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1.
J Photochem Photobiol B ; 203: 111735, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31864090

RESUMO

Complexation behavior of cyclophane amide molecular receptors towards 7,7,8,8-tetracyanoquinodimethane (TCNQ) studied. TD-B3LYP/6-31 + G(d,p) based density functional theory was employed to investigate the photophysical characteristics of the complexes obtained. Syn isomers of cyclophane amide molecular hosts show preferred conformation over other conformations. Molecular Orbital analysis indicates the electronic structure change, which reflects in the absorption spectra of the cyclophane amide-1@TCNQ, and cyclophane amide-2@TCNQ charge-transfer (CT) complexes. Binding energy studies with B3LYP-D3/6-31 + G (d,p) theory demonstrated that the more effective binding of the pyridine-2,6-dicarboxamide macrocycles than for their isophthalamide analogs. Both the CT complexes show intermolecular bifurcated hydrogen bonding (N-H(host)···N(guest)···H-N(host)) interactions (2.06 to 2.08 Å), and π(host)···π(guest) interactions (3.2 to 3.4 Å). Calculated BSSE corrected complexation energy (ΔE) be associated with the formation of the inclusion complexes in the range - 28 to -37 kJ mol-1, indicating spontaneity of host-guest complex formation in both the cases. From the calculated vibrational spectra of these complexes, the formation of inclusion complexes via N - H(host)···N(guest) and π(host)···π(guest) intermolecular interactions established by the frequency shift in the N - H vibrations. Mulliken population analysis performed to recognize the CT process and the variation in charges between the free and complex TCNQ molecules suggests the intermolecular charge transfer. This study indicates that these cyclophane amides can be a decent CT complexation host for the guests like TCNQ.


Assuntos
Teoria da Densidade Funcional , Éteres Cíclicos/química , Nitrilos/química , Piperidinas/química , Ligações de Hidrogênio , Conformação Molecular , Eletricidade Estática
2.
Eur J Med Chem ; 185: 111785, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669851

RESUMO

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H3R and both enzymes. Two derivatives were chosen - 5 (IC50 = 0.46 µM (AChE); 0.44 µM (BuChE); Ki = 159.8 nM (H3R)) and 17 (IC50 = 0.50 µM (AChE); 0.76 µM (BuChE); Ki = 228.2 nM (H3R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Cavalos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 185: 111770, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711793

RESUMO

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 µM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Benzodioxóis/síntese química , Benzodioxóis/química , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Anticancer Res ; 39(12): 6507-6513, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810915

RESUMO

BACKGROUND/AIM: Osteosarcoma is the most malignant type of bone tumor. Patients with osteosarcoma metastases have a poorer prognosis than those without metastases. Thus, the prognosis of osteosarcoma patients with metastases must be improved. MATERIALS AND METHODS: The present study investigated the inhibitory effects of 6-hydroxythiobinupharidine isolated from Nuphar pumilum on migration of LM8 murine osteosarcoma cells by a migration assay and also examined the expression of proteins related to actin dynamics by western blot. The present study also developed an automatic cell counting system using machine learning to count migrated cells by Fiji and Trainable Weka Segmentation. RESULTS: 6-Hydroxythiobinupharidine inhibited migration of LM8 osteosarcoma cells in a dose-dependent manner, and decreased protein expression of Lin11, Isl-1, and Mec-3 domain kinase 1 (LIMK1) and the levels of phosphorylated Cofilin. CONCLUSION: 6-Hydroxythiobinupharidine suppressed migration of LM8 osteosarcoma cells by decreasing expression of LIMK1. 6-Hydroxythiobinupharidine could be potentially used as an anti-metastatic compound.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Ósseas/metabolismo , Quinases Lim/metabolismo , Nuphar/química , Osteossarcoma/metabolismo , Piperidinas/farmacologia , Fatores de Despolimerização de Actina/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/veterinária , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Aprendizado de Máquina , Camundongos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/veterinária , Fosforilação , Piperidinas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-31704620

RESUMO

A novel, high throughput and sensitive LC-MS/MS assay method was developed and fully validated for quantitative determination of pioglitazone, its hydroxyl metabolite and alogliptin in human plasma. A simple and rapid sample preparation procedure based on protein precipitation technique with acetonitrile was utilized. Chromatographic separation was achieved on C8 (50 × 4.6 mm, 5 µm) Kinetex® analytical column using methanol and 0.1% formic acid in a gradient elution mode at a flow rate of 0.7 mL/min with injection volume of 8 µL. Detection was performed on a triple quadrupole mass spectrometer accompanied with electrospray ionization (ESI) technique in positive mode, operating in multiple reaction monitoring, with the transitions of 357.2 → 119.1, 373.1 → 150.1, 340.3 → 116.1, 361.1 → 138.1 and 343.2 → 116.1 m/z for pioglitazone, its hydroxyl metabolite, alogliptin, pioglitazone-d4 (IS-1) and alogliptin-d3 (IS-2), in order. Analysis was achieved within 4 min over a linear concentration range of 10-3000 ng/mL, 5-2000 ng/mL and 3-300 ng/mL, for pioglitazone, hydroxyl pioglitazone and alogliptin, in order. The method was fully validated according to FDA guidelines. The developed method was used for estimation of the three studied analytes in human plasma and pharmacokinetic parameters were demonstrated after oral dose administration of Oseni® tablets to Egyptian healthy volunteers.


Assuntos
Cromatografia Líquida/métodos , Pioglitazona/sangue , Piperidinas/sangue , Espectrometria de Massas em Tandem/métodos , Uracila/análogos & derivados , Humanos , Modelos Lineares , Pioglitazona/química , Pioglitazona/metabolismo , Pioglitazona/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Uracila/sangue , Uracila/química , Uracila/farmacocinética
6.
Eur J Med Chem ; 183: 111726, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585275

RESUMO

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 µM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides , Antineoplásicos , Azepinas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactonas , Piperidinas , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Compostos Heterocíclicos de Anel em Ponte/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Lactonas/química , Lactonas/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Piperidinas/química , Piperidinas/farmacologia , Verapamil/farmacologia
7.
J Enzyme Inhib Med Chem ; 34(1): 1711-1715, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31547734

RESUMO

α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explosion of dendritic structures revealed by fluorescence and phase-contrast microscopy. We have further demonstrated that this aberrant α-syn aggregation can be blocked using a recently discovered non-immunosuppressive synthetic inhibitor of FKBP12, ElteN378. The role of FKBP12 and of ElteN378 in the α-syn aggregation mechanism has been elucidated using molecular dynamics simulations based on an effective coarse-grained model. The reported data not only reveal a new potent synthetic drug as a candidate for early stage treatment of α-syn dependent neurodegenerations but also pave the way to a deeper understanding of the mechanism of action of FKBP12 on α-syn oligomeric aggregation, a topic which is still controversial.


Assuntos
Piperidinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Proteína 1A de Ligação a Tacrolimo/antagonistas & inibidores , alfa-Sinucleína/química , Dendrímeros/química , Cinética , Simulação de Dinâmica Molecular , Piperidinas/química , Ligação Proteica , Conformação Proteica , Transdução de Sinais , Proteína 1A de Ligação a Tacrolimo/química , Proteína 1A de Ligação a Tacrolimo/metabolismo
8.
J Chromatogr Sci ; 57(9): 806-814, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31504287

RESUMO

Domperidone, a gastroprokinetic agent, is a common drug to treat emesis. It was subjected to acid, base-mediated hydrolysis, peroxide-mediated oxidation, photolysis and thermal degradation according to ICH guidelines to observe stability of the selected drug under the stress conditions. Although the drug is resistant to base hydrolysis, photolysis and thermal stressors, two degradants (DP-ISO1 and DP-ISO2) were formed in acid mediated hydrolysis. Oxidation with hydrogen peroxide also resulted in one product (DP-OX). All three degradants were isolated from the crude reaction mixture by preparative high-performance liquid chromatography and supercritical fluid chromatography. Structures of isolated compounds were unambiguously characterized as 5-chloro-1-(1-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO1), 5-chloro-1-(3-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO2), 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidine 1-oxide (DP-OX) by analysis of mass spectrometry, 1D and 2D nuclear magnetic resonance spectra. To the best of our knowledge, DP-ISO1 and DP-ISO2 are new and DP-OX was previously reported as domperidone impurity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Domperidona/análise , Domperidona/química , Contaminação de Medicamentos , Estabilidade de Medicamentos , Hidrólise , Imidazóis/química , Isomerismo , Oxirredução , Fotólise , Piperidinas/química
9.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
10.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374998

RESUMO

A series of 2-nm gold nanoparticles passivated with different thiols all featuring at least one triazacyclonanone-Zn(II) complex and different flanking units (a second Zn(II) complex, a triethyleneoxymethyl derivative or a guanidinium of arginine of a peptide) were prepared and studied for their efficiency in the cleavage of the RNA-model substrate 2-hydroxypropyl-p-nitrophenyl phosphate. The source of catalysis for each of them was elucidated from the kinetic analysis (Michaelis-Menten profiles, pH dependence and kinetic isotope effect). The data indicated that two different mechanisms were operative: One involving two Zn(II) complexes and the other one involving a single Zn(II) complex and a flanking guanidinium cation. The mechanism based on a dinuclear catalytic site appeared more efficient than the one based on the cooperativity between a metal complex and a guanidinium.


Assuntos
Compostos Aza/química , Complexos de Coordenação/química , Nanopartículas Metálicas/química , Piperidinas/química , RNA/química , Catálise , Ouro/química , Cinética , Modelos Moleculares , Estrutura Molecular , Compostos de Sulfidrila/química , Zinco/química
11.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295928

RESUMO

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center.


Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Enzimas/metabolismo , Oxirredução , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Antineoplásicos/química , Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Enzimas/química , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Coelhos , Ratos , Proteínas Recombinantes
12.
Carbohydr Polym ; 222: 115042, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320080

RESUMO

In this work, biodegradable cellulose-based biosorbents (MOFs/OCBs) with dual function of dye removal and microbial inactivation were fabricated by in situ anchoring metal-organic frameworks (MOFs) on the TEMPO oxidized corncobs (OCBs). Results showed that delignification and oxidation can develop the OCBs with more cellulose content, carboxyl groups and specific surface area, thus facilitating the deposition of MOFs. The porous and carbohydrate-rich OCBs can serve as supports and stabilizers for MOFs, allowing for enhanced stability and recyclability of MOFs powders. The MOFs, namely HKUST-1 and ZIF-8, can endow the OCBs multiple functions of good adsorption capacity to methyl orange (from 8% of OCBs to 55% of HKUST-1/OCBs and 84% of ZIF-8/OCBs) and excellent antibacterial activity (from 0 of OCBs to 90.2% of HKUST-1/OCBs and 44.8% of ZIF-8/OCBs). Such a concept may offer a new pathway for preparing economical and efficient biosorbents for environmental remedy purposes.


Assuntos
Antibacterianos/farmacologia , Celulose/química , Corantes/isolamento & purificação , Estruturas Metalorgânicas/farmacologia , Componentes Aéreos da Planta/química , Adsorção , Antibacterianos/química , Corantes/química , Reutilização de Equipamento , Escherichia coli/efeitos dos fármacos , Cinética , Estruturas Metalorgânicas/química , Compostos Organometálicos/química , Piperidinas/química , Poluentes Químicos da Água/química , Zea mays/química
13.
Pak J Pharm Sci ; 32(3): 987-996, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278711

RESUMO

Heterocyclic chemistry is an important field of organic chemistry due to therapeutic potential. The minor modification in the structure of poly-functional compounds has great effect on therapeutic ability. In the presented research work, substituted 1,3,4-oxadiazole derivatives, 8a-p, have been synthesized by the reaction of 1-(4-bromomethylbenzenesulfonyl)-3-methylpiperidine (7) and 5-substituted-1,3,4-oxadiazole-2-thiol (4a-p). The 5-substituted-1,3,4-oxadiazole-2-thiol were synthesized by converting carboxylic acids correspondingly into esters, hydrazides and oxadiazoles. Secondly the electrophile, 1-(4-Bromomethylbenzenesulfonyl)-3-methylpiperidine (7), was prepared by the reaction of 3-methylpiperidine with 4-bromomethylbenzenesulfonyl chloride in the presence of water and Na2CO3 under pH of 9-10. The compounds were structurally corroborated through spectroscopic data analysis of IR, EI-MS and 1H-NMR. The screening for antibacterial activity revealed the compounds to be moderate to excellent inhibitors against bacteria under study. Anti-enzymatic activity was assessed against urease enzyme and 1-{[4-({[5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}methyl)phenyl]sulfonyl}-3-methylpiperidine (8d) was the most active one.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxidiazóis/química , Piperidinas/química , Espectrofotometria Infravermelho , Sulfonamidas/química
14.
Eur J Med Chem ; 179: 680-693, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280020

RESUMO

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ±â€¯0.07 µM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ±â€¯1.25 and 5.94 ±â€¯1.08 µM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Piperidinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
15.
Eur J Pharm Sci ; 137: 104988, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291598

RESUMO

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ±â€¯1.57 nm), narrow size distribution (polydispersity index 0.195 ±â€¯0.002) and efficient entrapment (entrapment efficiency 92.2 ±â€¯2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.


Assuntos
Alcaloides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Benzodioxóis/administração & dosagem , Epilepsia/tratamento farmacológico , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Administração Oral , Alcaloides/química , Alcaloides/farmacocinética , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Benzodioxóis/química , Benzodioxóis/farmacocinética , Disponibilidade Biológica , Liberação Controlada de Fármacos , Embrião não Mamífero , Masculino , Camundongos , Nanopartículas/química , Piperidinas/química , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual , Peixe-Zebra
16.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
17.
Food Chem ; 298: 125067, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260989

RESUMO

An ultra-high performance supercritical fluid chromatography-photodiode array detection-mass spectrometry (UHPSFC-MS) method for quality control of Piper longum L. has been developed and optimized. Hexane/isopropanol (70/30, v/v) was determined as the final injection solvent and methanol as the organic modifier. A design-of-experimental (DoE) approach was used to optimize column temperature, back-pressure and the gradient slope simultaneously using Trefoil CEL1 column. The back-pressure, temperature, flow rate were set at 130 bar, 32.5 °C and 1.0 mL/min, respectively. Positive electrospray ionization was used in the single ion monitoring mode. The 12 analytes were analyzed within 8 min using the optimized conditions. The linearities of the standard calibrations were satisfactory with coefficients of determination (R2) > 0.995. The recovery measured varied from 96.34% to 105.00% with relative standard deviation (RSD) ≤ 4.68%. The method was sensitive, reliable and effective, and successfully applied to simultaneous determination of 12 compounds in 28 batches of P. longum.


Assuntos
Alcaloides/química , Cromatografia com Fluido Supercrítico/métodos , Piper/química , Alcaloides/isolamento & purificação , Benzodioxóis/química , Benzodioxóis/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Cromatografia com Fluido Supercrítico/normas , Frutas/química , Frutas/metabolismo , Limite de Detecção , Espectrometria de Massas , Metanol/química , Piper/metabolismo , Piperidinas/química , Piperidinas/isolamento & purificação , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/isolamento & purificação , Análise de Componente Principal , Controle de Qualidade , Solventes/química , Temperatura Ambiente
18.
Biomed Chromatogr ; 33(11): e4645, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31306503

RESUMO

AdipoRon is an orally active adiponectin receptor agonist. The aim of this study was to characterize the metabolites of AdipoRon in rat and human liver microsomes using ultra-high performance liquid chromatography combined with Q-Exactive Orbitrap tandem mass spectrometry (UPLC-Q-Exactive-Orbitrap-MS) together with data processing techniques including extracted ion chromatograms and a mass defect filter. AdipoRon (10 µm) was incubated with liver microsomes in the presence of NADPH and this resulted in a total of 11 metabolites being detected. The identities of these metabolites were characterized by comparing their accurate masses and fragment ions as well as their retention times with those of AdipoRon using MetWorks software. Metabolites M1-M3, M6, and M8-M11 were identified for the first time. Metabolite M4, the major metabolite both in rat and human liver microsomes, was further confirmed using the reference standard. Our results revealed that the metabolic pathways of AdipoRon in liver microsomes were N-dealkylation (M2), hydroxylation (M, M5-M9), carbonyl reduction (M4) and the formation of amide (M10 and M11). Our results provide valuable information about the in vitro metabolism of AdipoRon, which would be helpful for us to understand the mechanism of the elimination of AdipoRon and, in turn, its effectiveness and toxicity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Piperidinas/análise , Piperidinas/farmacocinética , Ratos
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1122-1123: 39-48, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150952

RESUMO

Resveratrol and piperine are proven for their therapeutic benefits to treat various diseases. Due to their synergistic actions and combined drug delivery application, a rapid and specific RP-HPLC method was developed and validated as per ICH guidelines, by using an isosbestic point. The chromatographic separation was performed with Luna 5 µ 100 ŠC-18(2) HPLC column by using acetonitrile (ACN): phosphate buffer (0.01% orthophosphoric acid) (55:45) as mobile phase, at 1 mL/min of flow rate and 330 nm. The developed method was found to be linear over the concentration range of 0.25-8 µg/mL with correlation coefficient value >0.999. The developed method was accurate (percent recovery 98.06-101.74%), precise (percent relative standard deviation <2.0%), and robust. The limit of detection and limit of quantification for resveratrol were found to be 0.02 and 0.08 µg/mL, respectively and 0.04 and 0.11 µg/mL, for piperine, respectively. The developed method was also validated in human plasma as per ICH guidelines. Moreover, stress degradation studies of both phytoconstituents were studied and the relevancy of the developed method was analyzed on cubosome nanoformulation. A good separation of drug peaks was observed in the presence of the degradation products. This method could thus be used for regular in vitro and in vivo estimation of piperine and resveratrol.


Assuntos
Alcaloides/sangue , Benzodioxóis/sangue , Cromatografia Líquida de Alta Pressão/métodos , Piperidinas/sangue , Alcamidas Poli-Insaturadas/sangue , Resveratrol/sangue , Alcaloides/química , Benzodioxóis/química , Cromatografia de Fase Reversa/métodos , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Reprodutibilidade dos Testes , Resveratrol/química
20.
Mater Sci Eng C Mater Biol Appl ; 102: 45-52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147016

RESUMO

Tyrosinase inhibitors could effectively limit the activity of tyrosinase in melanocytes to reduce the excessive synthesis and deposition of melanin. However, low skin permeability and lacking in targeting greatly restricted their application. Herein, ZnO quantum dots were synthesized by gel-sol method and grafted with BQ-788, which have been employed as transdermal and targeting carrier to delivery ellagic acid to melanocytes. Ellagic acid loaded ZnO quantum dots with the size distribution of around 9 nm could targetedly bind to melanocytes and enter the melanocytes by endocytosis within 1 h. The ellagic acid release behavior was controlled by the decreasing of pH via the rapid dissolution of ZnO. When the concentration of BQ-788/EA@ZnO was 12.5 µg/mL, the inhibition rate on tyrosinase activity and melanin deposition were up to 44.23 ±â€¯4.97% and 37.50 ±â€¯5.23%, respectively. In view of their good biocompatibility, they were of great potential in clinically external application for tyrosinase inhibition.


Assuntos
Ácido Elágico/química , Inibidores Enzimáticos/farmacologia , Melanócitos/enzimologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pontos Quânticos/química , Óxido de Zinco/química , Administração Cutânea , Adulto , Materiais Biocompatíveis/farmacologia , Células Cultivadas , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Piperidinas/síntese química , Piperidinas/química , Pontos Quânticos/ultraestrutura , Tirosina/metabolismo , Óxido de Zinco/síntese química
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