Luque FJ

References (35)

Title : Acetylcholinesterase: A Versatile Template to Coin Potent Modulators of Multiple Therapeutic Targets - Luque_2024_Acc.Chem.Res__
Author(s) : Luque FJ , Munoz-Torrero D
Ref : Acc Chem Res , : , 2024
Abstract : Conspectus; The enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic deficit, prominently Alzheimer's disease (AD). Working at a rate near the diffusion limit, it is considered one of nature's most efficient enzymes. This is particularly meritorious considering that its catalytic site is buried at the bottom of a 20-A-deep cavity, which is preceded by a bottleneck with a diameter shorter than that of the trimethylammonium group of ACh, which has to transit through it. Not only the particular architecture and amino acid composition of its active site gorge enable AChE to largely overcome this potential drawback, but it also offers plenty of possibilities for the design of novel inhibitor drug candidates. In this Account, we summarize our different approaches to colonize the vast territory of the AChE gorge in the pursuit of increased occupancy and hence of inhibitors with increased affinity. We pioneered the use of molecular hybridization to design inhibitors with extended binding at the CAS, reaching affinities among the highest reported so far. Further application of molecular hybridization to grow CAS extended binders by attaching a PAS-binding moiety through suitable linkers led to multisite inhibitors that span the whole length of the gorge, reaching the PAS and even interacting with midgorge residues. We show that multisite AChE inhibitors can also be successfully designed the other way around, by starting with an optimized PAS binder and then colonizing the gorge and CAS. Molecular hybridization from a multicomponent reaction-derived PAS binder afforded a single-digit picomolar multisite AChE inhibitor with more than 1.5 million-fold increased potency relative to the initial hit. This illustrates the powerful alliance between molecular hybridization and gorge occupancy for designing potent AChE inhibitors.Beyond AChE, we show that the stereoelectronic requirements imposed by the AChE gorge for multisite binding have a templating effect that leads to compounds that are active in other key biological targets in AD and other neurological and non-neurological diseases, such as BACE-1 and the aggregation of amyloidogenic proteins (beta-amyloid, tau, alpha-synuclein, prion protein, transthyretin, and human islet amyloid polypeptide). The use of known pharmacophores for other targets as the PAS-binding motif enables the rational design of multitarget agents with multisite binding within AChE and activity against a variety of targets or pathological events, such as oxidative stress and the neuroinflammation-modulating enzyme soluble epoxide hydrolase, among others.We hope that our results can contribute to the development of drug candidates that can modify the course of neurodegeneration and may inspire future works that exploit the power of molecular hybridization in other proteins featuring large cavities.
ESTHER : Luque_2024_Acc.Chem.Res__
PubMedSearch : Luque_2024_Acc.Chem.Res__
PubMedID: 38333993

Title : In-vitro and in-silico studies of annelated 1,4,7,8-tetrahydroazocine ester derivatives as nanomolar selective inhibitors of human butyrylcholinesterase - de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
Author(s) : de Candia M , Titov AA , Viayna A , Kulikova LN , Purgatorio R , Piergiovanni B , Niso M , Catto M , Voskressensky LG , Luque FJ , Altomare CD
Ref : Chemico-Biological Interactions , :110741 , 2023
Abstract : Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment Alzheimer disease and related dementias, herein we investigated diverse newly and previously synthesized beta-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (K(i) = 7.8 +/- 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC(50) of 0.27 microM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes.
ESTHER : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedSearch : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedID: 37839515

Title : Screening and Biological Evaluation of Soluble Epoxide Hydrolase Inhibitors: Assessing the Role of Hydrophobicity in the Pharmacophore-Guided Search of Novel Hits - Vazquez_2023_J.Chem.Inf.Model__
Author(s) : Vazquez J , Ginex T , Herrero A , Morisseau C , Hammock BD , Luque FJ
Ref : J Chem Inf Model , : , 2023
Abstract : The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC(50) < 20 nM, including two with IC(50) values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site.
ESTHER : Vazquez_2023_J.Chem.Inf.Model__
PubMedSearch : Vazquez_2023_J.Chem.Inf.Model__
PubMedID: 37141492

Title : Three to Tango: Inhibitory Effect of Quercetin and Apigenin on Acetylcholinesterase, Amyloid- Aggregation and Acetylcholinesterase-Amyloid Interaction - Alvarez-Berbel_2022_Pharmaceutics_14_
Author(s) : Alvarez-Berbel I , Espargaro A , Viayna A , Caballero AB , Busquets MA , Gamez P , Luque FJ , Sabate R
Ref : Pharmaceutics , 14 : , 2022
Abstract : One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid- plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid- aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on A40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the A40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.
ESTHER : Alvarez-Berbel_2022_Pharmaceutics_14_
PubMedSearch : Alvarez-Berbel_2022_Pharmaceutics_14_
PubMedID: 36365159

Title : Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation, Intracellular Oxidative Stress, and Neuroinflammation - Hofmann_2021_Chemistry_27_6015
Author(s) : Hofmann J , Ginex T , Espargaro A , Scheiner M , Gunesch S , Arago M , Stigloher C , Sabate R , Luque FJ , Decker M
Ref : Chemistry , 27 :6015 , 2021
Abstract : Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-beta 42 (Abeta42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Abeta42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Abeta42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5microm (83 % cell survival), whereas curcumin only showed very low protection at 10microm (21 % cell survival).
ESTHER : Hofmann_2021_Chemistry_27_6015
PubMedSearch : Hofmann_2021_Chemistry_27_6015
PubMedID: 33666306

Title : From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects - Pont_2021_Eur.J.Med.Chem_225_113779
Author(s) : Pont C , Ginex T , Grinan-Ferre C , Scheiner M , Mattellone A , Martinez N , Arce EM , Soriano-Fernandez Y , Naldi M , De Simone A , Barenys M , Gomez-Catalan J , Perez B , Sabate R , Andrisano V , Loza MI , Brea J , Bartolini M , Bolognesi ML , Decker M , Pallas M , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 225 :113779 , 2021
Abstract : Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Abeta42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
ESTHER : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedSearch : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedID: 34418785

Title : Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6 - Perez-Areales_2020_J.Med.Chem_63_9360
Author(s) : Perez-Areales FJ , Garrido M , Aso E , Bartolini M , De Simone A , Espargaro A , Ginex T , Sabate R , Perez B , Andrisano V , Puigoriol-Illamola D , Pallas M , Luque FJ , Loza MI , Brea J , Ferrer I , Ciruela F , Messeguer A , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 63 :9360 , 2020
Abstract : Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, beta-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Abeta42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
ESTHER : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedSearch : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedID: 32706255

Title : Interplay between Ionization and Tautomerism in Bioactive beta-Enamino Ester-Containing Cyclic Compounds: Study of Annulated 1,2,3,6-Tetrahydroazocine Derivatives - Viayna_2020_J.Phys.Chem.B_124_28
Author(s) : Viayna A , Antermite SG , de Candia M , Altomare CD , Luque FJ
Ref : J Phys Chem B , 124 :28 , 2020
Abstract : Depending on the chemical scaffold, a bioactive species could reflect the interplay between ionization and tautomerism, which is often complicated by the possibility of populating different conformational states, in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for beta-enamino esters of 1,2,3,6-tetrahydroazocino-fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental pKa values (i.e., alpha,beta-diesters and beta-esters ranging within 6.1-7.3 and 8.2-9.0 pKa intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual pKa values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between the calculated and experimental pKa values was found when the tautomeric preference of the protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism, and conformational preferences in multifunctional (bio)organic compounds.
ESTHER : Viayna_2020_J.Phys.Chem.B_124_28
PubMedSearch : Viayna_2020_J.Phys.Chem.B_124_28
PubMedID: 31841339

Title : Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein-huprine hybrids - Perez-Areales_2017_Future.Med.Chem_9_965
Author(s) : Perez-Areales FJ , Betari N , Viayna A , Pont C , Espargaro A , Bartolini M , De Simone A , Rinaldi Alvarenga JF , Perez B , Sabate R , Lamuela-Raventos RM , Andrisano V , Luque FJ , Munoz-Torrero D
Ref : Future Med Chem , 9 :965 , 2017
Abstract : AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS &
METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Abeta42 and tau aggregation, of antioxidant activity, and of brain permeation.
RESULTS: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Abeta42 and tau antiaggregating and antioxidant activities. CONCLUSION: Second-generation naphthyridine- and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.
ESTHER : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedSearch : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedID: 28632395

Title : Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies - Sola_2015_J.Med.Chem_58_6018
Author(s) : Sola I , Aso E , Frattini D , Lopez-Gonzalez I , Espargaro A , Sabate R , Di Pietro O , Luque FJ , Clos MV , Ferrer I , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 58 :6018 , 2015
Abstract : We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as beta-amyloid (Abeta)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Abeta42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.
ESTHER : Sola_2015_J.Med.Chem_58_6018
PubMedSearch : Sola_2015_J.Med.Chem_58_6018
PubMedID: 26181606

Title : Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties - Perez-Areales_2014_Bioorg.Med.Chem_22_5298
Author(s) : Perez-Areales FJ , Di Pietro O , Espargaro A , Vallverdu-Queralt A , Galdeano C , Ragusa IM , Viayna E , Guillou C , Clos MV , Perez B , Sabate R , Lamuela-Raventos RM , Luque FJ , Munoz-Torrero D
Ref : Bioorganic & Medicinal Chemistry , 22 :5298 , 2014
Abstract : Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS(+), DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Abeta42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Abeta42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.
ESTHER : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedSearch : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedID: 25156301

Title : Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents - Viayna_2014_J.Med.Chem_57_2549
Author(s) : Viayna E , Sola I , Bartolini M , De Simone A , Tapia-Rojas C , Serrano FG , Sabate R , Juarez-Jimenez J , Perez B , Luque FJ , Andrisano V , Clos MV , Inestrosa NC , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 57 :2549 , 2014
Abstract : We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Abeta42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Abeta-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Abeta lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.
ESTHER : Viayna_2014_J.Med.Chem_57_2549
PubMedSearch : Viayna_2014_J.Med.Chem_57_2549
PubMedID: 24568372

Title : Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies - Di Pietro_2014_Eur.J.Med.Chem_84C_107
Author(s) : Di Pietro O , Perez-Areales FJ , Juarez-Jimenez J , Espargaro A , Clos MV , Perez B , Lavilla R , Sabate R , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 84C :107 , 2014
Abstract : Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O --> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Abeta42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.
ESTHER : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedSearch : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedID: 25016233

Title : 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies - Di Pietro_2013_Eur.J.Med.Chem_73C_141
Author(s) : Di Pietro O , Viayna E , Vicente-Garcia E , Bartolini M , Ramon R , Juarez-Jimenez J , Clos MV , Perez B , Andrisano V , Luque FJ , Lavilla R , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 73C :141 , 2013
Abstract : A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O --> NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.
ESTHER : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedSearch : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedID: 24389509

Title : Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases - Galdeano_2012_J.Med.Chem_55_661
Author(s) : Galdeano C , Viayna E , Sola I , Formosa X , Camps P , Badia A , Clos MV , Relat J , Ratia M , Bartolini M , Mancini F , Andrisano V , Salmona M , Minguillon C , Gonzalez-Munoz GC , Rodriguez-Franco MI , Bidon-Chanal A , Luque FJ , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 55 :661 , 2012
Abstract : A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.
ESTHER : Galdeano_2012_J.Med.Chem_55_661
PubMedSearch : Galdeano_2012_J.Med.Chem_55_661
PubMedID: 22185619

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 : Novel huprine derivatives with inhibitory activity toward beta-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates - Viayna_2010_ChemMedChem_5_1855
Author(s) : Viayna E , Gomez T , Galdeano C , Ramirez L , Ratia M , Badia A , Clos MV , Verdaguer E , Junyent F , Camins A , Pallas M , Bartolini M , Mancini F , Andrisano V , Arce MP , Rodriguez-Franco MI , Bidon-Chanal A , Luque FJ , Camps P , Munoz-Torrero D
Ref : ChemMedChem , 5 :1855 , 2010
Abstract : A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced beta-amyloid (Abeta) aggregation and beta-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Abeta aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.
ESTHER : Viayna_2010_ChemMedChem_5_1855
PubMedSearch : Viayna_2010_ChemMedChem_5_1855
PubMedID: 20859987

Title : Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study - Rayo_2010_J.Mol.Model_16_1753
Author(s) : Rayo J , Munoz L , Rosell G , Hammock BD , Guerrero A , Luque FJ , Pouplana R
Ref : J Mol Model , 16 :1753 , 2010
Abstract : Carboxylesterases (CEs) are a family of ubiquitous enzymes with broad substrate specificity, and their inhibition may have important implications in pharmaceutical and agrochemical fields. One of the most potent inhibitors both for mammalian and insect CEs are trifluoromethyl ketones (TFMKs), but the mechanism of action of these chemicals is not completely understood. This study examines the balance between reactivity versus steric effects in modulating the activity against human carboxylesterase 1. The intrinsic reactivity of the ketone moiety is determined from quantum mechanical computations, which combine gas phase B3LYP calculations with hydration free energies estimated with the IEF/MST model. In addition, docking and molecular dynamics simulations are used to explore the binding mode of the inhibitors along the deep gorge that delineates the binding site. The results point out that the activity largely depends on the nature of the fluorinated ketone, since the activity is modulated by the balance between the intrinsic electrophilicity of the carbonyl carbon atom and the ratio between keto and hydrate forms. However, the results also suggest that the correct alignment of the alkyl chain in the binding site can exert a large influence on the inhibitory activity, as this effect seems to override the intrinsic reactivity features of the fluorinated ketone. Overall, the results sustain a subtle balance between reactivity and steric effects in modulating the inhibitory activity of TFMK inhibitors.
ESTHER : Rayo_2010_J.Mol.Model_16_1753
PubMedSearch : Rayo_2010_J.Mol.Model_16_1753
PubMedID: 20676708

Title : Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-Alzheimer agents - Galdeano_2010_Curr.Pharm.Des_16_2818
Author(s) : Galdeano C , Viayna E , Arroyo P , Bidon-Chanal A , Blas JR , Munoz-Torrero D , Luque FJ
Ref : Curr Pharm Des , 16 :2818 , 2010
Abstract : Dual binding site acetylcholinesterase inhibitors have recently emerged as a new class of anti-Alzheimer agents with potential to positively modify the course of the disease. These compounds exhibit a multifunctional pharmacological profile arising from interaction with several biological targets involved upstream and downstream in the neurodegenerative cascade of Alzheimer's disease (AD). The primary target of these compounds is the enzyme acetylcholinesterase (AChE). Interaction of dual binding site AChE inhibitors with AChE results in a potent inhibitory activity of AChE and AChE-induced beta-amyloid peptide (Abeta) aggregation. Some dual binding site AChE inhibitors take on added value a significant ability to additionally inhibit the enzymes butyrylcholinesterase and BACE-1, involved in the co-regulation of the hydrolysis of the neurotransmitter acetylcholine and in Abeta formation, respectively. The structural determinants which mediate the interaction of dual binding site AChE inhibitors with these three important enzymes for AD treatment are herein reviewed.
ESTHER : Galdeano_2010_Curr.Pharm.Des_16_2818
PubMedSearch : Galdeano_2010_Curr.Pharm.Des_16_2818
PubMedID: 20698824

Title : Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates - Camps_2010_Chem.Biol.Interact_187_411
Author(s) : Camps P , Formosa X , Galdeano C , Gomez T , Munoz-Torrero D , Ramirez L , Viayna E , Gomez E , Isambert N , Lavilla R , Badia A , Clos MV , Bartolini M , Mancini F , Andrisano V , Bidon-Chanal A , Huertas O , Dafni T , Luque FJ
Ref : Chemico-Biological Interactions , 187 :411 , 2010
Abstract : Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.
ESTHER : Camps_2010_Chem.Biol.Interact_187_411
PubMedSearch : Camps_2010_Chem.Biol.Interact_187_411
PubMedID: 20167211

Title : Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds - Camps_2009_J.Med.Chem_52_5365
Author(s) : Camps P , Formosa X , Galdeano C , Munoz-Torrero D , Ramirez L , Gomez E , Isambert N , Lavilla R , Badia A , Clos MV , Bartolini M , Mancini F , Andrisano V , Arce MP , Rodriguez-Franco MI , Huertas O , Dafni T , Luque FJ
Ref : Journal of Medicinal Chemistry , 52 :5365 , 2009
Abstract : Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.
ESTHER : Camps_2009_J.Med.Chem_52_5365
PubMedSearch : Camps_2009_J.Med.Chem_52_5365
PubMedID: 19663388

Title : Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation - Camps_2008_J.Med.Chem_51_3588
Author(s) : Camps P , Formosa X , Galdeano C , Gomez T , Munoz-Torrero D , Scarpellini M , Viayna E , Badia A , Clos MV , Camins A , Pallas M , Bartolini M , Mancini F , Andrisano V , Estelrich J , Lizondo M , Bidon-Chanal A , Luque FJ
Ref : Journal of Medicinal Chemistry , 51 :3588 , 2008
Abstract : A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
ESTHER : Camps_2008_J.Med.Chem_51_3588
PubMedSearch : Camps_2008_J.Med.Chem_51_3588
PubMedID: 18517184

Title : New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties - Leon_2008_Bioorg.Med.Chem_16_7759
Author(s) : Leon R , de los Rios C , Marco-Contelles J , Huertas O , Barril X , Luque FJ , Lopez MG , Garcia AG , Villarroya M
Ref : Bioorganic & Medicinal Chemistry , 16 :7759 , 2008
Abstract : In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthy ridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K(+) depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease.
ESTHER : Leon_2008_Bioorg.Med.Chem_16_7759
PubMedSearch : Leon_2008_Bioorg.Med.Chem_16_7759
PubMedID: 18640842

Title : Binding of 13-amidohuprines to acetylcholinesterase: exploring the ligand-induced conformational change of the gly117-gly118 peptide bond in the oxyanion hole - Camps_2006_J.Med.Chem_49_6833
Author(s) : Camps P , Gomez E , Munoz-Torrero D , Badia A , Clos MV , Curutchet C , Munoz-Muriedas J , Luque FJ
Ref : Journal of Medicinal Chemistry , 49 :6833 , 2006
Abstract : The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition.
ESTHER : Camps_2006_J.Med.Chem_49_6833
PubMedSearch : Camps_2006_J.Med.Chem_49_6833
PubMedID: 17154513

Title : Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE - Alonso_2005_Bioorg.Med.Chem_13_6588
Author(s) : Alonso D , Dorronsoro I , Rubio L , Munoz P , Garcia-Palomero E , del Monte M , Bidon-Chanal A , Orozco M , Luque FJ , Castro A , Medina M , Martinez A
Ref : Bioorganic & Medicinal Chemistry , 13 :6588 , 2005
Abstract : A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.
ESTHER : Alonso_2005_Bioorg.Med.Chem_13_6588
PubMedSearch : Alonso_2005_Bioorg.Med.Chem_13_6588
PubMedID: 16230018

Title : Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease - Munoz-Ruiz_2005_J.Med.Chem_48_7223
Author(s) : Munoz-Ruiz P , Rubio L , Garcia-Palomero E , Dorronsoro I , del Monte-Millan M , Valenzuela R , Usan P , de Austria C , Bartolini M , Andrisano V , Bidon-Chanal A , Orozco M , Luque FJ , Medina M , Martinez A
Ref : Journal of Medicinal Chemistry , 48 :7223 , 2005
Abstract : New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).
ESTHER : Munoz-Ruiz_2005_J.Med.Chem_48_7223
PubMedSearch : Munoz-Ruiz_2005_J.Med.Chem_48_7223
PubMedID: 16279781

Title : Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase\/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptors - Marco_2004_Bioorg.Med.Chem_12_2199
Author(s) : Marco JL , de los Rios C , Garcia AG , Villarroya M , Carreiras MC , Martins C , Eleuterio A , Morreale A , Orozco M , Luque FJ
Ref : Bioorganic & Medicinal Chemistry , 12 :2199 , 2004
Abstract : The synthesis and the biological activity of compounds 5-40 as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as modulators of voltage-dependent Ca(2+) channels and nicotinic receptors, are described. These molecules are tacrine analogues, which have been prepared from polyfunctionalized 6-amino-5-cyano-4H-pyrans, 6-amino-5-cyano-pyridines and 5-amino-2-aryl-3-cyano-1,3-oxazoles via Friedlander reaction with selected cycloalkanones. These compounds are moderate acetylcholinesterase and butyrylcholinesterase inhibitors, the BuChE/AChE selectivity of the most active molecules ranges from 10.0 (compound 29) to 76.9 (compound 16). Interestingly, the 'oxazolo-tacrine' derivatives are devoid of any activity. All compounds showed an important inhibitory effect on the nicotinic acetylcholine receptor. Most of them also blocked L-type Ca(2+) channels, and three of them, 64, 19 and 67, the non-L type of Ca(2+) channels. Molecular modelling studies suggest that these compounds might bind at the peripheral binding site of AChE, which opens the possibility to design inhibitors able to bind at both, the catalytic and peripheral binding sites of the enzyme.
ESTHER : Marco_2004_Bioorg.Med.Chem_12_2199
PubMedSearch : Marco_2004_Bioorg.Med.Chem_12_2199
PubMedID: 15080920

Title : Modulation of binding strength in several classes of active site inhibitors of acetylcholinesterase studied by comparative binding energy analysis - Martin-Santamaria_2004_J.Med.Chem_47_4471
Author(s) : Martin-Santamaria S , Munoz-Muriedas J , Luque FJ , Gago F
Ref : Journal of Medicinal Chemistry , 47 :4471 , 2004
Abstract : The comparative binding energy (COMBINE) methodology has been used to identify the key residues that modulate the inhibitory potencies of three structurally different classes of acetylcholinesterase inhibitors (tacrines, huprines, and dihydroquinazolines) targeting the catalytic active site of this enzyme. The extended set of energy descriptors and the partial least-squares methodology used by COMBINE analysis on a unique training set containing all the compounds yielded an interpretable model that was able to fit and predict the activities of the whole series of inhibitors reasonably well (r2 = 0.91 and q2 = 0.76, 4 principal components). A more robust model (q2 = 0.81 and SDEP = 0.25, 3 principal components) was obtained when the same chemometric analysis was applied to the huprines set alone, but the method was unable to provide predictive models for the other two families when they were treated separately from the rest. This finding appears to indicate that the enrichment in chemical information brought about by the inclusion of different classes of compounds into a single training set can be beneficial when an internally consistent set of pharmacological data can be derived. The COMBINE model was externally validated when it was shown to predict the activity of an additional set of compounds that were not employed in model construction. Remarkably, the differences in inhibitory potency within the whole series were found to be finely tuned by the electrostatic contribution to the desolvation of the binding site and a network of secondary interactions established between the inhibitor and several protein residues that are distinct from those directly involved in the anchoring of the ligand. This information can now be used to advantage in the design of more potent inhibitors.
ESTHER : Martin-Santamaria_2004_J.Med.Chem_47_4471
PubMedSearch : Martin-Santamaria_2004_J.Med.Chem_47_4471
PubMedID: 15317459

Title : Molecular modelling approaches to the design of acetylcholinesterase inhibitors: new challenges for the treatment of Alzheimer's disease - Munoz-Muriedas_2004_Curr.Pharm.Des_10_3131
Author(s) : Munoz-Muriedas J , Lopez JM , Orozco M , Luque FJ
Ref : Curr Pharm Des , 10 :3131 , 2004
Abstract : The interest for acetylcholinesterase as a target for the palliative treatment of Alzheimer's disease has been renewed in the last years owing to the evidences that support the role of this enzyme in accelerating the aggregation and deposition of the beta-amyloid peptide. A large amount of structural information on the acetylcholinesterase enzyme and of its complexes with inhibitors acting at the catalytic site, the peripheral binding site, or both is now available. Based on that, molecular modelling studies can be intensively used to decipher the molecular determinants that mediate the relationship between chemical structure and inhibitory potency. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. At this point, inhibitors able to interact at the peripheral binding site are of particular relevance, as they might disrupt the interactions between the enzyme acetylcholinesterase and the beta-amyloid peptide. Therefore, these compounds might not only ameliorate the cholinergic deficit, but also be capable of slowing down the progression of the disease.
ESTHER : Munoz-Muriedas_2004_Curr.Pharm.Des_10_3131
PubMedSearch : Munoz-Muriedas_2004_Curr.Pharm.Des_10_3131
PubMedID: 15544503

Title : 3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 A resolution: kinetic and molecular dynamic correlates - Dvir_2002_Biochemistry_41_2970
Author(s) : Dvir H , Wong DM , Harel M , Barril X , Orozco M , Luque FJ , Munoz-Torrero D , Camps P , Rosenberry TL , Silman I , Sussman JL
Ref : Biochemistry , 41 :2970 , 2002
Abstract : Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.
ESTHER : Dvir_2002_Biochemistry_41_2970
PubMedSearch : Dvir_2002_Biochemistry_41_2970
PubMedID: 11863435
Gene_locus related to this paper: torca-ACHE

Title : Rational design of reversible acetylcholinesterase inhibitors - Barril_2002_Mini.Rev.Med.Chem_2_27
Author(s) : Barril X , Kalko SG , Orozco M , Luque FJ
Ref : Mini Rev Med Chem , 2 :27 , 2002
Abstract : A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.
ESTHER : Barril_2002_Mini.Rev.Med.Chem_2_27
PubMedSearch : Barril_2002_Mini.Rev.Med.Chem_2_27
PubMedID: 12369955

Title : Synthesis, in Vitro Pharmacology, and Molecular Modeling of syn-Huprines as Acetylcholinesterase Inhibitors - Camps_2001_J.Med.Chem_44_4733
Author(s) : Camps P , Gomez E , Munoz-Torrero D , Badia A , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 44 :4733 , 2001
Abstract : Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.
ESTHER : Camps_2001_J.Med.Chem_44_4733
PubMedSearch : Camps_2001_J.Med.Chem_44_4733
PubMedID: 11741490

Title : New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease - Camps_2000_J.Med.Chem_43_4657
Author(s) : Camps P , El Achab R , Morral J , Munoz-Torrero D , Badia A , Banos JE , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 43 :4657 , 2000
Abstract : Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.
ESTHER : Camps_2000_J.Med.Chem_43_4657
PubMedSearch : Camps_2000_J.Med.Chem_43_4657
PubMedID: 11101357

Title : Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease - Camps_1999_J.Med.Chem_42_3227
Author(s) : Camps P , El Achab R , Gorbig DM , Morral J , Munoz-Torrero D , Badia A , Eladi Banos J , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 42 :3227 , 1999
Abstract : Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.
ESTHER : Camps_1999_J.Med.Chem_42_3227
PubMedSearch : Camps_1999_J.Med.Chem_42_3227
PubMedID: 10464010

Title : Predicting relative binding free energies of tacrine-huperzine A hybrids as inhibitors of acetylcholinesterase - Barril_1999_J.Med.Chem_42_5110
Author(s) : Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 42 :5110 , 1999
Abstract : The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo californica acetylcholinesterase (AChE) has been studied by computational methods. Molecular dynamics simulations have been performed for the AChE-drug complex considering two different ionization states of the protein and two different orientations of the drug in the binding pocket, which were chosen from a previous screening procedure. Analysis of structural fluctuations and of the pattern of interactions between drug and enzyme clearly favor one binding mode for the tacrine-huperzine A hydrid, which mixes effectively some of the binding features of tacrine and huperzine A. The differences in inhibitory activity for a series of related derivatives have been successfully predicted by free energy calculations, which reinforces the confidence in the binding mode and its usefulness for molecular modeling studies. The same techniques have been used to make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used to verify a posteriori the goodness of the binding mode. Finally, we have also investigated the effect of replacing Phe300 in the Torpedo californica enzyme by Tyr, which is present in the human AChE. The results indicate that the Phe330-->Tyr mutation is expected to have little effect on the binding affinities. Overall, the whole of results supports the validity of the putative binding model to explain the binding of tacrine-huperzine A hybrids to AChE.
ESTHER : Barril_1999_J.Med.Chem_42_5110
PubMedSearch : Barril_1999_J.Med.Chem_42_5110
PubMedID: 10602696