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1.
J Enzyme Inhib Med Chem ; 35(1): 85-95, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707866

RESUMO

To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
2.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690898

RESUMO

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sítios Internos de Entrada Ribossomal/efeitos dos fármacos , Quinoxalinas/farmacologia , RNA Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Humanos , Sítios Internos de Entrada Ribossomal/genética , Conformação Molecular , Quinoxalinas/química , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
3.
Chirality ; 31(9): 700-710, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31298441

RESUMO

This study investigated the resilience of bacterial diversity in soils restored after autoclaving, in terms of richness, evenness and community structure, and its feedback on the enantioselective transformation of racemic quizalofop-ethyl (rac-QE). Microbial biomass carbon (MBC) and bacterial richness (indexed by operational taxonomic units [OTUs]) in restored soil recovered to approximately 50% and 29%, respectively, of the native soil within 43 days. Bacterial evenness was much lower in restored soil than in native soil. The relative proportions of dominant bacterial genera differed significantly (P < .05) between restored and native soils. Importantly, two major bacterial genera that recolonized restored soil were not detected in native soil. Highly enantioselective transformation of rac-QE was observed in restored soils, whereas QE enantiomers exhibited comparable transformation rates in native soils. The second-round enantioselective transformation of rac-QE was altered by the first-round transformation of enantiopure quizalofop-P-ethyl (R-P-QE) in restored and native soils through selective effects of R-P-QE on the bacterial community. The transformation rate of rac-QE was predominantly determined by bacterial abundance and richness, while the enantioselectivity was correlated more with bacterial structure.


Assuntos
Bactérias/metabolismo , Biodiversidade , Propionatos/química , Propionatos/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Microbiologia do Solo , Biotransformação , Cinética , Estereoisomerismo
4.
Acta Pharm ; 69(2): 177-196, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259731

RESUMO

Surpassing heart diseases, cancer is taking the lead as the deadliest disease because of its fast rate of spreading in all parts of the world. Tireless commitment to searching for novel therapeutic medicines is a worthwhile adventure in synthetic chemistry because of the drug resistance predicament and regular outbreak of new diseases due to abnormal cell growth and proliferation. Medicinal chemistry researchers and pharmacists have unveiled quinoxaline templates as precursors of importance and valuable intermediates in drug discovery because they have been established to possess diverse pharmacological potentials. Hence, this review highlights the current versatile routes to accessing functionalized quinoxaline motifs and harnessing their documented therapeutic potentials for anticancer drug development.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Quinoxalinas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Quinoxalinas/química , Quinoxalinas/farmacologia
5.
Eur J Med Chem ; 177: 291-301, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158745

RESUMO

Based on our previous research on the fluorinated phenylquinoxaline scaffold, in this study, different positions of N,N-dimethyl amino group, and alkyl linkers with various lengths were introduced into this scaffold to regulate their lipophilicity and binding affinity to Tau. Four novel 99mTc/Re complexes with diethyl iminodiacetate chelator were synthesized and evaluated as Tau imaging tracers in the brain of Alzheimer's disease. Their specific binding to neurofibrillary tangles was verified by in vitro fluorescence staining and further confirmed by the results of immunofluorescence staining on the same brain sections from AD patient and Tg-tau mice. From in vitro binding assay using recombinant Tau aggregates, complex 4.2 with 6-N(CH3)2 and longer carbon chain (n = 4) displayed the highest affinity (Kd = 59.95 nM). [99mTc]4.2 was achieved by the ligand exchange reaction between dicarboxylic precursor and [99mTc(CO)3(H2O)3]+ intermediate with radiochemical yield over 45%. Ex vivo biodistribution studies on normal ICR mice revealed that [99mTc]4.2 exhibited moderate initial brain uptake (0.61% ID/g) and more structure optimizations are still required to improve the blood-brain barrier permeability.


Assuntos
Doença de Alzheimer/diagnóstico , Complexos de Coordenação/química , Corantes Fluorescentes/química , Compostos de Organotecnécio/química , Quinoxalinas/química , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Quelantes/síntese química , Quelantes/química , Quelantes/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Iminoácidos/síntese química , Iminoácidos/química , Iminoácidos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/metabolismo , Fragmentos de Peptídeos/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Rênio/química , Distribuição Tecidual
6.
Molecules ; 24(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247891

RESUMO

Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases.


Assuntos
Catepsina L/antagonistas & inibidores , Fasciola hepatica/efeitos dos fármacos , Fasciola hepatica/enzimologia , Quinoxalinas/farmacologia , Animais , Sítios de Ligação , Catepsina L/química , Bovinos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Quinoxalinas/química , Espermatozoides/efeitos dos fármacos , Espermatozoides/enzimologia , Relação Estrutura-Atividade
7.
J Agric Food Chem ; 67(23): 6603-6613, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31094200

RESUMO

The excretion, metabolism, distribution, and residue depletion of olaquindox (OLA), an antibacterial and growth-promoting agent used in food-producing animals for decades without a clear understanding of metabolic fate, was completely studied in pigs, broilers, carp, and rats using a radio-tracing approach combined with liquid chromatography-ion trap/time-of-flight mass spectroscopy to define the scientific marker residue (MR). After a single gavage of [3H]OLA, over 92% of the dose was excreted via urine. OLA was transformed into eight metabolites (O1-O8) in pigs and broilers, four metabolites (O1, O2, O4, and O7) in carp, and nine metabolites (O1-O9) in rats. O2 was the major residue in edible tissues of four species and persisted for the longest time in the kidneys with the longest half-life of 3.52-4.6 d. Bisdesoxyolaquindox (O2) is designated to be the MR, and the kidneys are considered to be the target tissue for OLA in food producing animals. Monitoring for this metabolite would improve the food safety evaluation and residue control of this drug.


Assuntos
Antibacterianos/química , Carpas/metabolismo , Galinhas/metabolismo , Resíduos de Drogas/química , Quinoxalinas/química , Suínos/metabolismo , Animais , Antibacterianos/metabolismo , Biomarcadores/química , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão , Resíduos de Drogas/metabolismo , Rim/química , Rim/metabolismo , Fígado , Espectrometria de Massas , Carne/análise , Estrutura Molecular , Quinoxalinas/metabolismo , Ratos , Drogas Veterinárias/química , Drogas Veterinárias/metabolismo
8.
Molecules ; 24(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121813

RESUMO

An expedient synthesis of hitherto unexplored novel hybrid heterocycles comprising dispiropyrrolidine, N-styrylpiperidone and indeno[1,2-b]quinoxaline units has been developed via domino multicomponent 1,3-dipolar cycloaddition strategy employing a new class of azomethine ylide in ionic liquid, 1-butyl-3-methylimidazolium bromide. This domino protocol involves, 1,3-dipolar cycloaddition and concomitant enamine reaction affording the dispiropyrrolidine tethered N-styrylpiperidone hybrid heterocycles in moderate to good yield in a single step. These compounds were evaluated for their antimicrobial activity against bacterial and fungal pathogens, therein compounds 8f, 8h, and 8l displayed significant activity against tested microbial pathogens. The synergistic effect revealed that the combination of compound 8h with streptomycin and vancomycin exhibited potent synergistic activity against E. coli ATCC 25922. In addition, molecular docking simulation has also been studied for the most active compound.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antibacterianos/química , Reação de Cicloadição , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Imidazóis/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinoxalinas/química , Estreptomicina/farmacologia , Relação Estrutura-Atividade , Vancomicina/farmacologia
9.
Eur J Med Chem ; 174: 198-215, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035240

RESUMO

A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50 = 0.39 ±â€¯0.13 µM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.


Assuntos
Artrite/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Indóis/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Quinoxalinas/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Adjuvante de Freund , Índio , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Estrutura Molecular , Esclerose Múltipla/induzido quimicamente , Glicoproteína Oligodendrócito-Mielina , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/toxicidade , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/toxicidade , Ratos , Relação Estrutura-Atividade , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
10.
Macromol Rapid Commun ; 40(13): e1900120, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31021506

RESUMO

A wide-bandgap conjugated polymer, PNQx-2F2T, based on a ring-fused unit of quinoxalino[6,5-f ]quinoxaline (NQx), is synthesized for use as electron donor in polymer solar cells (PSCs). The polymer shows intense light absorption in the range from 300 to 740 nm and favorable energy levels of frontier molecular orbitals. The polymer has afforded decent device performance when blended with either fullerene-based acceptor [6,6]-phenyl-C71 -butylric acid methyl ester ([70]PCBM) or non-fullerene acceptor 3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-indanone-methyl))-5,5,11,11-tetrakis(4-n-hexylphenyl)-dithieno[2,3-d: 2',3'-d']-s-indaceno[1,2-b:5,6-b']dithiophene (IT-M). The highest PCEs of 7.9% and 7.5% have been achieved for [70]PCBM or IT-M based PSCs, respectively. Moreover, the influence of molecular weight of PNQx-2F2T on solar cell performance has been investigated. It is found that fullerene-based devices prefer higher polymer molecular weight, while non-fullerene devices are not susceptible to the molecular weight of PNQx-2F2T. The device results are extensively explained by electrical and morphological characterizations. This work not only evidences the potential of NQx for constructing high-performance photovoltaic polymers but also demonstrates a useful structure-performance relationship for efficiency enhancement of non-fullerene PSCs via the development of new conjugated polymers.


Assuntos
Fulerenos/química , Polímeros/química , Quinoxalinas/química , Energia Solar , Estrutura Molecular
11.
Ann Clin Lab Sci ; 49(2): 224-231, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028068

RESUMO

BACKGROUND: Sialic acids are a diverse family of sugar units attached to the outermost ends of sugar chains, which were demonstrated to be related to many diseases. We hypothesized sialic acids could be used as biomarkers for diagnosis of rheumatoid arthritis (RA). METHODS: The serum level of the main sialic acids, N-acetyl-D-neuraminic acid (Neu5Ac) in 163 RA patients and 50 healthy individuals were detected by pre-column derivatization-high performance liquid chromatography method. And three biomarkers to diagnose RA in clinic, C-reactive protein (CRP), rheumatoid factor (RF), and cyclic citrullinated peptides (CCP) in serum of these subjects were analyzed using enzyme-linked immunosorbent assay (ELISA). The data was analyzed using the receiver operating characteristic (ROC) curve and the Youden index. RESULTS: We found the concentration of Neu5Ac in RA group was significantly higher than healthy group. There was a positive correlation between the concentration of Neu5Ac and the RA disease activity score (DAS). The sensitivity and specificity of Neu5Ac were significantly greater than CRP, RF, CCP. CONCLUSIONS: Higher serum levels of Neu5Ac were significantly associated with the presence as well as severity of RA. Neu5Ac may be a potential biomarker for prediction and severity of RA in clinical practice.


Assuntos
Artrite Reumatoide/sangue , Ácido N-Acetilneuramínico/sangue , Adulto , Área Sob a Curva , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Fluorescência , Humanos , Masculino , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/química , Peptídeos Cíclicos/sangue , Quinoxalinas/química , Curva ROC , Fator Reumatoide/sangue , Sensibilidade e Especificidade
12.
Molecules ; 24(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934622

RESUMO

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Drogas , Quinoxalinas/química , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinoxalinas/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
13.
Eur J Med Chem ; 171: 255-264, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30925340

RESUMO

Anticancer anthracyclines are cytotoxic drugs that can induce antitumor immune response as a secondary effect through immunogenic cell death (ICD) mechanism. However, the immunogenic potency is quite limited, possibly due to that these chemotherapeutic agents are not specifically developed as ICD inducers. Thus, new drug entities through studies focusing on enhanced ICD induction would significantly promote antitumor immune response in the vaccination application. We report here a naphthyl quinoxaline thymidine conjugate as a new class of cytotoxic compounds that effectively induced in vivo antitumor activity through the vaccination application. Synthesized naphthyl quinoxaline conjugates were weak fluorescent thymidine analog yet exhibited a pronounced anticancer activity in the low nanomolar range post UVA activation. The potent activity of naphthyl conjugate was able to induce the marked detection of ICD markers including ATP and HMGB1 extracellular and calreticulin intracellularly at 2 h post UVA activation. Most importantly, mice vaccinated with cells treated with naphthyl conjugate plus UVA exhibited complete tumor growth inhibition in the tumor challenge study, and the induced immunogenic inhibition was much more effective than that of mitoxantrone anthracycline drug. All these results demonstrate the high potential of naphthyl quinoxaline conjugate for the cancer cell vaccine against tumor.


Assuntos
Antineoplásicos/farmacologia , Quinoxalinas/farmacologia , Timidina/farmacologia , Raios Ultravioleta , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Quinoxalinas/química , Relação Estrutura-Atividade , Timidina/química , Vacinação
14.
Colloids Surf B Biointerfaces ; 178: 317-328, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884347

RESUMO

Multi-targeted approaches for inhibition of сervical cancer cells in vitro were developed by implementing two different strategies and drug combination for creation of new therapeutic target agents and for nanotechnological-enhancement of intracellular delivery. New 2-benzimidazolylquinoxalines derivatives were synthesized and characterized by combining two different pharmacophores - benzimidazole and quinoxaline rings directly bonded in their structures. Spectrophotometric technique for determination of content of compounds in various media was developed to evaluate their solubility in water and micellar solutions of surfactants. The bioavailability of poorly water-soluble 2-benzimidazolylquinoxalines was improved by PEGylated liposomes as antitumor drug delivery carriers. 2-benzimidazolylquinoxalines-loaded PEGylated liposomes, with size close to 100 nm and negative zeta potential ranging from -13 mV to -27 mV, were time-stable at room temperature. The design of liposomal formulations for improving cellular uptake and in vitro antitumor efficacy was performed by modification of liposome surface with the new arginine surfactant. The cell viability of 2-benzimidazolylquinoxalines-loaded arginine liposomes on human cancer M-Hela cells was 16% at the concentration 0.15 mg/ml. Moreover, these liposomes showed a lower toxicity (40%) against normal human Gang liver cells both at the lowest and highest tested concentrations.


Assuntos
Arginina/química , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Quinoxalinas/química , Células HeLa , Humanos , Tensoativos/química
15.
Molecules ; 24(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871147

RESUMO

We have synthesized quinoxaline analogs (1⁻25), characterized by ¹H-NMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent compound among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21 and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure-activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.


Assuntos
Inibidores Enzimáticos/síntese química , Quinoxalinas/síntese química , Timidina Fosforilase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
16.
Molecules ; 24(3)2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678061

RESUMO

Despite major advancements in the development of various chemotherapeutic agents, treatment for lung cancer remains costly, ineffective, toxic to normal non-cancerous cells, and still hampered by a high level of remissions. A novel cohort of quinoxaline derivatives designed to possess a wide spectrum of biological activities was synthesized with promising targeted and selective anticancer drug activity. Hence, this study was aimed at determining in vitro anticancer activity effects of a newly synthesized class of 3-(quinoxaline-3-yl) prop-2-ynyl quinoxaline derivatives on A549 lung cancer cells. An assessment of the quinoxaline derivatives ferric reducing power, free radical scavenging activity, cytotoxic activity, and ability to induce reactive oxygen species (ROS) production was performed using the Ferric Reducing Antioxidant Power (FRAP), 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assays, respectively. The ability of the quinoxaline derivatives to induce apoptosis in A549 cells was assessed using the Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell Assay. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) displayed a dose-dependent reducing power, free-radical scavenging activity, inhibition of cell viability, and stimulation of ROS production which was accompanied by induction of apoptosis in A549 lung cancer cells. None of the quinoxaline derivatives induced cell death or ROS production in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer, and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop-2-yn-1-ol induce apoptotic cell death in A549 lung cancer cells.


Assuntos
Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quinoxalinas/farmacologia , Células A549 , Antioxidantes/síntese química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Quinoxalinas/síntese química , Quinoxalinas/química , Espécies Reativas de Oxigênio/química
17.
Eur J Med Chem ; 165: 293-308, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30685528

RESUMO

Inspired by the common structural characteristics of numerous known antitumor compounds targeting DNA or topoisomerase I, 3-(benzazol-2-yl)-quinoxaline-based scaffold was designed via the combination of two important privileged structure units -quinoxaline and benzazole. Thirty novel 3-(benzazol-2-yl)-quinoxaline derivatives were synthesized and evaluated for their biological activities. The MTT assay indicated that most compounds possessed moderate to potent antiproliferation effects against MGC-803, HepG2, A549, HeLa, T-24 and WI-38 cell lines. 3-(Benzoxazol- -2-yl)-2-(N-3-dimethylaminopropyl)aminoquinoxaline (12a) exhibited the most potent cytotoxicity, with IC50 values ranging from 1.49 to 10.99 µM against the five tested cancer and one normal cell line. Agarose-gel electrophoresis assays suggested that 12a did not interact with intact DNA, but rather it strongly inhibited topoisomerase I (Topo I) via Topo I-mediated DNA unwinding to exert its anticancer activity. The molecular modeling study indicated that 12a adopt a unique mode to interact with DNA and Topo I. Detailed biological study of 12a in MGC-803 cells revealed that 12a could arrest the cell cycle in G2 phase, inducing the generation of reactive oxygen species (ROS), the fluctuation of intracellular Ca2+, and the loss of mitochondrial membrane potential (ΔΨm). Western Blot analysis indicated that 12a-treatment could significantly up-regulate the levels of pro-apoptosis proteins Bak, Bax, and Bim, down-regulate anti-apoptosis proteins Bcl-2 and Bcl-xl, and increase levels of cyclin B1 and CDKs inhibitor p21, cytochrome c, caspase-3, caspase-9 and their activated form in MGC-803 cells in a dose-dependent manner to induce cell apoptosis via a caspase-dependent intrinsic mitochondria-mediated pathway. Studies in MGC-803 xenograft tumors models demonstrated that 12a could significantly reduce tumor growth in vivo at doses as low as 6 mg/kg with low toxicity. Its convenient preparation and potent anticancer efficacy in vivo makes the 3-(benzazol-2-yl)quinoxaline scaffold a promising new chemistry entity for the development of novel chemotherapeutic agents.


Assuntos
Antineoplásicos/química , Desenho de Drogas , Quinoxalinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Cálcio/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Xenoenxertos , Humanos , Quinoxalinas/síntese química , Quinoxalinas/química , Espécies Reativas de Oxigênio
18.
Int J Mol Sci ; 20(3)2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691132

RESUMO

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8⁻3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1⁻38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Mieloma Múltiplo/metabolismo , Compostos Organosselênicos/farmacologia , Quinoxalinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mutação , Compostos Organosselênicos/química , Fosforilação/efeitos dos fármacos , Conformação Proteica , Proteínas Proto-Oncogênicas B-raf/genética , Quinoxalinas/química , Fator de Transcrição STAT3/química , Transdução de Sinais/efeitos dos fármacos
19.
Chem Biol Drug Des ; 93(4): 617-627, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30635972

RESUMO

A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19-0.51 µM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose-dependent manner. Western blot analysis showed that compound 12 induced up-regulation of p21 and affected the expression of cell cycle-related proteins. The binding mode was also probed by molecular docking.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Quinoxalinas/química , Espécies Reativas de Oxigênio/metabolismo , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia , Regulação para Cima/efeitos dos fármacos
20.
Curr Comput Aided Drug Des ; 15(2): 182-192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30317999

RESUMO

BACKGROUND: The Quantitative structure activity relationship for thirty two novel substituted quinoxalines was performed for their antitubercular (Mycobacterium tuberculosis H37Rv) and antileptospiral (Leptospirainterrogans) activities. The quinoxalines were substituted with azetidinones, thiazolidinones and fluoroquinolones. Several compounds exhibited good activity against both the infections and they all possess fluoroquinolone moiety with the quinoxaline. METHODS: The models developed showed good linear relationship (r2 = 0.71-0.88), with an internal predictive ability (q2> 0.61) and good external predictive ability (pred_r2>0.71). The compounds were separated into a training set on which regression was performed and a test set on which the predictive ability of the model was tested. Other statistical parameters including Ro2, Ro'2, k, k' and Z- score were in the acceptable range. RESULTS AND CONCLUSION: The descriptors obtained explained the necessity of spatial orientation of atoms including branching and adjacency, presence of electronegative groups, balance between lipophilic elements and their binding strengths.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Quinoxalinas/química , Quinoxalinas/farmacologia , Desenho de Drogas , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade
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