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1.
SAR QSAR Environ Res ; 32(9): 745-767, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34494463

RESUMO

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors play a key role in treating Alzheimer's disease. This study proposes an approach that integrates a modified binary particle swarm optimization (PSO) with a machine learning algorithm for building QSAR models to predict the activity of inhibitors for AChE and BuChE enzymes. More precisely, it uses a transfer function to convert the continuous search space of PSO to binary. Furthermore, it utilizes the concepts of catfish effect and chaotic map to improve exploration ability in searching for an optimum subset of descriptors for QSAR model constructions. Then, through a statistical method, it employs a machine learning algorithm to evaluate the fitness value of each candidate subset of features. Different combinations of four transfer functions with four machine learning algorithms, including K-nearest neighbour, multiple linear regression, support vector machine, and regression tree, were used to build several variants of the proposed algorithm. QSAR models constructed by each version were verified by internal and external validations. The best variants were selected based on a method called sum of ranking differences.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Bases de Dados de Compostos Químicos , Simulação de Acoplamento Molecular , Reprodutibilidade dos Testes
2.
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
3.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443482

RESUMO

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood-brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Acetilcolinesterase/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Simulação por Computador , Desenho de Fármacos , Humanos , Quinoxalinas/síntese química , Quinoxalinas/toxicidade , Relação Estrutura-Atividade
5.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361702

RESUMO

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.


Assuntos
Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Cumarínicos/síntese química , Curcumina/análogos & derivados , Inibidores da Monoaminoxidase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Curcumina/farmacologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Córtex Motor/citologia , Córtex Motor/enzimologia , Nanopartículas/química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/farmacologia , Picratos/antagonistas & inibidores , Cultura Primária de Células , Ratos , Relação Estrutura-Atividade
6.
Eur J Pharm Sci ; 166: 105976, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34419572

RESUMO

Alzheimer's disease (AD) is the most common type of dementia, the exact etiology of the disease has not been known yet. The use of single-target drugs limits the efficacy of drugs and has certain side effects. In this study, the 'hidden' multi-target strategy was used in combination with chrysin's metal chelating site and rivastigmine's anti-cholinesterase pharmacophore to form an ester, which improves the hydrophobicity and protects the phenolic hydroxyl group at the same time. Four derivatives (1-4) were synthesized as the hidden multifunctional agents for AD therapy. Most of the compounds displayed good activities of anti-cholinesterase, antioxidant, appropriate blood brain barrier (BBB) penetration and certain inhibitory activity of ß-amyloid (Aß) aggregation. Compound 3 was demonstrated as the highest selective butyrylcholinesterase (BuChE) inhibitor and targeted both the catalytic active site (CAS) and the peripheral anion site (PAS). And it could be hydrolyzed by BuChE to release chrysin with good ability to chelate Cu2+ and Fe2+. At the same time, phenol fragment can exert its good antioxidant effect. Overall, these findings demonstrated that compound 3 might be considered as a potential hidden multifunctional candidate in the therapy of AD.


Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Antioxidantes/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Flavonoides , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
7.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361659

RESUMO

In this study six unsymmetrical thiourea derivatives, 1-isobutyl-3-cyclohexylthiourea (1), 1-tert-butyl-3-cyclohexylthiourea (2), 1-(3-chlorophenyl)-3-cyclohexylthiourea (3), 1-(1,1-dibutyl)-3-phenylthiourea (4), 1-(2-chlorophenyl)-3-phenylthiourea (5) and 1-(4-chlorophenyl)-3-phenylthiourea (6) were obtained in the laboratory under aerobic conditions. Compounds 3 and 4 are crystalline and their structure was determined for their single crystal. Compounds 3 is monoclinic system with space group P21/n while compound 4 is trigonal, space group R3:H. Compounds (1-6) were tested for their anti-cholinesterase activity against acetylcholinesterase and butyrylcholinesterase (hereafter abbreviated as, AChE and BChE, respectively). Potentials (all compounds) as sensing probes for determination of deadly toxic metal (mercury) using spectrofluorimetric technique were also investigated. Compound 3 exhibited better enzyme inhibition IC50 values of 50, and 60 µg/mL against AChE and BChE with docking score of -10.01, and -8.04 kJ/mol, respectively. The compound also showed moderate sensitivity during fluorescence studies.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Mercúrio/análise , Transdução de Sinais/efeitos dos fármacos , Materiais Inteligentes/química , Tioureia/análogos & derivados , Tioureia/metabolismo , Inibidores da Colinesterase/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular/métodos , Estrutura Molecular , Ligação Proteica , Espectrometria de Fluorescência/métodos , Relação Estrutura-Atividade , Tioureia/química , Difração de Raios X/métodos
8.
Eur J Med Chem ; 223: 113735, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34371367

RESUMO

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 µM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd = 13 nM, k2 = 0.26 min-1), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aß1-42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.


Assuntos
Butirilcolinesterase/química , Canabidiol/química , Carbamatos/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Humanos , Cinética , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
9.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208297

RESUMO

Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Aminas/química , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Monoaminoxidase/química , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular , Inibidores da Colinesterase/síntese química , Humanos , Ligantes , Masculino , Camundongos , Modelos Animais , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Receptores Histamínicos H3/química , Relação Estrutura-Atividade
10.
Int J Biol Macromol ; 185: 750-760, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216669

RESUMO

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are considered important target for drug design against Alzheimer's disease. In the present study in silico analysis; theoretical analysis of biointerface between ligand and interacting amino acid residues of proteins; and in vitro analysis of enzyme inhibition kinetics were carried out to delineate the inhibitory property of amine compounds against AChE/BChE. High throughput virtual screening of amine compounds identified three compounds (2-aminoquinoline, 2-aminobenzimidazole and 2-amino-1-methylbenzimidazole) that best interacted with AChE/BChE. Molecular docking analysis revealed the interaction of these compounds in the active site gorge of AChE/BChE, in particular with amino acid residues present in the peripheral anionic site. Molecular dynamics simulation confirmed the stable binding of these compounds with AChE/BChE. Binding energy calculated through MMGBSA method identified the non-covalent interactions (electrostatic and Van der Waals interactions) have contributed to the stable binding of the amine compounds with the AChE/BChE. Biointerface between amine compounds and AChE/BChE were visualized through Hirshfeld surface analysis. The inter-fragment interaction energies for the possible contacts between amine compounds and amino acid residues were carried out for the first time. All the amine compounds showed mixed-type of inhibition with moderate Ki value in in vitro analysis.


Assuntos
Acetilcolinesterase/química , Aminas/farmacologia , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Aminas/química , Sítios de Ligação , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
11.
J Med Chem ; 64(13): 9302-9320, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34152756

RESUMO

A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/deficiência , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Cinamatos/síntese química , Cinamatos/química , Cinamatos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Melatonina/síntese química , Melatonina/química , Melatonina/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade
12.
Chem Biodivers ; 18(8): e2100207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34096170

RESUMO

Gundelia species are known as "Kenger-kereng dikeni" in Anatolia, and their aerial parts are consumed as food. Also, roots and seeds (disseminules) of the Gundelia species are used to prepare gum and coffee. The chemical contents of ethanol and hexane extracts of disseminules of 17 Gundelia species, 13 of them are endemic, were studied using LC/MS/MS and GC/MS. Additionally, their antioxidant potential and enzyme inhibitory capacity against acetyl- and butyryl-cholinesterase, urease, and tyrosinase were determined. The unsaturated fatty acid ratios of Gundelia species were higher than their saturated fatty acid ratio. The highest sum of oleic and linoleic acid was detected in G. tournefortii var. tenuisecta (70.42 %). ß-Sitosterol, α-amyrin, 3-acetyllupeol were identified in 17 Gundelia species by GC/MS, while chlorogenic acid and luteolin by LC/MS/MS as major compounds. The ethanol and hexane extracts of G. siirtica, G. rosea, and G. mesopotamica indicated good cholinesterase inhibitory activity. Among all species, ethanol extract of G. colemerikensis exhibited the best activity in ABTS (IC50 : 32.30±0.98 µg/mL), DPPH (IC50 : 59.91±0.89 µg/mL), and CUPRAC (A0.5 : 57.41±1.03 µg/mL) assays. Ethanol extract of G. colemerikensis also displayed the highest inhibitory activity against butyrylcholinesterase (51.14±0.25 % at 200 µg/mL), urease (51.71±1.75 % at 200 µg/mL), and tyrosinase (39.50±0.85 % at 200 µg/mL) enzymes. According to the chemometric analysis of fatty acids, four groups were observed. Therefore, it is suggested that G. colemerikensis can be used in the pharmaceutical, food, and cosmetic industries due to its antioxidant and enzyme inhibition properties.


Assuntos
Asteraceae/química , Inibidores Enzimáticos/química , Compostos Fitoquímicos/química , Extratos Vegetais/química , Antioxidantes/química , Asteraceae/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Frutas/química , Frutas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/metabolismo , Análise de Componente Principal , Sementes/química , Sementes/metabolismo , Espectrometria de Massas em Tandem , Urease/antagonistas & inibidores , Urease/metabolismo
13.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
14.
Future Med Chem ; 13(13): 1105-1125, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960203

RESUMO

Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Miconazol/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Humanos , Masculino , Camundongos , Miconazol/síntese química , Miconazol/química , Modelos Moleculares , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos
15.
Commun Biol ; 4(1): 573, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990679

RESUMO

Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood-brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/toxicidade , Oximas/farmacologia , Animais , Ativação Enzimática , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
16.
Bioorg Chem ; 111: 104922, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945941

RESUMO

Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aß aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aß. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Pirrolidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxidiazóis/síntese química , Oxidiazóis/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
17.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810550

RESUMO

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Ácido Aminossalicílico/química , Butirilcolinesterase/metabolismo , Carbamatos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Análise por Conglomerados , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Análise de Componente Principal , Solventes , Relação Estrutura-Atividade , Células THP-1
18.
Eur J Med Chem ; 218: 113397, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33838585

RESUMO

Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: ß-secretase enzyme (BACE1) and amyloid ß (Aß) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 µM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 µM; inhibition of Aß aggregation = 57.9% at 10 µM; mGAT1 IC50 = 10.96 µM; and mGAT2 IC50 = 19.05 µM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 µM and IC50 = 2.95 µM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 41: 128000, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798702

RESUMO

(S, S)-1-hydroxy-1-oxo-2-c,5-t-diphenylphospholane or Fiaud's acid is used as a novel and effective chiral organocatalyst for bis α-aminophosphonates synthesis with excellent diastereoselectivity and yields within short reaction time. All synthesized bis α-aminophosphonates revealed a good to excellent antifungal capacity, where the six compounds 4a, 4b, 4e, 4h, 4k and 4l are the best fungicide inhibiting the growth of Fusarium oxysporumandBotrytis cinereaby 65% to 84% with IC50 values <0.02 mg/mL. Similarly, these six products exhibited a strong antioxidant effect, whereas a low inhibition activity was obtained with both AChE and BChE. Furthermore, they displayed a very weak inhibitory activity against tyrosinase except for the compound4l.These findings suggest a possible use of these compounds as synthetic pesticides with less hazardous effects with antioxidant, and anti-tyrosinase properties.


Assuntos
Antifúngicos/farmacologia , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Botrytis/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Fusarium/efeitos dos fármacos , Cavalos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores
20.
Bioorg Chem ; 111: 104893, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33882364

RESUMO

To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure-activity relationship analysis.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Esteroides/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Estrutura Molecular , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade
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