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1.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
2.
Phys Chem Chem Phys ; 21(33): 18105-18118, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31396604

RESUMO

With the emergence of drug-resistant Plasmodium falciparum, the treatment of malaria has become a significant challenge; therefore, the development of antimalarial drugs acting on new targets is extremely urgent. In Plasmodium falciparum, type II nicotinamide adenine dinucleotide (NADH) dehydrogenase (NDH-2) is responsible for catalyzing the transfer of two electrons from NADH to flavin adenine dinucleotide (FAD), which in turn transfers the electrons to coenzyme Q (CoQ). As an entry enzyme for oxidative phosphorylation, NDH-2 has become one of the popular targets for the development of new antimalarial drugs. In this study, reliable motion trajectories of the NDH-2 complex with its co-factors (NADH and FAD) and inhibitor, RYL-552, were obtained by comparative molecular dynamics simulations. The influence of cofactor binding on the global motion of NDH-2 was explored through conformational clustering, principal component analysis and free energy landscape. The molecular interactions of NDH-2 before and after its binding with the inhibitor RYL-552 were analyzed, and the key residues and important hydrogen bonds were also determined. The results show that the association of RYL-552 results in the weakening of intramolecular hydrogen bonds and large allosterism of NDH-2. There was a significant positive correlation between the angular change of the key pocket residues in the NADH-FAD-pockets that represents the global functional motion and the change in distance between NADH-C4 and FAD-N5 that represents the electron transfer efficiency. Finally, the possible non-competitive inhibitory mechanism of RYL-552 was proposed. Specifically, the association of inhibitors with NDH-2 significantly affects the global motion mode of NDH-2, leading to widening of the distance between NADH and FAD through cooperative motion induction; this reduces the electron transfer efficiency of the mitochondrial respiratory chain. The simulation results provide useful theoretical guidance for subsequent antimalarial drug design based on the NDH-2 structure and the respiratory chain electron transfer mechanism.


Assuntos
Antimaláricos/química , Cetonas/química , NADH Desidrogenase/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Quinolinas/química , Transporte de Elétrons , Flavina-Adenina Dinucleotídeo/química , Ligações de Hidrogênio , Modelos Moleculares , Estrutura Molecular , NAD/química , NADH Desidrogenase/química , Oxirredução , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica
3.
Phys Chem Chem Phys ; 21(28): 15779-15786, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282523

RESUMO

Small-molecule fluorescent probes having optimized optical properties, such as high photostability and brightness, local microenvironment sensitivity and specific subcellular localizations, are increasingly available. Although the basis for designing efficient fluorophores for bioimaging applications is well established, implementing an improvement in a given photophysical characteristic always tends to compromise another optical property. This problem has enormous consequences for in vivo imaging, where ensuring a specific localization and precise control of the probe response is challenging. Herein we discuss a fluorescent probe, CC334, as a case study of the chromenylium-cyanine family that commonly exhibits highly complex photophysical schemes and highly interfered bioanalytical responses. By an exhaustive and concise analysis of the CC334 optical responses including detailed spectroscopic calibrations, steady-state microenvironment effects, ultrafast photophysics analysis and computational studies, we elucidate a new strategy to apply the probe in the singlet oxygen reactive oxygen species (1O2-ROS) monitoring using in vitro and in vivo models. The probe provides a new avenue for designing fluorescent probes to understand the dynamic behavior of subcellular environments.


Assuntos
Benzopiranos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Cobalto/química , Ferrocianetos/química , Quinolinas/química , Espécies Reativas de Oxigênio/química , Análise Espectral
4.
J Agric Food Chem ; 67(31): 8581-8589, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31321975

RESUMO

Intermediates in aromatic amino acid biosynthesis can serve as substrates for the synthesis of bioactive compounds. In this study we used two intermediates in the shikimate pathway of Escherichia coli, chorismate and anthranilate, to synthesize three bioactive compounds: 4-hydroxycoumarin (4-HC), 2,4-dihydroxyquinoline (DHQ), and 4-hydroxy-1-methyl-2(1H)-quinolone (NMQ). We introduced genes for the synthesis of salicylic acid from chorismate to supply the substrate for 4-HC and the gene encoding N-methyltransferase for the synthesis of N-methylanthranilate from anthranilate. Polyketide synthases and coenzyme (Co)A ligases were tested to determine the optimal combination of genes for the synthesis of each compound. We also tested several constructs and identified the best one for increasing levels of endogenous substrates for chorismate, anthranilate, and malonyl-CoA. With the use of these strategies, 255.4 mg/L 4-HC, 753.7 mg/L DHQ, and 17.5 mg/L NMQ were synthesized. This work provides a basis for the synthesis of diverse coumarin and quinoline derivatives with potential medical applications.


Assuntos
4-Hidroxicumarinas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Metabólica , Policetídeo Sintases/genética , Quinolinas/metabolismo , 4-Hidroxicumarinas/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ácido Corísmico/metabolismo , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Photorhabdus/enzimologia , Photorhabdus/genética , Policetídeo Sintases/metabolismo , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/genética , Quinolinas/química , ortoaminobenzoatos/metabolismo
5.
Water Sci Technol ; 79(11): 2086-2094, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31318346

RESUMO

Activated carbon made from agricultural waste (walnut shells) was investigated as a suitable adsorbent for effectively removing quinoline from industrial wastewater. The activated carbon was treated with phosphoric acid and oxidized by ammonium persulfate and its ability to adsorb pyridine and quinoline in aqueous solution was investigated. Kinetic parameters for the adsorption process were determined through pseudo-first-order and pseudo-second-order kinetic models and intraparticle diffusion models. Equilibrium experiments and adsorption isotherms were analyzed using Langmuir and Freundlich adsorption isotherms. After reaching equilibrium, the activated carbon adsorbed quinoline in preference to pyridine: the equilibrium adsorptions from individual aqueous solutions (200 µL L-1) of quinoline and pyridine were 166.907 mg g-1 and 72.165 mg g-1, respectively. Thermodynamic studies of quinoline adsorption were conducted at different temperatures and indicated that quinoline adsorption was an endothermic and spontaneous process. The column-adsorption of quinoline and pyridine was consistent with the Thomas model and the Yoon-Nelson model. The removal efficiency of quinoline reached more than 97% for a velocity of 6 mL min-1 at the initial adsorption stage.


Assuntos
Quinolinas/química , Poluentes Químicos da Água/química , Adsorção , Sulfato de Amônio/química , Carvão Vegetal , Concentração de Íons de Hidrogênio , Juglans/química , Cinética , Modelos Químicos , Quinolinas/análise , Soluções , Termodinâmica , Poluentes Químicos da Água/análise
6.
Eur J Med Chem ; 177: 338-349, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158748

RESUMO

A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.


Assuntos
Antineoplásicos/farmacologia , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estirenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Heme Oxigenase-1/metabolismo , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/química , Estirenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo
7.
Eur J Med Chem ; 178: 154-167, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181480

RESUMO

A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 µM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 µM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Enzyme Inhib Med Chem ; 34(1): 955-972, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072147

RESUMO

In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 µM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.


Assuntos
Antineoplásicos/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Tiadiazóis/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , MAP Quinase Quinase 1/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/química , Triterpenos/química
9.
Eur J Med Chem ; 175: 349-356, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096155

RESUMO

Twelve 2,3-dihydro-[1,4]-dioxino[2,3-f]quinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC50) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC50 = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC50 = 1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d. Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinolinas/química , Quinolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Ureia/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Eur J Med Chem ; 175: 20-33, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071547

RESUMO

In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.


Assuntos
Acridinas/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Espermina/química , Espermina/farmacologia , Telomerase/antagonistas & inibidores , Fenômenos Biofísicos , Dicroísmo Circular , Quadruplex G , Humanos , Espectrometria de Fluorescência , Telômero
11.
Eur J Med Chem ; 175: 201-214, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078867

RESUMO

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus, while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride, while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida de Alta Pressão , Desenho de Drogas , Fungos/classificação , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Quinolinas/síntese química , Relação Estrutura-Atividade
12.
Molecules ; 24(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083287

RESUMO

The role of glycerol as a green bio-based solvent, reactant, and/or a catalyst in the synthesis of novel heterocycles, under pressure, is studied. Synthesis of novel quinolines in good yields using a new modified Skraup synthesis, utilizing glycerol and pressure Q-tubes, is demonstrated. Novel aniline trimers are prepared using glycerol, and substituted anilines under pressure, in acidic medium and water. Glycerol was employed as a catalyst and a green solvent in the synthesis of novel pyridazines 13a-c. The mechanisms of the reactions and the catalytic effect of glycerol in protic and aprotic media are fully discussed. The structures of the synthesized compounds were determined via X-ray crystallography and spectroscopic methods.


Assuntos
Compostos de Anilina/química , Glicerol/química , Catálise , Química Verde/métodos , Estrutura Molecular , Quinolinas/química
13.
Eur J Med Chem ; 171: 434-461, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928713

RESUMO

γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled receptors. Each class of GABA receptor has distinct pharmacology and physiology. GABAA receptors are heteropentameric transmembrane protein complexes made up of α1-6, ß1-3, γ1-3, δ, ε, θ, π subunits, giving rise to numerous allosteric binding sites and have thus attracted much attention targets for the treatment of conditions such as epilepsy, anxiety and sleep disorders. The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.


Assuntos
Moduladores GABAérgicos/farmacologia , Receptores de GABA/metabolismo , Sítio Alostérico/efeitos dos fármacos , Carbolinas/química , Carbolinas/farmacologia , Etomidato/química , Etomidato/farmacologia , Moduladores GABAérgicos/química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Ligantes , Estrutura Molecular , Propofol/química , Propofol/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Esteroides/química , Esteroides/farmacologia
14.
Dalton Trans ; 48(20): 6685-6689, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30997474

RESUMO

Bifunctional Lewis acidic group 15 compounds have emerged as appealing platforms for anion sensing and organocatalysis. As part of our interest in the chemistry of these compounds, we have now compared the catalytic properties of [o-(MePPh2)C6H4SbPh2]+ ([3]+), [o-(PPh2)C6H4SbPh3]+ ([4]+), [o-(MePPh2)C6H4SbPh3]2+ ([5]2+), and [o-C6H4(SbMePh2)2]2+ ([6]2+) using the transfer hydrogenation of 2-phenyl-quinoline and 3-bromoquinoline with a Hantzsch ester benchmark reactions. This study, which also involved an evaluation of the catalytic properties of [Ph4Sb]+ and [Ph3MeP]+, shows that antimony cations are generally more active than their phosphorus counterparts and neutral stiboranes. Our results also demonstrate that dicationic systems such as [6]2+ are superior activators.


Assuntos
Antimônio/química , Derivados de Benzeno/química , Ácidos de Lewis/química , Compostos Organometálicos/química , Compostos Organofosforados/química , Quinolinas/química , Boratos/química , Catálise , Cátions , Hidrogenação , Estrutura Molecular , Fosfinas/química , Estereoisomerismo , Relação Estrutura-Atividade
15.
Chem Pharm Bull (Tokyo) ; 67(4): 382-388, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930442

RESUMO

As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial. In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results. Alpha linked immunosorbent assay (LISA) methylation assay was performed to test their inhibitory activity against PRMT5. The in vitro enzymatic assay results indicated that four compounds (2, 4, 10 and 37) showed PRMT5 inhibitory activity, while 4 and 10 displayed the most potent activity with IC50 values of 8.1 ± 1.1 and 6.5 ± 0.6 µM, respectively. The inhibitory activity results of 20 extra analogs of 4 further confirmed the potency of this scaffold. As expected, compounds 4 and 10 exhibited moderate anti-proliferative activity against mantle cell lymphoma Jeko-1 and leukemia cell MV4-11. Besides, Western blot assay results showed that 4 could reduce the H4R3me2s level in a dose-dependent manner, indicating that it could inhibit the activity of PRMT5 in cellular context. Detailed interactions between 4 and PRMT5 were characterized by binding mode analysis through molecular docking. The compounds discovered in this study will inspire medicinal chemists to further explore this series of PRMT5 inhibitors.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Quinolinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Proteína-Arginina N-Metiltransferases/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirróis/metabolismo , Pirróis/farmacologia , Quinolinas/metabolismo , Quinolinas/farmacologia , Relação Estrutura-Atividade
16.
Anal Bioanal Chem ; 411(15): 3353-3360, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957206

RESUMO

Lamotrigine is one of the most widely used antiepileptic drugs in the treatment of epilepsy. This kind of drug needs to be used in the long term and should be quantitatively detected in the blood of patients to avoid drug toxicity caused by individual differences and environmental and pathological changes in the process of taking. The detection of antiepileptic drugs in human blood is challenging because of their low contents and the interference of complex matrices. Thus, the sample enrichment method has been commonly used to improve the sensitivity of detection. In this work, we have synthesized a new "bi-(4-vinyl phenylquinoline) amide" compound and used it as the monomer to produce the hyper-cross-linked microporous polymer for the enrichment of lamotrigine. This material has a high adsorption capacity, specificity, and linearity, which can improve the detection sensitivity of lamotrigine by high-performance liquid chromatography (HPLC). The mechanism of this phenomenon has also been investigated. Finally, we have developed the microporous polymer enrichment coupled with HPLC method for the quantitative determination of lamotrigine in rat and human serum samples. This method has excellent precision, accuracy, and recovery, meeting the test of biological sample. The low limit of quantitation was 0.625 µg/mL. Graphical abstract.


Assuntos
Anticonvulsivantes/sangue , Monitoramento de Medicamentos/métodos , Lamotrigina/sangue , Polivinil/química , Quinolinas/química , Microextração em Fase Sólida/métodos , Adsorção , Amidas/química , Animais , Anticonvulsivantes/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Lamotrigina/isolamento & purificação , Limite de Detecção , Masculino , Porosidade , Ratos , Ratos Sprague-Dawley
17.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986908

RESUMO

The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-N-arylhydrazine-1-carbothioamide (5a-b) intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound 6i) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC50 activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of 6i was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolinas/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Oxidiazóis/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Triazóis/uso terapêutico
18.
Biomed Pharmacother ; 112: 108707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970513

RESUMO

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 µM), tryphan blue (15.6 µM) and LDH (14.2 µM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Cumarínicos/síntese química , Quinolinas/química , Tiazóis/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Simulação por Computador , Cumarínicos/química , Cumarínicos/uso terapêutico , Cumarínicos/toxicidade , Dose Letal Mediana , Camundongos , Relação Estrutura-Atividade
19.
Chem Biodivers ; 16(6): e1900056, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957398

RESUMO

In this article, three series of dihydrotriazine derivatives bearing a quinoline moiety (5a, 5b, 8a-8c, and 9a-9m) have been designed, synthesized, and evaluated as antibacterial agents. Compounds 8a-8c were found to be the most potent of all of the compounds tested with an MIC value of 1 µg/mL against several Gram-positive (S. aureus 4220 and MRSA CCARM 3506) and Gram-negative (E. coli 1924) strains of bacteria. In addition, 3-[4-amino-6-(phenethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-[(3-chlorobenzyl)oxy]quinolin-2-ol (8a) showed potent inhibitory activity (MIC=2 µg/mL) against Pseudomonas aeruginosa 2742, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. Structure-activity relationships (SAR) analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency of the quinoline compounds. In vitro enzyme study implied that compound 8a also displayed DHFR inhibition.


Assuntos
Anti-Infecciosos/síntese química , Quinolinas/química , Triazinas/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Quinolinas/metabolismo , Quinolinas/farmacologia , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismo
20.
Yakugaku Zasshi ; 139(4): 581-589, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930393

RESUMO

In this review, we focus on our recent work on the development of novel helical foldamers based on the cis conformational properties of aromatic amide bonds. First, we describe the conformational properties of N-alkylated pyrroleamides and their oligomers. The conformation of the amide bond on the pyrrole ring is altered by N-alkylation, and the ratio of the cis conformer is lower in N-methylated amides with an N-pyrrole ring compared with that in N-methylbenzanilide. Pyrrole-containing oligomers, in which benzene and pyrrole rings are linked alternately by amide bonds with chiral N-substituents, show significant CD signals that depend on the chain length, temperature, and solvent properties, indicating that the oligoamides take folded conformations in solvents. Second, we describe the design and synthesis of alternately N-alkylated aromatic oligoamides as novel helical oligoamides with larger cavities compared with those of poly(N-alkylated p-benzamides). Spectroscopic studies and calculated optimized structures indicate that these oligoamides adopt helical structures with a cavity of about 9 Å in diameter. Finally, we describe the synthesis of a series of strained aromatic oligoamide macrocycles based on the cis conformational preference of the aromatic N-alkylated amide bond, building on the work of Huc et al. on the construction of large macrocycles by cyclization of helical quinoline oligoamides. The crystal structures are also presented. Our findings demonstrate that N-alkylated amides with the cis conformation are useful building blocks for unique aromatic foldamers.


Assuntos
Amidas/química , Compostos Heterocíclicos/química , Substâncias Macromoleculares/química , Conformação Molecular , Cristalização , Ciclização , Fenômenos de Química Orgânica , Pirróis/química , Quinolinas/química
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