Publications by authors named "Lhassane Ismaili"

44 Publications

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

Synthesis of new Hantzsch adducts showing Ca channel blockade capacity, cholinesterase inhibition and antioxidant power.

Future Med Chem 2021 Oct 17;13(20):1717-1729. Epub 2021 Aug 17.

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

Alzheimer's disease is a chronic neurodegenerative chronic disease with a heavy social and economic impact in our developed societies, which still lacks an efficient therapy. This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, , along with the evaluation of their Ca channel blockade capacity, cholinesterase inhibition and antioxidant power. Compound  showed submicromolar inhibition of butyrylcholinesterase, Ca channel antagonism and an antioxidant effect. Compound  is an interesting compound that deserves further investigation for Alzheimer's disease therapy.
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http://dx.doi.org/10.4155/fmc-2021-0176DOI Listing
October 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

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

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

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

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

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

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

Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer's disease therapy.

J Enzyme Inhib Med Chem 2019 Dec;34(1):479-489

a Neurosciences intégratives et cliniques, Pôle Chimie Organique et Thérapeutique , University Bourgogne Franche-Comté , Besançon , France.

We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC = 11.90 ± 0.05 nM), moderate hAChE (IC = 1.73 ± 0.34 μM), hMAO A (IC = 2.78 ± 0.12 μM), and MAO B (IC = 21.29 ± 3.85 μM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure.
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http://dx.doi.org/10.1080/14756366.2018.1545766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366423PMC
December 2019

Synthesis, antioxidant and Aβ anti-aggregation properties of new ferulic, caffeic and lipoic acid derivatives obtained by the Ugi four-component reaction.

Bioorg Chem 2019 04 21;85:221-228. Epub 2018 Dec 21.

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. Electronic address:

We report herein the synthesis antioxidant and Aβ anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1-12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aβ self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2018.12.029DOI Listing
April 2019

Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy.

J Enzyme Inhib Med Chem 2019 Dec;34(1):163-170

b Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques EA 481 , Univ. Bourgogne Franche-Comté , Besançon , France.

In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
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http://dx.doi.org/10.1080/14756366.2018.1538136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263107PMC
December 2019

Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease.

Eur J Med Chem 2018 Jul 19;155:839-846. Epub 2018 Jun 19.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address:

Notwithstanding the combination of cholinesterase (ChE) inhibition and calcium channel blockade within a multitarget therapeutic approach is envisaged as potentially beneficial to confront Alzheimer's disease (AD), this strategy has been scarcely investigated. To explore this promising line, a series of 5-amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido [4,5-b]quinoline-2(1H)-thiones (tacripyrimidines) (4a-l) were designed by juxtaposition of tacrine, a ChE inhibitor (ChEI), and 3,4-dihydropyrimidin-2(1H)-thiones, as efficient calcium channel blockers (CCBs). In agreement with their design, all tacripyrimidines, except the unsubstituted parent compound and its p-methoxy derivative, acted as moderate to potent CCBs with activities generally similar or higher than the reference CCB drug nimodipine and were modest-to-good ChEIs. Most interestingly, the 3'-methoxy derivative (4e) emerged as the first well balanced ChEI/CCB agent, acting as low micromolar hChEI (3.05 μM and 3.19 μM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1 μM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.044DOI Listing
July 2018

Multicomponent Reactions for Multitargeted Compounds for Alzheimer`s Disease.

Curr Top Med Chem 2017 ;17(31):3319-3327

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal.

Alzheimer's Disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (Aβ) oligomers formation and Aβ fibril deposition. Multi-Target- Directed Ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent Reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds. The biological diversity of MCRs is very rich providing great possibilities for researchers interested in bioactive small molecular weight compounds. Since the MTDL strategy has been used to develop compounds endowed with the capacity to interact with different targets, versatile compound libraries may be obtained by MCRs according to the well established features of each target. Thus, either MTDLs or monotarget compounds have been developed by MCRs to address different factors implicated in AD. This work focuses on antioxidants, calcium channel modulators, both AChE and BuChE inhibitors, BACE1 inhibitors, and modulators of the nuclear factor (erythroid-derived 2)-like 2. First, we discuss the Biginelli reaction and its use for developing new interesting compounds for AD, followed by the contribution of Ugi reaction and, finally, the interest of other MCRs in the same topic.
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http://dx.doi.org/10.2174/1568026618666180112155424DOI Listing
March 2018

Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H R Antagonism for Neurodegenerative Diseases.

Angew Chem Int Ed Engl 2017 10 1;56(41):12765-12769. Epub 2017 Sep 1.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
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http://dx.doi.org/10.1002/anie.201706072DOI Listing
October 2017

Synthesis and biological assessment of racemic benzochromenopyrimidinetriones as promising agents for Alzheimer's disease therapy.

Future Med Chem 2017 05 15;9(8):715-721. Epub 2017 May 15.

Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques EA 481, UFR SMP, 19 Rue Ambroise Paré, Université Bourgogne Franche-Comté, F-25000 Besançon, France.

Aim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs.

Results: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 μmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power.

Conclusion: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.
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http://dx.doi.org/10.4155/fmc-2017-0004DOI Listing
May 2017

New (benz)imidazolopyridino tacrines as nonhepatotoxic, cholinesterase inhibitors for Alzheimer disease.

Future Med Chem 2017 05 9;9(8):723-729. Epub 2017 May 9.

Laboratoire des Produits Naturels d'Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université des frères Mentouri-Constantine. Constantine 25000, Algeria.

Aim: Due to the multifactorial nature of Alzheimer's disease, there is an urgent search for new more efficient, multitarget-directed drugs.

Results: This paper describes the synthesis, antioxidant and in vitro biological evaluation of ten (benz)imidazopyridino tacrines (7-16), showing less toxicity than tacrine at high doses, and potent cholinesterase inhibitory capacity, in the low micromolar range. Among them, compound 10 is a nonhepatotoxic tacrine at 1000 mM, showing moderate, but totally selective electric eel acetylcholinesterase inhibition, whereas molecule 16 is twofold less toxic than tacrine at 1000 μM, showing moderate and almost equipotent inhibition for electric eel acetylcholinesterase and equine butyrylcholinesterase.

Conclusion: (Benz)imidazopyridino tacrines (7-16) have been identified as a new and promising type of tacrines for the potential treatment of Alzheimer's disease.
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http://dx.doi.org/10.4155/fmc-2017-0019DOI Listing
May 2017

Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy.

Eur J Med Chem 2017 Jan 23;126:576-589. Epub 2016 Nov 23.

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

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.
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http://dx.doi.org/10.1016/j.ejmech.2016.11.050DOI Listing
January 2017

The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.

J Med Chem 2016 11 31;59(21):9967-9973. Epub 2016 Oct 31.

Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université Bourgogne Franche-Comté , 19 rue Ambroise Paré, CS 25000 Besançon, France.

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01178DOI Listing
November 2016

ASS234, As a New Multi-Target Directed Propargylamine for Alzheimer's Disease Therapy.

Front Neurosci 2016 28;10:294. Epub 2016 Jun 28.

Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques EA 481, Université Franche-Comté, Université Bourgogne Franche-Comté, UFR SMP Besançon, France.

Highlights: ASS2324 is a hybrid compound resulting from the juxtaposition of donepezil and the propargylamine PF9601N ASS2324 is a multi-target directed propargylamine able to bind to all the AChE/BuChE and MAO A/B enzymesASS2324 shows antioxidant, neuroprotective and suitable permeability propertiesASS2324 restores the scopolamine-induced cognitive impairment to the same extent as donepezil, and is less toxicASS2324 prevents β-amyloid induced aggregation in the cortex of double transgenic miceASS2324 is the most advanced anti-Alzheimer agent for pre-clinical studies that we have identified in our laboratories The complex nature of Alzheimer's disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines (MTDP) showing antioxidant, anti-beta-amyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase (MAO) inhibition capacities. Here, we describe these properties in the MTDL ASS234, our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aβ-aggregation, and possessing antioxidant and neuroprotective properties.
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http://dx.doi.org/10.3389/fnins.2016.00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923252PMC
July 2016

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease.

Molecules 2016 May 14;21(5). Epub 2016 May 14.

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

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.
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http://dx.doi.org/10.3390/molecules21050634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273488PMC
May 2016

Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer's Disease Therapy.

Molecules 2016 Mar 24;21(4):400. Epub 2016 Mar 24.

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

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound).
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http://dx.doi.org/10.3390/molecules21040400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273229PMC
March 2016

Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy.

ChemMedChem 2016 Jun 25;11(12):1318-27. Epub 2016 Jan 25.

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

Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %).
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http://dx.doi.org/10.1002/cmdc.201500539DOI Listing
June 2016

Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease.

Prog Neurobiol 2017 04 18;151:4-34. Epub 2016 Jan 18.

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

Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.
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http://dx.doi.org/10.1016/j.pneurobio.2015.12.003DOI Listing
April 2017

Donepezil-ferulic acid hybrids as anti-Alzheimer drugs.

Future Med Chem 2015 ;7(1):15-21

NanoMedicine, Imagery & Therapeutics Lab EA 4662, Laboratoire de Chimie Organique et Thérapeutique UFR SMP, CHU Jean Minjoz, Université de Franche-Comté, 19 rue Ambroise Paré, 25030-Besançon, France.

Background: Due to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget drugs.

Results: Donepezil-ferulic acid hybrids (DFAHs) were prepared by the one-pot Ugi-4CR in low-to-moderate yields. DFAHs are potent antioxidant agents, showing oxygen radical absorbance capacity values in the range 4.80-8.71 trolox equivalents, quite higher compared with those recorded for ferulic acid and melatonin. From the ChEs inhibition studies, we conclude that DFAH 8, bearing an ethylene linker, and DFAH 12, bearing a propylene linker, both substituted with a melatonin motif, are the most potent inhibitors, in the nanomolar range.

Conclusion: We have identified DFAH 8 as a very potent antioxidant, and totally selective equineButyrylCholinEsterase (eqBuChE) inhibitor.
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http://dx.doi.org/10.4155/fmc.14.148DOI Listing
September 2015
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