loza, Marina Naldi, F. Javier Luque, Angela De Simone, Manuela Bartolini, Maria Laura Bolognesi, Michael Decker, Yolanda Soriano-Fernández, José Brea, Caterina Pont, Noemí Martínez, Diego Muñoz-Torrero, Alexia Mattellone, Belén Pérez, Marta Barenys, Raimon Sabaté, Jesús Gómez-Catalán, Christian Griñán-Ferré, Tiziana Ginex, Vincenza Andrisano, Mercè Pallàs, Pont C., Ginex T., Grinan-Ferre C., Scheiner M., Mattellone A., Martinez N., Arce E.M., Soriano-Fernandez Y., Naldi M., De Simone A., Barenys M., Gomez-Catalan J., Perez B., Sabate R., Andrisano V., Loza M.I., Brea J., Bartolini M., Bolognesi M.L., Decker M., Pallas M., Luque F.J., and Munoz-Torrero D.

Subjects
Zebra danio, Peix zebra, Drug Evaluation, Preclinical, tau Proteins, Alzheimer's disease, Cryptic pocket, Multitarget compound, SAMP8, Zebrafish embryo, Disease, Molecular Dynamics Simulation, Heterocyclic Compounds, 4 or More Rings, chemistry.chemical_compound, Structure-Activity Relationship, Alzheimer Disease, Drug Discovery, Healthy control, Aspartic Acid Endopeptidases, Humans, Pharmacology, Virtual screening, Anti alzheimer, Amyloid beta-Peptides, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Envelliment cerebral, Organic Chemistry, Brain, General Medicine, Recombinant Proteins, Cell biology, Malaltia d'Alzheimer, Neuroprotective Agents, Tau phosphorylation, Synaptophysin, biology.protein, Aging brain, Aminoquinolines, Amyloid Precursor Protein Secretases, Lead compound
Abstract

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

Published
2021

31. Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–5

Author

Arduino Mangoni, Jean Eynde, Josef Jampilek, Dimitra Hadjipavlou-Litina, Hong Liu, Jóhannes Reynisson, Maria Sousa, Paula Gomes, Katalin Prokai-Tatrai, Tiziano Tuccinardi, Jean-Marc Sabatier, F. Luque, Jarkko Rautio, Rafik Karaman, M. Vasconcelos, Sandra Gemma, Stefania Galdiero, Christopher Hulme, Simona Collina, Michael Gütschow, George Kokotos, Carlo Siciliano, Raffaele Capasso, Luigi Agrofoglio, Rino Ragno, Diego Muñoz-Torrero, Flinders University [Adelaide, Australia], University of Mons [Belgium] (UMONS), Comenius University in Bratislava, Aristotle University of Thessaloniki, Chinese Academy of Sciences [Beijing] (CAS), Keele University [Keele], Universidade do Porto, University of North Texas Health Science Center [Fort Worth], University of Pisa - Università di Pisa, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Barcelona, University of Eastern Finland, Al-Quds University, University of Siena (University of Siena), University of Naples Federico II, University of Arizona, University of Pavia, University of Bonn, National and Kapodistrian University of Athens (NKUA), University of Calabria, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Universitat de Barcelona, Universidade do Porto = University of Porto, Università degli Studi di Siena = University of Siena (UNISI), University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Pavia = University of Pavia (UNIPV), Universität Bonn = University of Bonn, Università della Calabria [Arcavacata di Rende] (Unical), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Instituto de Investigação e Inovação em Saúde, Leloup, Ludovic, Mangoni, A. A., Eynde, J. J. V., Jampilek, J., Hadjipavlou-Litina, D., Liu, H., Reynisson, J., Sousa, M. E., Gomes, P. A. C., Prokai-Tatrai, K., Tuccinardi, T., Sabatier, J. -M., Luque, F. J., Rautio, J., Karaman, R., Vasconcelos, M. H., Gemma, S., Galdiero, S., Hulme, C., Collina, S., Gutschow, M., Kokotos, G., Siciliano, C., Capasso, Raffaele, Agrofoglio, L. A., Ragno, R., and Munoz-Torrero, D.

Subjects
Chemistry, Pharmaceutical, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Drug Discovery / trends, Química farmacèutica, 010402 general chemistry, 01 natural sciences, Analytical Chemistry, RS, lcsh:QD241-441, 03 medical and health sciences, lcsh:Organic chemistry, Drug Discovery, [CHIM] Chemical Sciences, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, breakthroughs in medicinal chemistry, new targets, new mechanisms, new drugs, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Organic Chemistry, 3. Good health, 0104 chemical sciences, [SDV] Life Sciences [q-bio], Chemistry, Editorial, Chemistry, Pharmaceutical / trends, n/a, Chemistry (miscellaneous), Pharmaceutical, Molecular Medicine, Pharmaceutical chemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs.

Published
2019
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32. A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

Author

Santiago Vázquez, Deborah Pivetta, Vincenza Andrisano, Diego Muñoz-Torrero, Andreea L. Turcu, Belén Pérez, Alba Espargaró, F. Javier Pérez-Areales, Caterina Pont, Angela De Simone, Raimon Sabaté, Francesc X. Sureda, Manuela Bartolini, Marta Barniol-Xicota, Perez-Areales F.J., Turcu A.L., Barniol-Xicota M., Pont C., Pivetta D., Espargaro A., Bartolini M., De Simone A., Andrisano V., Perez B., Sabate R., Sureda F.X., Vazquez S., Munoz-Torrero D., and Universitat de Barcelona

Subjects
Multi-target-directed ligands, NMDA antagonists, Química farmacèutica, Adamantane, Pharmacology, 01 natural sciences, chemistry.chemical_compound, Drug Discovery, Cholinesterase Inhibitor, Butyrylcholinesterase, Butyrylcholinesterase inhibitors, 0303 health sciences, Molecular Structure, Chemistry, Butyrylcholinesterase inhibitor, Malalties neurodegeneratives, Memantine, Neurodegenerative Diseases, General Medicine, Alzheimer's disease, Cerebral cortex, Acetylcholinesterase inhibitors, Brain permeability, Multitarget compounds, Acetylcholinesterase, Escorça cerebral, Neuroprotective Agents, Tacrine, NMDA receptor, medicine.drug, Human, Neuroprotective Agent, NMDA antagonist, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Structure-Activity Relationship, Alzheimer Disease, Multi-target-directed ligand, medicine, Potency, Structure–activity relationship, Humans, IC50, 030304 developmental biology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, 0104 chemical sciences, Malaltia d'Alzheimer, Acetylcholinesterase inhibitor, Multitarget compound, Cholinesterase Inhibitors, Pharmaceutical chemistry
Abstract

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.

Published
2019

33. Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases

Author

Axel Bidon-Chanal, Elisabet Viayna, Miriam Ratia, Carles Galdeano, M. Victòria Clos, Vincenza Andrisano, Cristina Minguillón, Gema C. González-Muñoz, Júlia Relat, Pelayo Camps, Albert Badia, F. Javier Luque, Diego Muñoz-Torrero, Irene Sola, Manuela Bartolini, Francesca Mancini, Xavier Formosa, Mario Salmona, M. Isabel Rodríguez-Franco, Galdeano C., Viayna E., Sola I., Formosa X., Camps P. Badia A., Clos M.V., Relat J., Ratia M., Bartolini M., Mancini F., Andrisano V., Salmona M., Minguillon C., Gonzalez-Munoz G. C., Rodriguez-Franco M. I., Bidon-Chanal A., Luque F. J., and Munoz-Torrero D.

Subjects
Models, Molecular, Molecular model, Prions, Peptide, Heterocyclic Compounds, 4 or More Rings, AMYLOID BETA-PEPTIDES, Permeability, Prion Diseases, ALZHEIMER DISEASE/DRUG THERAPY, CHOLINESTERASE INHIBITORS, Mice, chemistry.chemical_compound, Alzheimer Disease, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, STRUCTURE-ACTIVITY RELATIONSHIP, Butyrylcholinesterase, chemistry.chemical_classification, Brain, Membranes, Artificial, Stereoisomerism, Acetylcholinesterase, Peptide Fragments, Recombinant Proteins, In vitro, chemistry, Biochemistry, Tacrine, Aminoquinolines, Molecular Medicine, PRION DISEASES/*DRUG THERAPY, Ex vivo, medicine.drug
Abstract

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.

Published
2012
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34. Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

Author

Codony Gisbert, Sandra, Pont Masanet, Caterina, Griñán Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José, Bartolini, Pérez, Belén, Bartra, Clara, Sanfeliu i Pujol, Coral, Juárez Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs i Llibería, Mercè, 1964, Vázquez Cruz, Santiago, Muñoz-Torrero López-Ibarra, Diego, Codony S., Pont C., Grinan-Ferre C., Di Pede-Mattatelli A., Calvo-Tusell C., Feixas F., Osuna S., Jarne-Ferrer J., Naldi M., Bartolini M., Loza M.I., Brea J., Perez B., Bartra C., Sanfeliu C., Juarez-Jimenez J., Morisseau C., Hammock B.D., Pallas M., Vazquez S., Munoz-Torrero D., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Xunta de Galicia, European Commission, Generalitat de Catalunya, National Institute of Environmental Health Sciences (US), European Research Council, National Institute of Neurological Disorders and Stroke (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Ministerio de Educación, Cultura y Deporte (España), Griñán-Ferré, Christian, Calvó-Tusell, Carla, Osuna, Sílvia, Bartolini, Manuela, Loza, María Isabel, Juárez-Jiménez, Jordi, Pallàs, Mercè, Vázquez, Santiago, and Muñoz-Torrero, Diego

Subjects
Aging, Medicinal & Biomolecular Chemistry, Química farmacèutica, Drug development, Neurodegenerative, Alzheimer's Disease, Desenvolupament de medicaments, Medicinal and Biomolecular Chemistry, Mice, Alzheimer Disease, Drug Discovery, Acquired Cognitive Impairment, Animals, acetylcholinesterase, Alzheimer's disease, soluble epoxide hydrolase, Epoxide Hydrolases, Animal, Organic Chemistry, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Pharmacology and Pharmaceutical Sciences, Brain Disorders, Disease Models, Animal, Malaltia d'Alzheimer, 5.1 Pharmaceuticals, Disease Models, Neurological, Acetylcholinesterase, Molecular Medicine, Dementia, Cholinesterase Inhibitors, Development of treatments and therapeutic interventions, Pharmaceutical chemistry
Abstract

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration., This work was supported by grants PID2020-118127RB-I00, SAF2017-82771-R, PID2020-115683GA-I00, PGC2018- 102192-B-I00, PID2019-106285RB, and RTI2018-101032-JI00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, ED431C 2018/21 and ED431G 2019/02 from Xunta de Galicia, and 2017SGR106, 2017SGR1707, and 2019LLAV00017 from AGAUR. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Fellowships from Ministerio de Educación, Cultura y Deporte to C.P. (FPU15/01131), from the University of Barcelona to S.C., and a starting grant from the European Research Council (ERC-2015-StG-679001- NetMoDEzyme) to S.O. are gratefully acknowledged. We thank Ms. Cecilia Mariani for technical assistance in the assays with mAChE.

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35. Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages.

Author

Serrano FG, Tapia-Rojas C, Carvajal FJ, Cisternas P, Viayna E, Sola I, Munoz-Torrero D, and Inestrosa NC

Subjects
Aging drug effects, Aging metabolism, Aging pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease psychology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Cognitive Dysfunction drug therapy, Cognitive Dysfunction metabolism, Cognitive Dysfunction pathology, Disease Models, Animal, Humans, Inflammation drug therapy, Inflammation metabolism, Inflammation pathology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Mice, Transgenic, Peptide Fragments metabolism, Phosphorylation drug effects, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 genetics, Presenilin-1 metabolism, Synapses drug effects, Synapses metabolism, Synapses pathology, tau Proteins metabolism, Alzheimer Disease drug therapy, Aminoquinolines pharmacology, Anthraquinones pharmacology, Neuroprotective Agents pharmacology, Nootropic Agents pharmacology
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aβ and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AβPPswe/PS-1 Alzheimer´s model, including a reduction in the Aβ levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.

Published
2016
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