Diego Muñoz-torrero | University of Barcelona (original) (raw)
Papers by Diego Muñoz-torrero
Molecules (Basel, Switzerland), Jan 28, 2017
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a serie... more Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].
Molecules
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a serie... more 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 [...]
Journal of Medicinal Chemistry, 2012
A family of huprine−tacrine heterodimers has been developed to simultaneously block the active an... more 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 β-amyloid peptide (Aβ) 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 Aβ aggregation, and β-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.
We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity aga... more We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypano-cidal/anticholinesterase activity ratio.
Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and ch... more Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the anti-malarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
Current medicinal chemistry, 2013
Acta neuropathologica communications, 2015
The prion protein (PrP) binds to various molecular partners, but little is known about their pote... more The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases RESULTS: Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity. Using several truncated PrP variants and specific tight-binding AChE inhibitors (AChEis), we then demonstrate that the PrP-AChE interaction requires two mutually exclusive sub-sites in PrP N-terminal domain and an aromatic-rich region at the entrance of AChE active center gorge. We show that AChEis that target this site impair PrP-AChE complex formation and also limit the accumulation of pathological prion protein (PrPSc) in prion-infe...
Current Pharmaceutical Design, 2009
Abstract: Structural manipulation of already marketed drugs, or in general, of known biologically... more Abstract: Structural manipulation of already marketed drugs, or in general, of known biologically active compounds as a means to get novel drug candidates with improved profiles constitutes a widespread practice in medicinal chemistry. In most cases, from this ...
Bioorganic & medicinal chemistry, Jan 22, 2016
Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. ... more Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivati...
Bioorganic & medicinal chemistry, Jan 28, 2016
Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition... more Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N1- and C5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50 of 3.54μM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support t...
Molecules, 2015
We describe the multigram synthesis and in vivo efficacy studies of a donepezil-huprine hybrid th... more We describe the multigram synthesis and in vivo efficacy studies of a donepezil-huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic
![Research paper thumbnail of Alternative syntheses of bridgehead polycyclic 1,2-diamines and 2-aminoalcohols from di- and mono-oximes of some bicyclic diketones: Highly improved synthesis of tricyclo[3.3.1.03,7]nonane-3,7-diamine](https://attachments.academia-assets.com/49368226/thumbnails/1.jpg)
](Bridgehad plyylic 1.2-diamines k rrnd 46 have been obtatked from dioximes 2a and Zb. respectindy,... more Bridgehad plyylic 1.2-diamines k rrnd 46 have been obtatked from dioximes 2a and Zb. respectindy, by two ahmmtiw pmcdues: a) m-dlorv~ ocidoddoive Ming to 3a kmd 3 b, followed by rcdvaimr with aluminum amalgam. and b) reducti~ coupling with aluminum amalgam. Similarly, the r&trd 2-aminoalc&ols 9tt and9 b have been obtainedfrom the correspondiag monoo &KS ?a md 76.
Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 ... more Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 with a formamido or an acetamido group have been synthesized as potential high affinity acetylcholinesterase inhibitors. The synthetic sequence involves hydrolysis of two ...
ABSTRACT The enantioselective synthesis of the title compound, its conversion into a thiourea-typ... more ABSTRACT The enantioselective synthesis of the title compound, its conversion into a thiourea-type organocatalyst and the behavior of this organocatalyst in several enantioselective Michael reactions are described.
Tetrahedron Letters, 1995
llridgehead polytyclic 1,2-diamines and 2-aminoalcohols have been oxidized to the corresponding t... more llridgehead polytyclic 1,2-diamines and 2-aminoalcohols have been oxidized to the corresponding tric?,.,clic or tetracyclic nitro derivatives through an unusual sequence involving oxidative cleavage of the central carbon-carbon bond to the corresponding bicyclic or tricvclic dioximes and monooximes followed by an intramolecular oxidative coupling reaction.
ChemInform, 2002
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
![Research paper thumbnail of Easy synthesis of 7-alkylbicyclo[3.3.1]non-6-en-3-ones by silica gel-promoted fragmentation of 3-alkyl-2-oxaadamant-1-yl mesylates](https://attachments.academia-assets.com/49368227/thumbnails/1.jpg)
](Tetrahedron, 1996
A synthesis of 7-alkylbicyclo[3.3.1]non-6-en-3-ones 4b-f and 4j,k by reaction of the correspondin... more A synthesis of 7-alkylbicyclo[3.3.1]non-6-en-3-ones 4b-f and 4j,k by reaction of the corresponding 3-alkyl-2-oxaadamant-l-yl mesylates 3 with silica gel in methylene chloride at room temperature, is described. The method failed to give enones 4a,g and the related compounds 41,m, what can be rationalized on mechanistic grounds.
Synthetic Communications, 2001
Condensation of the readily available 7-methylbicyclo [3.3. 1] non-6-en-3-one with dimethyl acety... more Condensation of the readily available 7-methylbicyclo [3.3. 1] non-6-en-3-one with dimethyl acetylenedicarboxylate and ammonia or with acetylenedicarboxamide gave a 4-carboxamido (±)-huperzine A analogue, from which other analogues were easily ...
Molecules (Basel, Switzerland), Jan 28, 2017
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a serie... more Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].
Molecules
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a serie... more 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 [...]
Journal of Medicinal Chemistry, 2012
A family of huprine−tacrine heterodimers has been developed to simultaneously block the active an... more 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 β-amyloid peptide (Aβ) 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 Aβ aggregation, and β-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.
We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity aga... more We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypano-cidal/anticholinesterase activity ratio.
Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and ch... more Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the anti-malarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
Current medicinal chemistry, 2013
Acta neuropathologica communications, 2015
The prion protein (PrP) binds to various molecular partners, but little is known about their pote... more The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases RESULTS: Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity. Using several truncated PrP variants and specific tight-binding AChE inhibitors (AChEis), we then demonstrate that the PrP-AChE interaction requires two mutually exclusive sub-sites in PrP N-terminal domain and an aromatic-rich region at the entrance of AChE active center gorge. We show that AChEis that target this site impair PrP-AChE complex formation and also limit the accumulation of pathological prion protein (PrPSc) in prion-infe...
Current Pharmaceutical Design, 2009
Abstract: Structural manipulation of already marketed drugs, or in general, of known biologically... more Abstract: Structural manipulation of already marketed drugs, or in general, of known biologically active compounds as a means to get novel drug candidates with improved profiles constitutes a widespread practice in medicinal chemistry. In most cases, from this ...
Bioorganic & medicinal chemistry, Jan 22, 2016
Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. ... more Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivati...
Bioorganic & medicinal chemistry, Jan 28, 2016
Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition... more Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N1- and C5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50 of 3.54μM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support t...
Molecules, 2015
We describe the multigram synthesis and in vivo efficacy studies of a donepezil-huprine hybrid th... more We describe the multigram synthesis and in vivo efficacy studies of a donepezil-huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic
Bridgehad plyylic 1.2-diamines k rrnd 46 have been obtatked from dioximes 2a and Zb. respectindy,... more Bridgehad plyylic 1.2-diamines k rrnd 46 have been obtatked from dioximes 2a and Zb. respectindy, by two ahmmtiw pmcdues: a) m-dlorv~ ocidoddoive Ming to 3a kmd 3 b, followed by rcdvaimr with aluminum amalgam. and b) reducti~ coupling with aluminum amalgam. Similarly, the r&trd 2-aminoalc&ols 9tt and9 b have been obtainedfrom the correspondiag monoo &KS ?a md 76.
Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 ... more Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 with a formamido or an acetamido group have been synthesized as potential high affinity acetylcholinesterase inhibitors. The synthetic sequence involves hydrolysis of two ...
ABSTRACT The enantioselective synthesis of the title compound, its conversion into a thiourea-typ... more ABSTRACT The enantioselective synthesis of the title compound, its conversion into a thiourea-type organocatalyst and the behavior of this organocatalyst in several enantioselective Michael reactions are described.
Tetrahedron Letters, 1995
llridgehead polytyclic 1,2-diamines and 2-aminoalcohols have been oxidized to the corresponding t... more llridgehead polytyclic 1,2-diamines and 2-aminoalcohols have been oxidized to the corresponding tric?,.,clic or tetracyclic nitro derivatives through an unusual sequence involving oxidative cleavage of the central carbon-carbon bond to the corresponding bicyclic or tricvclic dioximes and monooximes followed by an intramolecular oxidative coupling reaction.
ChemInform, 2002
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Tetrahedron, 1996
A synthesis of 7-alkylbicyclo[3.3.1]non-6-en-3-ones 4b-f and 4j,k by reaction of the correspondin... more A synthesis of 7-alkylbicyclo[3.3.1]non-6-en-3-ones 4b-f and 4j,k by reaction of the corresponding 3-alkyl-2-oxaadamant-l-yl mesylates 3 with silica gel in methylene chloride at room temperature, is described. The method failed to give enones 4a,g and the related compounds 41,m, what can be rationalized on mechanistic grounds.
Synthetic Communications, 2001
Condensation of the readily available 7-methylbicyclo [3.3. 1] non-6-en-3-one with dimethyl acety... more Condensation of the readily available 7-methylbicyclo [3.3. 1] non-6-en-3-one with dimethyl acetylenedicarboxylate and ammonia or with acetylenedicarboxamide gave a 4-carboxamido (±)-huperzine A analogue, from which other analogues were easily ...