Altomare CD

References (36)

Title : Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo - Mugnaini_2024_ACS.Chem.Neurosci__
Author(s) : Mugnaini C , Brizzi A , Paolino M , Scarselli E , Castelli R , de Candia M , Gambacorta N , Nicolotti O , Kostrzewa M , Kumar P , Mahmoud AM , Borgonetti V , Iannotta M , Morace A , Galeotti N , Maione S , Altomare CD , Ligresti A , Corelli F
Ref : ACS Chem Neurosci , : , 2024
Abstract : Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC(50) values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with K(i) of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.
ESTHER : Mugnaini_2024_ACS.Chem.Neurosci__
PubMedSearch : Mugnaini_2024_ACS.Chem.Neurosci__
PubMedID: 38372253

Title : Novel 6-alkyl-bridged 4-arylalkylpiperazin-1-yl derivatives of azepino[4,3-b]indol-1(2H)-one as potent BChE-selective inhibitors showing protective effects against neurodegenerative insults - Samarelli_2024_Eur.J.Med.Chem_270_116353
Author(s) : Samarelli F , Purgatorio R , Lopopolo G , Deruvo C , Catto M , Andresini M , Carrieri A , Nicolotti O , De Palma A , Miniero DV , de Candia M , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 270 :116353 , 2024
Abstract : Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC(50) = 163 nM) and 14d (IC(50) = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-beta (Abeta) peptide at 100 microM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 microM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.
ESTHER : Samarelli_2024_Eur.J.Med.Chem_270_116353
PubMedSearch : Samarelli_2024_Eur.J.Med.Chem_270_116353
PubMedID: 38579622

Title : Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT(6)R ligands with noticeable action on AChE\/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease - Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
Author(s) : Czarnota-Lydka K , Sudol-Talaj S , Kucwaj-Brysz K , Kurczab R , Satala G , de Candia M , Samarelli F , Altomare CD , Carocci A , Barbarossa A , eslawska E , Gluch-Lutwin M , Mordyl B , Kubacka M , Wilczynska-Zawal N , Jastrzebska-Wiesek M , Partyka A , Khan N , Wiecek M , Nitek W , Honkisz-Orzechowska E , Latacz G , Wesolowska A , Carrieri A , Handzlik J
Ref : Eur Journal of Medicinal Chemistry , 259 :115695 , 2023
Abstract : Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT(6) receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT(6) receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K(i) < 200 nM) and selectivity towards 5-HT(6)R, with respect to 5-HT(2A)R, 5-HT(7)R, and D(2)R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT(6) agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT(6) (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
ESTHER : Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
PubMedSearch : Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
PubMedID: 37567058

Title : Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity - Kulikova_2023_Int.J.Mol.Sci_24_
Author(s) : Kulikova LN , Purgatorio R , Beloglazkin AA , Tafeenko VA , Reza RG , Levickaya DD , Sblano S , Boccarelli A , de Candia M , Catto M , Voskressensky LG , Altomare CD
Ref : Int J Mol Sci , 24 : , 2023
Abstract : About twenty molecules sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC(50) about 1 microM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC(50) 0.51 microM) and moderate inhibitor of both ChEs (IC(50)s 7-8 microM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC(50) of 3.51 microM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC(50)s in the range 4.83-11.3 microM.
ESTHER : Kulikova_2023_Int.J.Mol.Sci_24_
PubMedSearch : Kulikova_2023_Int.J.Mol.Sci_24_
PubMedID: 37175433

Title : Investigation on Novel E\/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity - Paolino_2023_Molecules_28_
Author(s) : Paolino M , de Candia M , Purgatorio R , Catto M , Saletti M , Tondo AR , Nicolotti O , Cappelli A , Brizzi A , Mugnaini C , Corelli F , Altomare CD
Ref : Molecules , 28 : , 2023
Abstract : The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC(50)s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.
ESTHER : Paolino_2023_Molecules_28_
PubMedSearch : Paolino_2023_Molecules_28_
PubMedID: 37570828

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 : A twenty-year journey exploring coumarin-based derivatives as bioactive molecules - Pisani_2022_Front.Chem_10_1002547
Author(s) : Pisani L , Catto M , Muncipinto G , Nicolotti O , Carrieri A , Rullo M , Stefanachi A , Leonetti F , Altomare CD
Ref : Front Chem , 10 :1002547 , 2022
Abstract : The coumarin core (i.e., 1-benzopyran-2 (2H)-one) is a structural motif highly recurrent in both natural products and bioactive molecules. Indeed, depending on the substituents and branching positions around the byciclic core, coumarin-containing compounds have shown diverse pharmacological activities, ranging from anticoagulant activities to anti-inflammatory, antimicrobial, anti-HIV and antitumor effects. In this survey, we have reported the main scientific results of the 20-years investigation on the coumarin core, exploited by the research group headed by Prof. Angelo Carotti (Bari, Italy) either as a scaffold or a pharmacophore moiety in designing novel biologically active small molecules.
ESTHER : Pisani_2022_Front.Chem_10_1002547
PubMedSearch : Pisani_2022_Front.Chem_10_1002547
PubMedID: 36300022

Title : Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity - Titov_2022_Molecules_27_
Author(s) : Titov AA , Purgatorio R , Obydennik AY , Listratova AV , Borisova TN , de Candia M , Catto M , Altomare CD , Varlamov AV , Voskressensky LG
Ref : Molecules , 27 : , 2022
Abstract : Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R(3) = CH(2)OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (K(i) = 4.9 microM), equipotent with the corresponding 6-phenyl derivative 3n (R(3) = Ph, K(i) = 4.5 microM), but 90-fold more water-soluble.
ESTHER : Titov_2022_Molecules_27_
PubMedSearch : Titov_2022_Molecules_27_
PubMedID: 36234811

Title : Design, synthesis and biological evaluation of light-driven on-off multitarget AChE and MAO-B inhibitors - Paolino_2022_RSC.Med.Chem_13_873
Author(s) : Paolino M , Rullo M , Maramai S , de Candia M , Pisani L , Catto M , Mugnaini C , Brizzi A , Cappelli A , Olivucci M , Corelli F , Altomare CD
Ref : RSC Med Chem , 13 :873 , 2022
Abstract : Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. In addition, an interesting tool to refine personalized therapies may arise from the use of bioactive species able to modify their activity as a result of light irradiation. To this aim, we designed and synthesized a small library of cinnamic acid-inspired isomeric compounds with light modulated activity able to inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), with remarkable selectivity over butyrylcholinesterase (BChE) and MAO-A, which have been investigated as the enzyme targets related to Alzheimer's disease (AD). The inhibitory activities were evaluated for the pure E-diastereomers and the E/Z-diastereomer mixtures, obtained upon UV irradiation. Molecular docking studies were carried out to rationalize the differences in the inhibition potency of the E and Z diastereomers of the best performing analogue 1c. Our preliminary findings may open-up the way for developing innovative multitarget photo-switch drugs against neurodegenerative diseases.
ESTHER : Paolino_2022_RSC.Med.Chem_13_873
PubMedSearch : Paolino_2022_RSC.Med.Chem_13_873
PubMedID: 35923722

Title : Novel Phenothiazine\/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer's Disease - Carocci_2022_Antioxidants.(Basel)_11_
Author(s) : Carocci A , Barbarossa A , Leuci R , Carrieri A , Brunetti L , Laghezza A , Catto M , Limongelli F , Chaves S , Tortorella P , Altomare CD , Santos MA , Loiodice F , Piemontese L
Ref : Antioxidants (Basel) , 11 : , 2022
Abstract : Alzheimer's disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Abeta(1-40) aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.
ESTHER : Carocci_2022_Antioxidants.(Basel)_11_
PubMedSearch : Carocci_2022_Antioxidants.(Basel)_11_
PubMedID: 36139705

Title : Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease - Brunetti_2022_Eur.J.Med.Chem_237_114358
Author(s) : Brunetti L , Leuci R , Carrieri A , Catto M , Occhineri S , Vinci G , Gambacorta L , Baltrukevich H , Chaves S , Laghezza A , Altomare CD , Tortorella P , Santos MA , Loiodice F , Piemontese L
Ref : Eur Journal of Medicinal Chemistry , 237 :114358 , 2022
Abstract : Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC(50) = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 microM) in a MTT assay.
ESTHER : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedSearch : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedID: 35462163

Title : Assessing the Role of a Malonamide Linker in the Design of Potent Dual Inhibitors of Factor Xa and Cholinesterases - Purgatorio_2022_Molecules_27_
Author(s) : Purgatorio R , Gambacorta N , Samarelli F , Lopopolo G , de Candia M , Catto M , Nicolotti O , Altomare CD
Ref : Molecules , 27 : , 2022
Abstract : The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure-activity relationship (SAR) studies aimed at investigating para- or meta-benzamidine as the P1 basic group as well as diversely decorated aryl moieties as P4 fragments. To this end, twenty-three malonamide derivatives were synthesized and tested as inhibitors of fXa and thrombin (thr); the molecular determinants behind potency and selectivity were also studied by employing molecular docking. The malonamide linker, compared to the glycinamide one, does significantly increase anti-fXa potency and selectivity. The meta-benzamidine (P1) derivatives bearing 2',4'-difluoro-biphenyl as the P4 moiety proved to be highly potent reversible fXa-selective inhibitors, achieving inhibition constants (K(i)) in the low nanomolar range. The most active compounds were also tested against cholinesterase (ChE) isoforms (acetyl- or butyrylcholinesterase, AChE, and BChE), and some of them returned single-digit micromolar inhibition potency against AChE and/or BChE, both being drug targets for symptomatic treatment of mild-to-moderate Alzheimer's disease. Compounds 19h and 22b were selected as selective fXa inhibitors with potential as multimodal neuroprotective agents.
ESTHER : Purgatorio_2022_Molecules_27_
PubMedSearch : Purgatorio_2022_Molecules_27_
PubMedID: 35807514

Title : Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer's Disease - Schino_2022_Pharmaceuticals.(Basel)_16_
Author(s) : Schino I , Cantore M , de Candia M , Altomare CD , Maria C , Barros J , Cachatra V , Calado P , Shimizu K , Freitas AA , Oliveira MC , Ferreira MJ , Lopes JNC , Colabufo NA , Rauter AP
Ref : Pharmaceuticals (Basel) , 16 : , 2022
Abstract : Alzheimer's Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Abeta plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N(7)/N(9) linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N(9)-linked 6-deoxy-alpha-d-mannosylpurine structure, while all three tested beta-d-derivatives appeared as non-selective inhibitors. The N(9)-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-alpha-l-mannosyl N(9-)linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.
ESTHER : Schino_2022_Pharmaceuticals.(Basel)_16_
PubMedSearch : Schino_2022_Pharmaceuticals.(Basel)_16_
PubMedID: 36678552

Title : Synthesis and biological evaluation of dantrolene-like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases - Bolognino_2021_ChemMedChem__
Author(s) : Bolognino I , Giangregorio N , Tonazzi A , Martinez AL , Altomare CD , Loza MI , Sablone S , Cellamare S , Catto M
Ref : ChemMedChem , : , 2021
Abstract : Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one novel dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A and AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 microM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.
ESTHER : Bolognino_2021_ChemMedChem__
PubMedSearch : Bolognino_2021_ChemMedChem__
PubMedID: 34047061

Title : Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential - Nevskaya_2021_Molecules_26_
Author(s) : Nevskaya AA , Anikina LV , Purgatorio R , Catto M , Nicolotti O , de Candia M , Pisani L , Borisova TN , Miftyakhova AR , Varlamov AV , Nevskaya EY , Borisov RS , Voskressensky LG , Altomare CD
Ref : Molecules , 26 : , 2021
Abstract : Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 microM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with K(i) in the low micromolar range (4.69 microM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC(50)) = 12 microM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced beta-amyloid (Abeta)(1-40) aggregation (IC(50) = 13 microM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.
ESTHER : Nevskaya_2021_Molecules_26_
PubMedSearch : Nevskaya_2021_Molecules_26_
PubMedID: 33445600

Title : Evaluation of water-soluble Mannich base prodrugs of 2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one as multitarget-directed agents for Alzheimer's disease - Purgatorio_2021_ChemMedChem_16_589
Author(s) : Purgatorio R , de Candia M , Catto M , Rullo M , Pisani L , Denora N , Carrieri A , Nevskaya AA , Voskressensky LG , Altomare CD
Ref : ChemMedChem , 16 :589 , 2021
Abstract : Aiming at addressing the poor aqueous solubility in in vivo assays of the recently disclosed 6-phenetyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), human butyrylcholinesterase inhibitor (hBChE, IC50 13 nM) and protective agent in NMDA-induced neurotoxicity, different Mannich base derivatives were studied. The N-(4-methylpiperazin-1-yl)methyl derivative 2c showed a 50-fold increase of solubility in pH 7.4 buffered solution, high stability in serum and pH 7.4 (half-life> 24 h) and rapid (< 3 min) conversion to 1 at acidic pH. Albeit less active than 1, 2c retained moderate hBChE inhibition (IC50 3.35 mM) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 mM. Moreover, 2c resulted a weaker serum albumin binder than 1, a blood-brain barrier permeant, and exerted negligible cytotoxicity on HepG2 cells.These findings suggest that 2c could be a water-soluble prodrug candidate of 1for oral administration or a slow-release injectable derivativein in vivoAD models.
ESTHER : Purgatorio_2021_ChemMedChem_16_589
PubMedSearch : Purgatorio_2021_ChemMedChem_16_589
PubMedID: 33156950

Title : Synthesis of 8-phenyl substituted 3-benzazecines with allene moiety, their thermal rearrangement and evaluation as acetylcholinesterase inhibitors - Kobzev_2021_Mol.Divers__
Author(s) : Kobzev MS , Titov AA , Alexandrova EV , Purgatorio R , Catto M , Sorokina EA , Borisova TN , Varlamov AV , Altomare CD , Voskressensky LG
Ref : Mol Divers , : , 2021
Abstract : Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (K(i)) in the low micromolar range.
ESTHER : Kobzev_2021_Mol.Divers__
PubMedSearch : Kobzev_2021_Mol.Divers__
PubMedID: 33538985

Title : First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease - Purgatorio_2021_Molecules_26_
Author(s) : Purgatorio R , Gambacorta N , de Candia M , Catto M , Rullo M , Pisani L , Nicolotti O , Altomare CD
Ref : Molecules , 26 : , 2021
Abstract : Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a K(i) value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental K(i) values, which were found equal to 0.058 and 6.95 microM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
ESTHER : Purgatorio_2021_Molecules_26_
PubMedSearch : Purgatorio_2021_Molecules_26_
PubMedID: 34500640

Title : Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents - Titov_2021_ACS.Chem.Neurosci__
Author(s) : Titov AA , Kobzev MS , Catto M , de Candia M , Gambacorta N , Denora N , Pisani L , Nicolotti O , Borisova TN , Varlamov AV , Voskressensky LG , Altomare CD
Ref : ACS Chem Neurosci , : , 2021
Abstract : Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.
ESTHER : Titov_2021_ACS.Chem.Neurosci__
PubMedSearch : Titov_2021_ACS.Chem.Neurosci__
PubMedID: 33395258

Title : Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multi-target Ligands Directed towards Relevant Alzheimer's Targets - Purgatorio_2020_ChemMedChem_15_1947
Author(s) : Purgatorio R , Kulikova L , Pisani L , Catto M , de Candia M , Carrieri A , Cellamare S , De Palma A , Beloglazkin A , Raesi GR , Voskressensky L , Altomare CD
Ref : ChemMedChem , 15 :1947 , 2020
Abstract : A number of 1,2,3,4-tetrahydrochromeno[3,2-c]pyridin-10-one derivatives were synthesized and screened against different targets involved in Alzheimer's Disease (AD) onset and progression, such as acetyl- and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of beta-amyloid (Abeta) and reactive oxygen species (ROS) production. Thus, compounds showing multifaceted profiles of promising anti-AD features were identified as derivatives 1c, 3b, 4 and 5a, returning well-balanced multi-targeting inhibitory activities. Moreover, compound 1f, a potent and selective human MAO B inhibitor (IC50 = 0.89 muM), proved to be a safe neuroprotectant in human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Abeta1-42 and pro-oxidant insult. Furthermore, structure-activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.
ESTHER : Purgatorio_2020_ChemMedChem_15_1947
PubMedSearch : Purgatorio_2020_ChemMedChem_15_1947
PubMedID: 32716595

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 : First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease - Guieu_2020_Molecules_26_
Author(s) : Guieu B , Lecoutey C , Legay R , Davis A , Sopkova de Oliveira Santos J , Altomare CD , Catto M , Rochais C , Dallemagne P
Ref : Molecules , 26 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC(50) = 0.4 microM) and (h)MAO-B (IC(50) = 6.4 microM).
ESTHER : Guieu_2020_Molecules_26_
PubMedSearch : Guieu_2020_Molecules_26_
PubMedID: 33375412

Title : Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor - Catto_2020_ACS.Med.Chem.Lett_11_869
Author(s) : Catto M , Pisani L , De la Mora E , Belviso BD , Mangiatordi GF , Pinto A , Palma A , Denora N , Caliandro R , Colletier JP , Silman I , Nicolotti O , Altomare CD
Ref : ACS Med Chem Lett , 11 :869 , 2020
Abstract : Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (+/-)-cis-1, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of 1 by HPLC and (ii) preparing two close achiral analogues of 1, i.e., compounds 4 and 6. An eudismic ratio as high as 20 was observed for the (-) enantiomer of cis-1. The X-ray crystal structure of the complex between the (-)-cis-1 eutomer (coded as MC1420) and T. californica AChE was determined at 2.8 A, and docking calculation results suggested that the eutomer in (1R,3S) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1S,3R) configuration. The achiral analogues 4 and 6 were less effective in inhibiting AChE compared to (+/-)-cis-1, but interestingly butylamide 4 emerged as a potent inhibitor of butyrylcholinesterase (BChE).
ESTHER : Catto_2020_ACS.Med.Chem.Lett_11_869
PubMedSearch : Catto_2020_ACS.Med.Chem.Lett_11_869
PubMedID: 32435398

Title : A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer's Disease - Bolognino_2019_Molecules_24_
Author(s) : Bolognino I , Giangregorio N , Pisani L , de Candia M , Purgatorio R , Tonazzi A , Altomare CD , Cellamare S , Catto M
Ref : Molecules , 24 : , 2019
Abstract : The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer's disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.
ESTHER : Bolognino_2019_Molecules_24_
PubMedSearch : Bolognino_2019_Molecules_24_
PubMedID: 31775359

Title : Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease - Purgatorio_2019_Eur.J.Med.Chem_177_414
Author(s) : Purgatorio R , de Candia M , Catto M , Carrieri A , Pisani L , De Palma A , Toma M , Ivanova OA , Voskressensky LG , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 177 :414 , 2019
Abstract : Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N(2)-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17muM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-beta (Abeta) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P<0.001) cell viability when impaired by Abeta1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.
ESTHER : Purgatorio_2019_Eur.J.Med.Chem_177_414
PubMedSearch : Purgatorio_2019_Eur.J.Med.Chem_177_414
PubMedID: 31158754

Title : Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones - Rullo_2019_Molecules_24_
Author(s) : Rullo M , Catto M , Carrieri A , de Candia M , Altomare CD , Pisani L
Ref : Molecules , 24 : , 2019
Abstract : A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
ESTHER : Rullo_2019_Molecules_24_
PubMedSearch : Rullo_2019_Molecules_24_
PubMedID: 31835376

Title : Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors - Pisani_2018_Eur.J.Med.Chem_161_292
Author(s) : Pisani L , Iacobazzi RM , Catto M , Rullo M , Farina R , Denora N , Cellamare S , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 161 :292 , 2018
Abstract : Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes' inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
ESTHER : Pisani_2018_Eur.J.Med.Chem_161_292
PubMedSearch : Pisani_2018_Eur.J.Med.Chem_161_292
PubMedID: 30366255

Title : Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo- and Heterodimerization of Coumarin-Based Moieties - Pisani_2017_ChemMedChem_12_1349
Author(s) : Pisani L , Catto M , De Palma A , Farina R , Cellamare S , Altomare CD
Ref : ChemMedChem , 12 :1349 , 2017
Abstract : Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Abeta) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-({4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yl}oxy)ethoxy]-6,7-dimethoxy -2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, the disease-related biological properties of 6 d were investigated. It performed mixed-type AChE enzyme kinetics (inhibition constant Ki =68 nm) and inhibited Abeta self-aggregation. Moreover, it displayed an outstanding ability to protect SH-SY5Y cells from Abeta1-42 damage.
ESTHER : Pisani_2017_ChemMedChem_12_1349
PubMedSearch : Pisani_2017_ChemMedChem_12_1349
PubMedID: 28570763

Title : Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity - Pisani_2017_Eur.J.Pharm.Sci_109_381
Author(s) : Pisani L , De Palma A , Giangregorio N , Miniero DV , Pesce P , Nicolotti O , Campagna F , Altomare CD , Catto M
Ref : Eur J Pharm Sci , 109 :381 , 2017
Abstract : Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Abeta) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Abeta fibrillization, 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Abeta aggregation and cholinesterases with IC50s in the low muM range. With the aim of increasing aqueous solubility, a Mannich-base functionalization led to the synthesis of N-methylpiperazine derivative 2. At acidic pH, an outstanding solubility increase of 2 over the parent compound 1 was proved through a turbidimetric method. HPLC analysis revealed an improved stability of the Mannich base 2 at pH2 along with a rapid release of 1 in human serum as well as an outstanding hydrolytic stability of the parent hydrazone. Coincubation of Abeta1-42 with 2 resulted in the accumulation of low MW oligomers, as detected with PICUP assay. Cell assays on SH-SY5Y cells revealed that 2 exerts strong cytoprotective effects in both cell viability and radical quenching assays, mainly related to its active metabolite 1. These findings show that 2 drives the formation of non-toxic, off-pathway Abeta oligomers unable to trigger the amyloid cascade and toxicity.
ESTHER : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedSearch : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedID: 28801274

Title : The position of fluorine in CP-118,954 affects AChE inhibition potency and PET imaging quantification for AChE expression in the rat brain - Lee_2017_Eur.J.Pharm.Sci_109_209
Author(s) : Lee BC , Moon BS , Park HS , Jung JH , Park DD , de Candia M , Denora N , Altomare CD , Kim SE
Ref : Eur J Pharm Sci , 109 :209 , 2017
Abstract : The in vitro inhibition potency against acetylcholinesterase (AChE) of fluorinated derivatives of CP-118,954 (1) has been shown to depend upon the position of aromatic fluorine (F) substitution on the N-benzyl moiety. Indeed, the meta-F-substituted compound 3 (IC50=1.4nM) shows similar potency with the parent compound 1 (IC50=1.2nM), whereas the ortho-F derivative 2 (IC50=3.2nM) and para-F derivative 4 (IC50=10.8nM) were found to be less potent AChE inhibitors. A comparative in vivo microdialysis study in rats showed that 3 has the strongest effect on the neuropharmacological properties as AChE inhibitor. For PET imaging studies, a radiolabeled ligand ([18F]3) was synthesized through nucleophilic aromatic substitution reaction of diaryliodonium salt-based aldehyde precursor followed by reductive alkylation in a two-step radiolabeling procedure with 11.5 +/- 1.2% (n=24, non-decay corrected) radiochemical yield and over 99% radiochemical purity. In a comparative PET imaging study of the three 18F-containing derivatives of CP-118,954 ([18F]2-4), [18F]3 showed the highest radioactivity in the AChE-rich region of normal rat brain which visually reflected the in vitro AChE-binding affinity of 3. These findings support [18F]3 as a promising AChE-targeted PET imaging ligand for the assessment of cholinergic activity into the brain, providing also insights into the AChE ligand disposition, which depends upon the position of the aromatic fluorine in the benzyl moiety.
ESTHER : Lee_2017_Eur.J.Pharm.Sci_109_209
PubMedSearch : Lee_2017_Eur.J.Pharm.Sci_109_209
PubMedID: 28818531

Title : Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents - Pisani_2016_J.Med.Chem_59_6791
Author(s) : Pisani L , Farina R , Catto M , Iacobazzi RM , Nicolotti O , Cellamare S , Mangiatordi GF , Denora N , Soto-Otero R , Siragusa L , Altomare CD , Carotti A
Ref : Journal of Medicinal Chemistry , 59 :6791 , 2016
Abstract : Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 muM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system.
ESTHER : Pisani_2016_J.Med.Chem_59_6791
PubMedSearch : Pisani_2016_J.Med.Chem_59_6791
PubMedID: 27347731

Title : Searching for Multi-Targeting Neurotherapeutics against Alzheimer's: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif - Pisani_2016_Molecules_21_
Author(s) : Pisani L , Farina R , Soto-Otero R , Denora N , Mangiatordi GF , Nicolotti O , Mendez-Alvarez E , Altomare CD , Catto M , Carotti A
Ref : Molecules , 21 : , 2016
Abstract : The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 microM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 microM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.
ESTHER : Pisani_2016_Molecules_21_
PubMedSearch : Pisani_2016_Molecules_21_
PubMedID: 26999091

Title : New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity - de Candia_2016_Eur.J.Med.Chem_125_288
Author(s) : de Candia M , Zaetta G , Denora N , Tricarico D , Majellaro M , Cellamare S , Altomare CD
Ref : Eur Journal of Medicinal Chemistry , 125 :288 , 2016
Abstract : Several 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). The effects of a number of compounds against NMDA-induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 muM NMDA, with significant effects (P < 0.05) at concentrations between 0.5 and 5 muM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome.
ESTHER : de Candia_2016_Eur.J.Med.Chem_125_288
PubMedSearch : de Candia_2016_Eur.J.Med.Chem_125_288
PubMedID: 27688184

Title : Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases - Farina_2015_J.Med.Chem_58_5561
Author(s) : Farina R , Pisani L , Catto M , Nicolotti O , Gadaleta D , Denora N , Soto-Otero R , Mendez-Alvarez E , Passos CS , Muncipinto G , Altomare CD , Nurisso A , Carrupt PA , Carotti A
Ref : Journal of Medicinal Chemistry , 58 :5561 , 2015
Abstract : The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
ESTHER : Farina_2015_J.Med.Chem_58_5561
PubMedSearch : Farina_2015_J.Med.Chem_58_5561
PubMedID: 26107513

Title : Ester derivatives of annulated tetrahydroazocines: a new class of selective acetylcholinesterase inhibitors - Carotti_2006_Bioorg.Med.Chem_14_7205
Author(s) : Carotti A , de Candia M , Catto M , Borisova TN , Varlamov AV , Mendez-Alvarez E , Soto-Otero R , Voskressensky LG , Altomare CD
Ref : Bioorganic & Medicinal Chemistry , 14 :7205 , 2006
Abstract : A series of ester derivatives of annulated tetrahydroazocines, namely 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indoles (5-10), 2,3,6,7-tetrahydro-1H-azocino[5,4-b]indoles (11-14), and 4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines (15-18), synthesized through an efficient 6-->8 membered ring expansion procedure, were investigated for their acetylcholinesterase (AChE) inhibitory activities. Most of the compounds acted as AChE inhibitors in vitro, with IC(50) values ranging from 5 to 40 microM. The most potent compounds 11 and 15, both as racemic mixtures, proved selective toward AChE, exhibiting selectivity ratios versus butyrylcholinesterase (BuChE) of ca. 15 and more than 20, respectively. Structure-activity studies highlighted, among other factors, lipophilicity as a property modulating the AChE inhibition potency, as shown by a reasonable parabolic correlation between pIC(50) and experimental 1-octanol/water partition coefficient (logP), which described the prevailing behavior of the examined compounds (r(2)=0.665). Molecular docking simulations using the X-ray crystal structure of AChE from Torpedo californica suggested possible binding modes of the tetrahydroazocine ester derivatives 11 and 15.
ESTHER : Carotti_2006_Bioorg.Med.Chem_14_7205
PubMedSearch : Carotti_2006_Bioorg.Med.Chem_14_7205
PubMedID: 16843666

Title : Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase - Bruhlmann_2001_J.Med.Chem_44_3195
Author(s) : Bruhlmann C , Ooms F , Carrupt PA , Testa B , Catto M , Leonetti F , Altomare CD , Carotti A
Ref : Journal of Medicinal Chemistry , 44 :3195 , 2001
Abstract : A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.
ESTHER : Bruhlmann_2001_J.Med.Chem_44_3195
PubMedSearch : Bruhlmann_2001_J.Med.Chem_44_3195
PubMedID: 11543689