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1.
Chem Res Toxicol ; 37(2): 323-339, 2024 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-38200616

RESUMO

Despite being extremely relevant for the protection of prenatal and neonatal health, the developmental toxicity (Dev Tox) is a highly complex endpoint whose molecular rationale is still largely unknown. The lack of availability of high-quality data as well as robust nontesting methods makes its understanding even more difficult. Thus, the application of new explainable alternative methods is of utmost importance, with Dev Tox being one of the most animal-intensive research themes of regulatory toxicology. Descending from TIRESIA (Toxicology Intelligence and Regulatory Evaluations for Scientific and Industry Applications), the present work describes TISBE (TIRESIA Improved on Structure-Based Explainability), a new public web platform implementing four fundamental advancements for in silico analyses: a three times larger dataset, a transparent XAI (explainable artificial intelligence) framework employing a fragment-based fingerprint coding, a novel consensus classifier based on five independent machine learning models, and a new applicability domain (AD) method based on a double top-down approach for better estimating the prediction reliability. The training set (TS) includes as many as 1008 chemicals annotated with experimental toxicity values. Based on a 5-fold cross-validation, a median value of 0.410 for the Matthews correlation coefficient was calculated; TISBE was very effective, with a median value of sensitivity and specificity equal to 0.984 and 0.274, respectively. TISBE was applied on two external pools made of 1484 bioactive compounds and 85 pediatric drugs taken from ChEMBL (Chemical European Molecular Biology Laboratory) and TEDDY (Task-Force in Europe for Drug Development in the Young) repositories, respectively. Notably, TISBE gives users the option to clearly spot the molecular fragments responsible for the toxicity or the safety of a given chemical query and is available for free at https://prometheus.farmacia.uniba.it/tisbe.


Assuntos
Inteligência Artificial , Animais , Recém-Nascido , Criança , Humanos , Reprodutibilidade dos Testes , Consenso
2.
Bioorg Med Chem ; 110: 117829, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39002183

RESUMO

In pharmaceutical science and drug design the versatility of the pyrrolidine scaffold relating to spatial arrangement, synthetic accessibility and pharmacological profile is a largely explored and most likely interesting one. Nonetheless, few evidences suggest the pivotal role of pyrrolidine as scaffold for multipotent agents in neurodegenerative diseases. We then challenged the enrolling in the field of Alzheimer disease of so far not ravelled targets of this chemical cliché with a structure based and computer-aided design strategy focusing on multi-target action, versatile synthesis as well as pharmacological safeness. To achieve these hits, ten enantiomeric pairs of compounds were obtained and tested, and the biological data will be here presented and discussed. Among the novel compounds, coumarin and sesamol scaffolds containing analogues resulted promising perspectives.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Pirrolidinas , Pirrolidinas/química , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Humanos , Doença de Alzheimer/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Estereoisomerismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Animais , Relação Estrutura-Atividade
3.
Arch Pharm (Weinheim) ; 357(3): e2300491, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38158335

RESUMO

Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent as BChE inhibitors (half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance, threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18 F-labeled congener 2a was synthesized, by applying the aromatic 18 F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positron emission tomography imaging. [18 F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g-1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood-brain barrier crossing. After a transient liver accumulation of [18 F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase , Relação Estrutura-Atividade , Transporte Biológico , Indóis
4.
J Chem Inf Model ; 63(18): 5916-5926, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37675493

RESUMO

The endocannabinoid system, which includes cannabinoid receptor 1 and 2 subtypes (CB1R and CB2R, respectively), is responsible for the onset of various pathologies including neurodegeneration, cancer, neuropathic and inflammatory pain, obesity, and inflammatory bowel disease. Given the high similarity of CB1R and CB2R, generating subtype-selective ligands is still an open challenge. In this work, the Cannabinoid Iterative Revaluation for Classification and Explanation (CIRCE) compound prediction platform has been generated based on explainable machine learning to support the design of selective CB1R and CB2R ligands. Multilayer classifiers were combined with Shapley value analysis to facilitate explainable predictions. In test calculations, CIRCE predictions reached ∼80% accuracy and structural features determining ligand predictions were rationalized. CIRCE was designed as a web-based prediction platform that is made freely available as a part of our study.


Assuntos
Internet , Aprendizado de Máquina , Ligantes , Receptores de Canabinoides
5.
J Chem Inf Model ; 63(1): 56-66, 2023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36520016

RESUMO

Herein, a robust and reproducible eXplainable Artificial Intelligence (XAI) approach is presented, which allows prediction of developmental toxicity, a challenging human-health endpoint in toxicology. The application of XAI as an alternative method is of the utmost importance with developmental toxicity being one of the most animal-intensive areas of regulatory toxicology. In this work, the established CAESAR (Computer Assisted Evaluation of industrial chemical Substances According to Regulations) training set made of 234 chemicals for model learning is employed. Two test sets, including as a whole 585 chemicals, were instead used for validation and generalization purposes. The proposed framework favorably compares with the state-of-the-art approaches in terms of accuracy, sensitivity, and specificity, thus resulting in a reliable support system for developmental toxicity ensuring informativeness, uncertainty estimation, generalization, and transparency. Based on the eXtreme Gradient Boosting (XGB) algorithm, our predictive model provides easy interpretative keys based on specific molecular descriptors and structural alerts enabling one to distinguish toxic and nontoxic chemicals. Inspired by the Organisation for Economic Co-operation and Development (OECD) principles for the validation of Quantitative Structure-Activity Relationships (QSARs) for regulatory purposes, the results are summarized in a standard report in portable document format, enclosing also details concerned with a density-based model applicability domain and SHAP (SHapley Additive exPlanations) explainability, the latter particularly useful to better understand the effective roles played by molecular features. Notably, our model has been implemented in TIRESIA (Toxicology Intelligence and Regulatory Evaluations for Scientific and Industry Applications), a free of charge web platform available at http://tiresia.uniba.it.


Assuntos
Algoritmos , Inteligência Artificial , Animais , Humanos , Relação Quantitativa Estrutura-Atividade
6.
Int J Mol Sci ; 24(9)2023 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-37175433

RESUMO

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 (IC50 about 1 µM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC50 0.51 µM) and moderate inhibitor of both ChEs (IC50s 7-8 µM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 of 3.51 µM. 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 IC50s in the range 4.83-11.3 µM.


Assuntos
Inibidores da Monoaminoxidase , Monoaminoxidase , Humanos , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Monoaminoxidase/metabolismo , Piridinas/farmacologia , Inibidores da Colinesterase/química
7.
Molecules ; 28(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36838649

RESUMO

In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl (5), 1-indol-3-yl (8), and azocino[4,5-b]quinoline (10) derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, 5c-h proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog 5g achieved an IC50 of 1.35 µM, a value close to that of the well-known MAO B inhibitor pargyline.


Assuntos
Inibidores da Monoaminoxidase , Pargilina , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Naftiridinas , Relação Estrutura-Atividade
8.
Molecules ; 28(15)2023 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-37570828

RESUMO

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 (IC50s 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.


Assuntos
Doença de Alzheimer , Monoaminoxidase , Humanos , Monoaminoxidase/metabolismo , Acetilcolinesterase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Relação Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico
9.
Mol Divers ; 26(2): 1243-1247, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33538985

RESUMO

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 (Ki) in the low micromolar range.


Assuntos
Butirilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Alcadienos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
10.
Molecules ; 27(13)2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35807514

RESUMO

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 (Ki) 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.


Assuntos
Benzamidinas , Inibidores da Colinesterase , Inibidores do Fator Xa , Malonatos , Acetilcolinesterase , Benzamidinas/química , Butirilcolinesterase , Inibidores da Colinesterase/química , Desenho de Fármacos , Fator Xa , Inibidores do Fator Xa/química , Fibrinolíticos/química , Glicina/análogos & derivados , Glicina/química , Malonatos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
11.
Molecules ; 27(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36234811

RESUMO

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 (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 µM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 µM), but 90-fold more water-soluble.


Assuntos
Inibidores da Colinesterase , Inibidores da Monoaminoxidase , Acetilcolinesterase/metabolismo , Álcoois , Alcadienos , Alcinos , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Humanos , Isoquinolinas , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Água
12.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500640

RESUMO

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 Ki 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 Ki values, which were found equal to 0.058 and 6.95 µM 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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Trombina/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Relação Estrutura-Atividade
13.
Molecules ; 26(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445600

RESUMO

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 µM). 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 Ki in the low micromolar range (4.69 µM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 µM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced ß-amyloid (Aß)1-40 aggregation (IC50 = 13 µM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.


Assuntos
Doença de Alzheimer/patologia , Isoquinolinas/farmacologia , Neoplasias/patologia , Bases de Schiff/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Butirilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Humanos , Isoquinolinas/química , Cinética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Bases de Schiff/química
14.
Bioorg Chem ; 104: 104169, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920352

RESUMO

An interaction of homophthalonitrile with salicylaldehydes proceeds as a novel domino reaction and results in the formation of nineteen 12H-chromeno[2,3-c]isoquinoline-5-amine derivatives. Four new bonds and two cycles are forged in a single synthetic operation, employing cheap and eco-friendly ammonium formate, acting both as a catalyst and a reducing agent. The in vitro cytotoxicity tests revealed antiproliferative activities against five human tumor cell lines, including the cisplatin-resistant ovarian carcinoma one (A2780cp8), with inhibitory potency data (IC50) in the low micromolar range in most cases. Molecular docking calculations and fluorescence quenching studies revealed possible binding properties with DNA of the active compounds.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzopiranos/síntese química , Benzopiranos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Molecules ; 25(15)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32752035

RESUMO

A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation.


Assuntos
Compostos de Bifenilo/farmacologia , Cisplatino/farmacologia , Metaboloma/efeitos dos fármacos , Vimblastina/farmacologia , Compostos de Bifenilo/química , Proliferação de Células/efeitos dos fármacos , Análise Discriminante , Humanos , Análise dos Mínimos Quadrados , Células MCF-7 , Espectroscopia de Ressonância Magnética , Niacinamida/química , Niacinamida/farmacologia , Análise de Componente Principal
16.
Molecules ; 26(1)2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33375412

RESUMO

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 (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Donepezila/síntese química , Donepezila/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Donepezila/química , Donepezila/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/uso terapêutico , Estereoisomerismo
17.
Molecules ; 25(23)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297547

RESUMO

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aß) aggregation, a hallmark of pathophysiology of Alzheimer's disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the 'active' compounds from the 'inactive' (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of 'active' compounds, i.e., those achieving finite IC50 values lower than 100 µM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aß anti-aggregating potency of the indole and isatin derivatives studied herein.


Assuntos
Peptídeos beta-Amiloides/química , Indóis/química , Isatina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Técnicas de Química Sintética , Citoproteção/efeitos dos fármacos , Desenho de Fármacos , Humanos , Indóis/farmacologia , Isatina/farmacologia , Ligantes , Conformação Molecular , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos
19.
Molecules ; 24(24)2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31835376

RESUMO

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.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , para-Aminobenzoatos/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
20.
Molecules ; 24(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775359

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cálcio/metabolismo , Dantroleno/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/patologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Carnitina/análogos & derivados , Carnitina/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Dantroleno/química , Reposicionamento de Medicamentos , Humanos , Hipertermia Maligna/tratamento farmacológico , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/química
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