Chioua M

References (26)

Title : Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases - Kolic_2024_Biomolecules_14_588
Author(s) : Kolic D , Sinko G , Jean L , Chioua M , Dias J , Marco-Contelles J , Kovarik, Z
Ref : Biomolecules , 14 :588 , 2024
Abstract : Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the bloodbrain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 1030% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
ESTHER : Kolic_2024_Biomolecules_14_588
PubMedSearch : Kolic_2024_Biomolecules_14_588

Title : 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases - Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
Author(s) : Knez D , Diez-Iriepa D , Chioua M , Gottinger A , Denic M , Chantegreil F , Nachon F , Brazzolotto X , Skrzypczak-Wiercioch A , Meden A , Pislar A , Kos J , Zakelj S , Stojan J , Salat K , Serrano J , Patricia Fernandez AP , Sanchez-Garcia A , Martinez-Murillo R , Binda C , Lopez-Munoz F , Gobec S , Marco-Contelle J
Ref : Acta Pharmaceutica Sinica B , 13 :2152 , 2023
Abstract : We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase -hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC50 = 4.46 +/- 0.18 micromol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19
ESTHER : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedSearch : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedID: 37250172
Gene_locus related to this paper: human-BCHE

Title : The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents - Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
Author(s) : Keuler T , Lemke C , Elsinghorst PW , Iriepa I , Chioua M , Martinez-Grau MA , Beadle CD , Vetman T , Lopez-Munoz F , Wille T , Bartz U , Deuther-Conrad W , Marco-Contelles J , Gutschow M
Ref : ACS Pharmacol Transl Sci , 5 :1097 , 2022
Abstract : The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the (1) and (2) receptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents.
ESTHER : Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
PubMedSearch : Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
PubMedID: 36407962

Title : Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy - Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
Author(s) : Bautista-Aguilera OM , Ismaili L , Chioua M , Andrys R , Schmidt M , Bzonek P , Martinez-Grau MA , Beadle CD , Vetman T , Lopez-Munoz F , Iriepa I , Refouvelet B , Musilek K , Marco-Contelles J
Ref : Int J Mol Sci , 21 : , 2020
Abstract : In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 microM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
ESTHER : Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
PubMedSearch : Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
PubMedID: 32486316

Title : Chromenones as Multineurotargeting Inhibitors of Human Enzymes - Lemke_2019_ACS.Omega_4_22161
Author(s) : Lemke C , Christmann J , Yin J , Alonso JM , Serrano E , Chioua M , Ismaili L , Martinez-Grau MA , Beadle CD , Vetman T , Dato FM , Bartz U , Elsinghorst PW , Pietsch M , Muller CE , Iriepa I , Wille T , Marco-Contelles J , Gutschow M
Ref : ACS Omega , 4 :22161 , 2019
Abstract : 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 IC50 values of 5.58 and 7.20 muM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
ESTHER : Lemke_2019_ACS.Omega_4_22161
PubMedSearch : Lemke_2019_ACS.Omega_4_22161
PubMedID: 31891098

Title : QuinoxalineTacrine QT78, a Cholinesterase Inhibitor as a Potential Ligand for Alzheimer's Disease Therapy - Ramos_2019_Molecules_24_
Author(s) : Ramos E , Palomino-Antolin A , Bartolini M , Iriepa I , Moraleda I , Diez-Iriepa D , Samadi A , Cortina CV , Chioua M , Egea J , Romero A , Marco-Contelles J
Ref : Molecules , 24 : , 2019
Abstract : We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer's disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 muM to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC50 (hAChE) = 22.0 +/- 1.3 muM; IC50 (hBuChE) = 6.79 +/- 0.33 muM). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer's disease.
ESTHER : Ramos_2019_Molecules_24_
PubMedSearch : Ramos_2019_Molecules_24_
PubMedID: 30999586

Title : Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease - Chioua_2018_Eur.J.Med.Chem_155_839
Author(s) : Chioua M , Buzzi E , Moraleda I , Iriepa I , Maj M , Wnorowski A , Giovannini C , Tramarin A , Portali F , Ismaili L , Lopez-Alvarado P , Bolognesi ML , Jozwiak K , Menendez JC , Marco-Contelles J , Bartolini M
Ref : Eur Journal of Medicinal Chemistry , 155 :839 , 2018
Abstract : 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 (3.05muM and 3.19muM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1muM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.
ESTHER : Chioua_2018_Eur.J.Med.Chem_155_839
PubMedSearch : Chioua_2018_Eur.J.Med.Chem_155_839
PubMedID: 29958119

Title : Synthesis and biological assessment of racemic benzochromenopyrimidinetriones as promising agents for Alzheimer's disease therapy - Dgachi_2017_Future.Med.Chem_9_715
Author(s) : Dgachi Y , Martin H , Bonet A , Chioua M , Iriepa I , Moraleda I , Chabchoub F , Marco-Contelles J , Ismaili L
Ref : Future Med Chem , 9 :715 , 2017
Abstract : 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]pyrimidi ne-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]pyrimi dine-7,12,14-trione (1a) is a nonhepatotoxic at 300 mumol/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.
ESTHER : Dgachi_2017_Future.Med.Chem_9_715
PubMedSearch : Dgachi_2017_Future.Med.Chem_9_715
PubMedID: 28504912

Title : Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases - Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
Author(s) : Bautista-Aguilera OM , Hagenow S , Palomino-Antolin A , Farre-Alins V , Ismaili L , Joffrin PL , Jimeno ML , Soukup O , Janockova J , Kalinowsky L , Proschak E , Iriepa I , Moraleda I , Schwed JS , Romero Martinez A , Lopez-Munoz F , Chioua M , Egea J , Ramsay RR , Marco-Contelles J , Stark H
Ref : Angew Chem Int Ed Engl , 56 :12765 , 2017
Abstract : The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg(-1) i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
ESTHER : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedSearch : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedID: 28861918

Title : New (benz)imidazolopyridino tacrines as nonhepatotoxic, cholinesterase inhibitors for Alzheimer disease - Boulebd_2017_Future.Med.Chem_9_723
Author(s) : Boulebd H , Ismaili L , Martin H , Bonet A , Chioua M , Marco Contelles J , Belfaitah A
Ref : Future Med Chem , 9 :723 , 2017
Abstract : 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 muM, 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.
ESTHER : Boulebd_2017_Future.Med.Chem_9_723
PubMedSearch : Boulebd_2017_Future.Med.Chem_9_723
PubMedID: 28485637

Title : Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Abeta1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy - Dgachi_2016_ChemMedChem_11_1318
Author(s) : Dgachi Y , Ismaili L , Knez D , Benchekroun M , Martin H , Szalaj N , Wehle S , Bautista-Aguilera OM , Luzet V , Bonnet A , Malawska B , Gobec S , Chioua M , Decker M , Chabchoub F , Marco-Contelles J
Ref : ChemMedChem , 11 :1318 , 2016
Abstract : 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 beta-amyloid (Abeta1-42 ) 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]pyrid o[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) mum], has strong antioxidant activity (3.61 mumol Trolox equivalents), and moderate Abeta1-42 antiaggregating power (40.3 %).
ESTHER : Dgachi_2016_ChemMedChem_11_1318
PubMedSearch : Dgachi_2016_ChemMedChem_11_1318
PubMedID: 26804623

Title : Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer's Disease Therapy - Boulebd_2016_Molecules_21_
Author(s) : Boulebd H , Ismaili L , Bartolini M , Bouraiou A , Andrisano V , Martin H , Bonet A , Moraleda I , Iriepa I , Chioua M , Belfaitah A , Marco-Contelles J
Ref : Molecules , 21 : , 2016
Abstract : 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 muM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 +/- 0.29 mumol.Trolox/mumol compound).
ESTHER : Boulebd_2016_Molecules_21_
PubMedSearch : Boulebd_2016_Molecules_21_
PubMedID: 27023499

Title : Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease - Dgachi_2016_Molecules_21_
Author(s) : Dgachi Y , Bautista-Aguilera OM , Benchekroun M , Martin H , Bonet A , Knez D , Godyn J , Malawska B , Gobec S , Chioua M , Janockova J , Soukup O , Chabchoub F , Marco-Contelles J , Ismaili L
Ref : Molecules , 21 : , 2016
Abstract : 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 muM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.
ESTHER : Dgachi_2016_Molecules_21_
PubMedSearch : Dgachi_2016_Molecules_21_
PubMedID: 27187348

Title : Pyranopyrazolotacrines as nonneurotoxic, Abeta-anti-aggregating and neuroprotective agents for Alzheimer's disease - Chioua_2015_Future.Med.Chem_7_845
Author(s) : Chioua M , Perez-Pena J , Garcia-Font N , Moraleda I , Iriepa I , Soriano E , Marco-Contelles J , Oset-Gasque MJ
Ref : Future Med Chem , 7 :845 , 2015
Abstract : AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines.
RESULTS: This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4',3':5,6]pyrano[2,3-b]quinolin-5-a mines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Abeta1-40 aggregation induced by acetylcholinesterase. CONCLUSION: A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease.
ESTHER : Chioua_2015_Future.Med.Chem_7_845
PubMedSearch : Chioua_2015_Future.Med.Chem_7_845
PubMedID: 26061104

Title : Multipotent cholinesterase\/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids - Bautista-Aguilera_2014_Drug.Des.Devel.Ther_8_1893
Author(s) : Bautista-Aguilera OM , Esteban G , Chioua M , Nikolic K , Agbaba D , Moraleda I , Iriepa I , Soriano E , Samadi A , Unzeta M , Marco-Contelles J
Ref : Drug Des Devel Ther , 8 :1893 , 2014
Abstract : The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BCHE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1+/-0.3 nM; equine butyrylcholinesterase [eqBCHE]: IC50 =600+/-80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BCHE than the reference compound ASS234. DPH14 is a potent human recombinant BCHE (hBCHE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBCHE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700+/-2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950+/-940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.
ESTHER : Bautista-Aguilera_2014_Drug.Des.Devel.Ther_8_1893
PubMedSearch : Bautista-Aguilera_2014_Drug.Des.Devel.Ther_8_1893
PubMedID: 25378907

Title : N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2- yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor - Bautista-Aguilera_2014_J.Med.Chem_57_10455
Author(s) : Bautista-Aguilera OM , Samadi A , Chioua M , Nikolic K , Filipic S , Agbaba D , Soriano E , de Andres L , Rodriguez-Franco MI , Alcaro S , Ramsay RR , Ortuso F , Yanez M , Marco-Contelles J
Ref : Journal of Medicinal Chemistry , 57 :10455 , 2014
Abstract : On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methyl prop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2- yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
ESTHER : Bautista-Aguilera_2014_J.Med.Chem_57_10455
PubMedSearch : Bautista-Aguilera_2014_J.Med.Chem_57_10455
PubMedID: 25418133

Title : Isoxazolotacrines as non-toxic and selective butyrylcholinesterase inhibitors for Alzheimer's disease - Cherif_2014_Future.Med.Chem_6_1883
Author(s) : Cherif O , Allouche F , Chabchoub F , Chioua M , Soriano E , Yanez M , Cacabelos R , Romero A , Lopez MG , Marco-Contelles J
Ref : Future Med Chem , 6 :1883 , 2014
Abstract : BACKGROUND: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease.
RESULTS: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 +/- 1.12 microM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity analysis. CONCLUSION: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease.
ESTHER : Cherif_2014_Future.Med.Chem_6_1883
PubMedSearch : Cherif_2014_Future.Med.Chem_6_1883
PubMedID: 25495982

Title : Synthesis, pharmacological assessment, and molecular modeling of acetylcholinesterase\/butyrylcholinesterase inhibitors: effect against amyloid-beta-induced neurotoxicity - Silva_2013_ACS.Chem.Neurosci_4_547
Author(s) : Silva D , Chioua M , Samadi A , Agostinho P , Garcao P , Lajarin-Cuesta R , de los Rios C , Iriepa I , Moraleda I , Gonzalez-Lafuente L , Mendes E , Perez C , Rodriguez-Franco MI , Marco-Contelles J , Carmo Carreiras M
Ref : ACS Chem Neurosci , 4 :547 , 2013
Abstract : The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2-7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14-18), and quinolinodonepezils (19-21) are described. Pyridonepezils 15-18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19-21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC(50) (hAChE) = 0.25 +/- 0.02 muM]. Pyridonepezils 15-18 and quinolinodonepezils 20-21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC(50) (EeAChE) = 0.0167 +/- 0.0002 muM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Abeta(1-42). All compounds were effective in preventing the enhancement of AChE activity induced by Abeta(1-42). Compounds 2-7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Abeta(1-42). Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca(2+) influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBCHE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BCHE and 18-BCHE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.
ESTHER : Silva_2013_ACS.Chem.Neurosci_4_547
PubMedSearch : Silva_2013_ACS.Chem.Neurosci_4_547
PubMedID: 23379636

Title : Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine - Samadi_2012_Eur.J.Med.Chem_52_251
Author(s) : Samadi A , de los Rios C , Bolea I , Chioua M , Iriepa I , Moraleda I , Bartolini M , Andrisano V , Galvez E , Valderas C , Unzeta M , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 52 :251 , 2012
Abstract : The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 +/- 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 +/- 0.2 muM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 +/- 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Abeta aggregation induced by hAChE by 30.6%.
ESTHER : Samadi_2012_Eur.J.Med.Chem_52_251
PubMedSearch : Samadi_2012_Eur.J.Med.Chem_52_251
PubMedID: 22503231

Title : Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: Synthesis, biological assessment, and molecular modeling - Samadi_2012_Eur.J.Med.Chem_57C_296
Author(s) : Samadi A , Estrada M , Perez C , Rodriguez-Franco MI , Iriepa I , Moraleda I , Chioua M , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 57C :296 , 2012
Abstract : The synthesis biological assessment and molecular modeling of new pyridonepezils1-8 able to inhibit human acetylcholinesterase hAChE and human butyrylcholinesterase hBCHE are described The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety present in donepezil and the 2-amino-6-chloropyridine heterocyclic ring system connected by an appropriate polymethylene linker Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile 13 or 2-amino-6-chloropyridine-3,5-dicarbonitrile 14 with 2-(1-benzylpiperidin-4-yl)alkylamines 9-12 The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors in the submicromolar while compounds 7 and 8 are on the nanomolar range the most potent 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile 7 showing a IC(50 hAChE 9.4 0.4 nM Inhibitors 2-8 are permeable as determined in the PAMPA assay Compared to donepezil compound 7 is in the same range of inhibitory activity for hAChE and 703-fold more selective for hAChE than for hBCHE Molecular modeling investigation on pyridonepezil7 supports its dual AChE inhibitory profile binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme The theoretical ADME analysis of pyridonepezils1-8 has been carried out Overall compound 7 a potent and selective dual AChEI can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.
ESTHER : Samadi_2012_Eur.J.Med.Chem_57C_296
PubMedSearch : Samadi_2012_Eur.J.Med.Chem_57C_296
PubMedID: 23078965

Title : Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives - Silva_2011_Eur.J.Med.Chem_46_4676
Author(s) : Silva D , Chioua M , Samadi A , Carmo Carreiras M , Jimeno ML , Mendes E , Rios Cde L , Romero A , Villarroya M , Lopez MG , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 46 :4676 , 2011
Abstract : The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedlander-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridi n-3-yl)acetamide (5) [IC(50) (EeAChE) = 0.069 +/- 0.006 muM; IC(50) (eqBuChE) = 6.3 +/- 0.6 muM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K(i) = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.
ESTHER : Silva_2011_Eur.J.Med.Chem_46_4676
PubMedSearch : Silva_2011_Eur.J.Med.Chem_46_4676
PubMedID: 21715067

Title : Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues - Martins_2011_Eur.J.Med.Chem_46_6119
Author(s) : Martins C , Carreiras MC , Leon R , de los Rios C , Bartolini M , Andrisano V , Iriepa I , Moraleda I , Galvez E , Garcia M , Egea J , Samadi A , Chioua M , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 46 :6119 , 2011
Abstract : The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedlander-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1-11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC(50) (eqBuChE)=2.9 +/- 0.4 muM; IC(50) (hBuChE)=119 +/- 15 muM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC(50) (EeAChE)=0.61 +/- 0.04 muM; IC(50) (eqBuChE)=0.074 +/- 0.009 muM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Abeta-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease.
ESTHER : Martins_2011_Eur.J.Med.Chem_46_6119
PubMedSearch : Martins_2011_Eur.J.Med.Chem_46_6119
PubMedID: 22000936

Title : Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease - Samadi_2011_Eur.J.Med.Chem_46_4665
Author(s) : Samadi A , Chioua M , Bolea I , de los Rios C , Iriepa I , Moraleda I , Bastida A , Esteban G , Unzeta M , Galvez E , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 46 :4665 , 2011
Abstract : The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedlander type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC(50) = 16 +/- 2; Ki = 12 +/- 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease.
ESTHER : Samadi_2011_Eur.J.Med.Chem_46_4665
PubMedSearch : Samadi_2011_Eur.J.Med.Chem_46_4665
PubMedID: 21669479

Title : Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase\/monoamine oxidase inhibitors for the treatment of Alzheimer's disease - Bolea_2011_J.Med.Chem_54_8251
Author(s) : Bolea I , Juarez-Jimenez J , de los Rios C , Chioua M , Pouplana R , Luque FJ , Unzeta M , Marco-Contelles J , Samadi A
Ref : Journal of Medicinal Chemistry , 54 :8251 , 2011
Abstract : A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2+/-1.1 nM) and MAO-B (IC50=43+/-8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35+/-0.01 muM) and BuChE (IC50=0.46+/-0.06 muM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Abeta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
ESTHER : Bolea_2011_J.Med.Chem_54_8251
PubMedSearch : Bolea_2011_J.Med.Chem_54_8251
PubMedID: 22023459

Title : Molecular modelling, synthesis and acetylcholinesterase inhibition of ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate - Soriano_2010_Bioorg.Med.Chem.Lett_20_2950
Author(s) : Soriano E , Samadi A , Chioua M , de los Rios C , Marco-Contelles J
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :2950 , 2010
Abstract : In silico analysis of ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate (2) predicts that this molecule should be successfully docked in the PAS, and easily accommodated in the CAS of AChE. The synthesis and the AChE/BuChE inhibition studies are reported, confirming that compound 2 is a potent and selective AChE inhibitor, and consequently, a new lead compound for further development into new dual CAS/PAS cholinergic agents for the treatment of Alzheimer's disease.
ESTHER : Soriano_2010_Bioorg.Med.Chem.Lett_20_2950
PubMedSearch : Soriano_2010_Bioorg.Med.Chem.Lett_20_2950
PubMedID: 20350807

Title : Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles - Samadi_2010_Bioorg.Med.Chem_18_5861
Author(s) : Samadi A , Marco-Contelles J , Soriano E , Alvarez-Perez M , Chioua M , Romero A , Gonzalez-Lafuente L , Gandia L , Roda JM , Lopez MG , Villarroya M , Garcia AG , Rios Cde L
Ref : Bioorganic & Medicinal Chemistry , 18 :5861 , 2010
Abstract : The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8-31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.
ESTHER : Samadi_2010_Bioorg.Med.Chem_18_5861
PubMedSearch : Samadi_2010_Bioorg.Med.Chem_18_5861
PubMedID: 20656495