Publications by authors named "Jose Marco-Contelles"

188 Publications

Privileged Quinolylnitrones for the Combined Therapy of Ischemic Stroke and Alzheimer's Disease.

Pharmaceuticals (Basel) 2021 Aug 27;14(9). Epub 2021 Aug 27.

Laboratory of Medicinal Chemistry (IQOG, CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer's disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen-glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide A, modeling toxic insults found among the effects of AD.
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http://dx.doi.org/10.3390/ph14090861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465398PMC
August 2021

Use of Radical Oxygen Species Scavenger Nitrones to Treat Oxidative Stress-Mediated Hearing Loss: State of the Art and Challenges.

Front Cell Neurosci 2021 1;15:711269. Epub 2021 Sep 1.

Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, CSIC, Madrid, Spain.

Nitrones are potent antioxidant molecules able to reduce oxidative stress by trapping reactive oxygen and nitrogen species. The antioxidant potential of nitrones has been extensively tested in multiple models of human diseases. Sensorineural hearing loss has a heterogeneous etiology, genetic alterations, aging, toxins or exposure to noise can cause damage to hair cells at the organ of Corti, the hearing receptor. Noxious stimuli share a battery of common mechanisms by which they cause hair cell injury, including oxidative stress, the generation of free radicals and redox imbalance. Therefore, targeting oxidative stress-mediated hearing loss has been the subject of much attention. Here we review the chemistry of nitrones, the existing literature on their use as antioxidants and the general state of the art of antioxidant treatments for hearing loss.
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http://dx.doi.org/10.3389/fncel.2021.711269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440819PMC
September 2021

Synthesis and biological assessment of new pyrimidopyrimidines as inhibitors of breast cancer resistance protein (ABCG2).

Bioorg Chem 2021 Nov 6;116:105326. Epub 2021 Sep 6.

Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques EA 481, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France. Electronic address:

Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC equal to 0.493 µM only 2-fold less active than Ko143.
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http://dx.doi.org/10.1016/j.bioorg.2021.105326DOI Listing
November 2021

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

RSC Med Chem 2021 Jun 20;12(6):1000-1004. Epub 2021 May 20.

Laboratory of Medicinal Chemistry, IQOG, CSIC C/Juan de la Cierva 3 28006 Madrid Spain

Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ/σ ligands. 6-(4-(Piperidin-1-yl)butoxy)-4-chromen-4-one (), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ/σ affinity. 6-(3-(Azepan-1-yl)propoxy)-4-chromen-4-one () showed a value for σ of 27.2 nM (selectivity (σ/σ) = 28), combining the desired σ receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4-chromen-4-one () was almost equipotent to , an established σ receptor antagonist.
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http://dx.doi.org/10.1039/d1md00105aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221265PMC
June 2021

(±)-: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

ACS Chem Neurosci 2021 04 2;12(8):1328-1342. Epub 2021 Apr 2.

Neurosciences intégratives et cliniques EA 481, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France.

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±) was identified as a promising new hit compound showing balanced activities toward the aforementioned recognized AD targets. Additional studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The studies have shown that (±) (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.
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http://dx.doi.org/10.1021/acschemneuro.0c00803DOI Listing
April 2021

Synthesis, Neuroprotection, and Antioxidant Activity of 1,1'-Biphenylnitrones as α-Phenyl--butylnitrone Analogues in In Vitro Ischemia Models.

Molecules 2021 Feb 20;26(4). Epub 2021 Feb 20.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain.

Herein, we report the neuroprotective and antioxidant activity of 1,1'-biphenyl nitrones () - as α-phenyl---butylnitrone analogues prepared from commercially available [1,1'-biphenyl]-4-carbaldehyde and [1,1'-biphenyl]-4,4'-dicarbaldehyde. The neuroprotection of - has been measured against oligomycin A/rotenone and in an oxygen-glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that - have better neuroprotective and antioxidant properties than α-phenyl---butylnitrone (), and they are quite similar to -acetyl-L-cysteine (), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone , bearing two --Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen-glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone , with one -Bn radical, and , with only one --Bu substituent. The antioxidant activity of - has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these , the final effect is also dependent on the substitutent that is being incorporated. Thus, bearing --Bu and -Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo--nitrone as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.
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http://dx.doi.org/10.3390/molecules26041127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926640PMC
February 2021

The Synthesis of Ipsenol and Ipsdienol: A Review (1968-2020).

Chem Rec 2021 Apr 4;21(4):858-878. Epub 2021 Feb 4.

Laboratory of Medicinal Chemistry (IQOG, CSIC), Juan de la Cierva 3, 28006-, Madrid, Spain.

Herein I present a review on the synthesis of ipsenol and ipsdienol, two aggregation pheromones of bark beetles, isolated from different species of genus Ips, and serious pests of conifer forests. I have covered the literature for around fifty years, since 1968 to 2020. This account has been divided in different sections and sub-sections, including a general and brief outlook on their isolation, structure and biological activity, to continue with the reported synthesis of racemic ipsenol and ipsdienol, including my own contribution to topic, and the presentation of reports describing the synthesis of enantiomerically pure ipsenol and ipsdienol. Particular attention has been devoted to identify and highlight racemic or enantiomerically pure "isoprene synthons", and isoprenylation methods employed in the synthesis of ipsenol and ipsdienol, of general interest for related terpene derivatives synthesis.
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http://dx.doi.org/10.1002/tcr.202000160DOI Listing
April 2021

2-Propargylamino-naphthoquinone derivatives as multipotent agents for the treatment of Alzheimer's disease.

Eur J Med Chem 2021 Feb 18;211:113112. Epub 2020 Dec 18.

University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; University of Defence in Brno, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address:

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD.
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http://dx.doi.org/10.1016/j.ejmech.2020.113112DOI Listing
February 2021

Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments.

Chem Rec 2021 Jan 10;21(1):162-174. Epub 2020 Nov 10.

Public Health Department, Faculty of Medicine and Nursing, University of the Basque Country., Leioa, Spain.

Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non-hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD.
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http://dx.doi.org/10.1002/tcr.202000107DOI Listing
January 2021

and ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases.

ACS Chem Neurosci 2020 11 3;11(22):3793-3801. Epub 2020 Nov 3.

Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.

Herein we report metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy.
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http://dx.doi.org/10.1021/acschemneuro.0c00489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677930PMC
November 2020

Homo-Tris-Nitrones Derived from α-Phenyl--butylnitrone: Synthesis, Neuroprotection and Antioxidant Properties.

Int J Mol Sci 2020 Oct 26;21(21). Epub 2020 Oct 26.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain.

Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones () , designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone () would result in an improved and stronger neuroprotection. The neuroprotection of , measured against oligomycin A/rotenone, showed that was the best neuroprotective agent at a lower dose (EC = 51.63 ± 4.32 μM), being similar in EC and maximal activity to α-phenyl---butylnitrone () and less potent than any of . The results of neuroprotection in an in vitro oxygen glucose deprivation model showed that was the most powerful (EC = 87.57 ± 3.87 μM), at lower dose, but 50-fold higher than its analogous , and ≈1.7-fold less potent than . had a very good antinecrotic (IC = 3.47 ± 0.57 μM), antiapoptotic, and antioxidant (EC = 6.77 ± 1.35 μM) profile, very similar to that of its analogous . In spite of these results, and still being attractive neuroprotective agents, and do not have better neuroprotective properties than , but clearly exceed that of .
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http://dx.doi.org/10.3390/ijms21217949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663103PMC
October 2020

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives.

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France.

We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate , have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against HO and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.
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http://dx.doi.org/10.3390/ijms21207652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589057PMC
October 2020

Recent Advances on Nitrones Design for Stroke Treatment.

J Med Chem 2020 11 18;63(22):13413-13427. Epub 2020 Sep 18.

Laboratory of Medicinal Chemistry, Institute of Organic Chemistry, CSIC; Juan de la Cierva, 3, 28006 Madrid, Spain.

The recent advances of tetramethylpyrazine nitrones and quinolylnitrones for the treatment of stroke have been reviewed and compared with other agents, showing promising therapeutic applications. As a result of a functional transformation of natural product ligustrazine, ()--butyl-1-(3,5,6-trimethylpyrazin-2-yl)methanimine oxide () is a multitarget small nitrone showing potent thrombolytic activity and free radicals scavenging power, in addition to nontoxicity and blood-brain barrier permeability. Similarly, antioxidant ()--butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide () is a novel agent for cerebral ischemia therapy as it is able to scavenge different types of free radical species, showing strong neuroprotection and reduced infarct size.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00976DOI Listing
November 2020

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models.

Sci Rep 2020 08 25;10(1):14150. Epub 2020 Aug 25.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain.

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1'Z)-1,1'-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC = 1.24 ± 0.39 μM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke.
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http://dx.doi.org/10.1038/s41598-020-70690-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447640PMC
August 2020

From Seeds of Linn. to a Cerebral Ischemia Medicine: The Long Journey of 3--Butylphthalide.

J Med Chem 2020 11 27;63(21):12485-12510. Epub 2020 Jul 27.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.

3--Butylphthalide () as well as its derivatives and analogues (), in racemic or enantiomerically pure forms, possess potent and diverse pharmacological properties and have shown a great potential therapeutic interest for many human conditions, especially for cerebral ischemia. This outlines the synthesis and therapeutic applications of .
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http://dx.doi.org/10.1021/acs.jmedchem.0c00887DOI Listing
November 2020

Triazolopyridopyrimidine: A New Scaffold for Dual-Target Small Molecules for Alzheimer's Disease Therapy.

Molecules 2020 Jul 13;25(14). Epub 2020 Jul 13.

Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax. B. P 802. 3000 Sfax, Tunisia.

Alzheimer's disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1',5':1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile() with IC equal to 1.32 μM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.
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http://dx.doi.org/10.3390/molecules25143190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397274PMC
July 2020

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms.

Antioxidants (Basel) 2020 Jun 22;9(6). Epub 2020 Jun 22.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, E-28040 Madrid, Spain.

Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5' AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.
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http://dx.doi.org/10.3390/antiox9060545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346137PMC
June 2020

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (-) and 13 dihydroquinolinones (-) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant MAO inhibition, but compounds , , and displayed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition. In particular, molecule was found to be a potent and quite selective non-competitive inhibitor of AChE (IC = 0.29 µM), with K value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
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http://dx.doi.org/10.3390/ijms21113913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312762PMC
May 2020

Characterization of a CholesteroNitrone (ISQ-201), a Novel Drug Candidate for the Treatment of Ischemic Stroke.

Antioxidants (Basel) 2020 Mar 31;9(4). Epub 2020 Mar 31.

Department of Research, IRYCIS, Hospital Ramón y Cajal, Ctra. Colmenar km 9.1, 28034 Madrid, Spain.

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.
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http://dx.doi.org/10.3390/antiox9040291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222207PMC
March 2020

Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels.

Molecules 2020 Mar 14;25(6). Epub 2020 Mar 14.

Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France.

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs -, resulting from the juxtaposition of nimodipine, a Ca channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (), as an attractive antioxidant (1.75 TE), Ca channel antagonist (46.95% at 10 μM), showing significant neuroprotection (38%) against HO at 10 μM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.
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http://dx.doi.org/10.3390/molecules25061329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144121PMC
March 2020

Chromenones as Multineurotargeting Inhibitors of Human Enzymes.

ACS Omega 2019 Dec 11;4(26):22161-22168. Epub 2019 Dec 11.

Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4-chromen-4-one ().
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http://dx.doi.org/10.1021/acsomega.9b03409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933783PMC
December 2019

Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy.

Bioorg Med Chem Lett 2020 02 9;30(3):126880. Epub 2019 Dec 9.

Laboratory of Medicinal Chemistry (IQOG-CSIC), C/ Juan de la Cierva, 3, 28006 Madrid, Spain. Electronic address:

Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
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http://dx.doi.org/10.1016/j.bmcl.2019.126880DOI Listing
February 2020

Synthesis of new ferulic/lipoic/comenic acid-melatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction.

Future Med Chem 2019 12;11(24):3097-3108

Laboratoire Neurosciences intégratives et cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France.

Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer's disease. This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of ()--(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides , -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides and -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4-pyran-2-carboxamides . We have identified compounds and , showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by HO in SH-SY5Y cells, and a performing activation of the Nrf2 signaling pathway, as very interesting new antioxidant agents for pathologies that curse with oxidative stress.
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http://dx.doi.org/10.4155/fmc-2019-0191DOI Listing
December 2019

New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition.

J Med Chem 2019 12 5;62(24):11416-11422. Epub 2019 Dec 5.

Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique , Université Bourgogne Franche-Comté, UFR Santé , 19, Rue Ambroise Paré , F-25000 Besançon , France.

New tritarget small molecules combining Ca channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound has been identified as a very promising lead, showing good Ca channels blockade activity (IC = 21 ± 1 μM), potent affinity against hH3R ( = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00937DOI Listing
December 2019

Synthesis and Biological Evaluation of Novel Chromone+Donepezil Hybrids for Alzheimer's Disease Therapy.

Curr Alzheimer Res 2019 ;16(9):815-820

Neurosciences Intégratives et Cliniques, Pôle Chimie Organique et Thérapeutique, EA 481, University, Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France.

Background: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets.

Objective: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals.

Methods: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed.

Results: Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development.

Conclusion: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.
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http://dx.doi.org/10.2174/1567205016666191011112624DOI Listing
September 2020

"", Lobby or Religion?

ACS Med Chem Lett 2019 Oct 25;10(10):1361-1362. Epub 2019 Sep 25.

Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva, 3, 28006-Madrid, Spain.

A recent review from Prof. Garrett on the causes and cures of Alzheimer's disease prompts the author to insist in that beyond the "" praxis other alternate, more open therapeutic strategic approaches are possible, and chemistry, medicinal chemistry, should be the starting point, where all the inspiring contributions should find their place to play the match of our health.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792146PMC
October 2019

Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer's disease therapy.

Neural Regen Res 2020 Jan;15(1):30-35

Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain.

There is no effective treatment to face Alzheimer's disease complexity. Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression. In this context, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234) has been tested achieving promising results. ASS234 has demonstrated to cross the blood-brain barrier in vivo, and a good in silico safety profile being less toxic than donepezil. Besides, ASS234 reversibly inhibits human acetyl- and butyryl-cholinesterase, and irreversibly inhibits human monoamine oxidase A and B. Moreover, this multitarget molecule has antioxidant and neuroprotective properties, and inhibits Αβ and Αβ self-aggregation. Inquiring about the mechanism of action, several signaling pathways related to Alzheimer's disease had been explored showing that ASS234 induces the wingless-type MMTV integration site (Wnt) family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes. Finally, in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus, ameliorating scopolamine-induced learning deficits. Here we gather the information regarding ASS234 evaluated so far, showing its ability to face different targets, necessary to counteract a neurodegenerative disease as complex as the Alzheimer's disease.
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http://dx.doi.org/10.4103/1673-5374.262679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862399PMC
January 2020

Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds: Exploring multiple activities as anti-Alzheimer agents.

Drug Dev Res 2020 04 30;81(2):215-231. Epub 2019 Aug 30.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ , was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.
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http://dx.doi.org/10.1002/ddr.21594DOI Listing
April 2020

Synthesis and Neuroprotective Properties of N-Substituted -Dialkoxyphosphorylated Nitrones.

ACS Omega 2019 May 16;4(5):8581-8587. Epub 2019 May 16.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain.

Herein, we report the synthesis and neuroprotective power of some N-substituted -(dialkoxy)phosphorylated nitrones -, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified ()---butyl-1-(diethoxyphosphoryl)methanimine oxide () as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 μM concentrations. Thus, nitrone could be a convenient promising compound for further investigation.
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http://dx.doi.org/10.1021/acsomega.9b00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648307PMC
May 2019

Multi-target 1,4-dihydropyridines showing calcium channel blockade and antioxidant capacity for Alzheimer's disease therapy.

Bioorg Chem 2019 10 16;91:103205. Epub 2019 Aug 16.

Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France. Electronic address:

In this work we describe the synthesis, Ca channel blockade capacity and antioxidant power of N,N-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.
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http://dx.doi.org/10.1016/j.bioorg.2019.103205DOI Listing
October 2019
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