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1.
Biomed Res Int ; 2020: 5324560, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029513

RESUMO

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.


Assuntos
Alcaloides/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Cryptolepis/química , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/antagonistas & inibidores , Alcaloides/química , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/enzimologia , Simulação por Computador , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Avaliação Pré-Clínica de Medicamentos , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Relação Quantitativa Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores
2.
Int J Nanomedicine ; 15: 5433-5443, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801698

RESUMO

Background: Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy. Methods: TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake. Results: The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer. Conclusion: In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.


Assuntos
Dendrímeros/química , Nanocápsulas/administração & dosagem , Nylons/química , Quinolinas/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Dendrímeros/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Fluoresceína-5-Isotiocianato , Humanos , Terapia de Alvo Molecular/métodos , Nanocápsulas/química , Poliaminas/química , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/química , Trastuzumab/farmacocinética
3.
Food Chem ; 331: 127264, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32619906

RESUMO

This work aimed to develop a method permitting an informed choice of antioxidants to reduce carcinogenic heterocyclic aromatic amine (HAA) formation during proteinaceous food cooking. Therefore, a three-step approach was developed. First, the most promising antioxidants were selected using molecular modeling approaches. For this, analog design was used to highlight the most suitable antioxidants based on their diversification potential using bioisosteric replacement. Then, structure activity relationship studies allowed drawing the relevant properties for inhibiting HAA formation and explained partly the inhibitory activity. Secondly, the approved antioxidants were tested in ground beef patties to assess their inhibitory properties against HAA formation. Resveratrol was found to be the most efficient as it totally inhibited MeIQ and reduced MeIQx and PhIP formation by 40 and 70%, respectively. Finally, natural ingredients rich in these antioxidants were evaluated. Oregano was found to totally inhibit MeIQ formation and to reduce by half MeIQx and PhIP formation.


Assuntos
Antioxidantes/química , Culinária/métodos , Compostos Heterocíclicos/química , Carne Vermelha , Relação Estrutura-Atividade , Aminas/química , Animais , Bovinos , Modelos Moleculares , Origanum/química , Extratos Vegetais , Quinolinas/química , Quinoxalinas/química , Resveratrol/química , Chá , Vinho
4.
Rev Soc Bras Med Trop ; 53: e20200091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578713

RESUMO

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Quinolinas/química
5.
Exp Parasitol ; 215: 107933, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525006

RESUMO

Schistosomiasis is still a public health problem. Praziquantel is the only drug available for treatment of all forms of human schistosomiasis. Although praziquantel is an effective drug against all species of human schistosomes, concerns about resistance have been raised, especially in endemic areas. A hybrid compound containing several pharmacophore within a single molecule is a promising strategy. Here, we described the anti-schistosomal effect of 4-(2-Chloroquinolin-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carbonitrile (PPQ-6), a hybrid drug based on quinoline and pyridine. PPQ-6 was given as two regimens (20 or 40 mg/kg). In both regimens, PPQ-6 significantly reduced liver and spleen indices, nitric oxide production, tissue egg load, hepatic granuloma size and count, immature eggs and total worm burden especially females. Our findings suggested that PPQ-6 is a promising anti-schistosomal agent; however more research is needed to elucidate its mechanism of action and report its activity on juvenile schistosomes and other species of human schistosomes.


Assuntos
Piridinas/farmacologia , Quinolinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Feminino , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Óxido Nítrico/análise , Piridinas/química , Piridinas/uso terapêutico , Quinolinas/química , Quinolinas/uso terapêutico , Distribuição Aleatória , Esquistossomicidas/química , Esquistossomicidas/uso terapêutico , Fatores Sexuais , Baço/parasitologia , Baço/patologia
6.
PLoS One ; 15(5): e0233893, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470030

RESUMO

BACKGROUND: A considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established. METHODS: Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at ≥24hr post dose in children, pregnant women and non-pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R2) and visual check. RESULTS: An LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C18 column (50x2.0mm, 5µm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI+ as the ion source. This method had a calibration range of 10-1000 ng/mL and carryover was negligible. Correlation analysis revealed a linear relationship: Ccap = 1.04×Cven+4.20 (R2 = 0.832) without transformation of data, and lnCcap = 1.01×lnCven+0.0125, (R2 = 0.945) with natural logarithm transformation. The mean ratio (±SD) of Ccap/Cven was 1.13±0.42, and median (IQR) was 1.08 (0.917, 1.33). CONCLUSIONS: Capillary and venous plasma PQ measures are nearly identical overall, but not readily exchangeable due to large variation. Further correlation study accounting for disposition phases may be necessary.


Assuntos
Capilares/química , Quinolinas/sangue , Veias/química , Adulto , Criança , Feminino , Humanos , Modelos Lineares , Gravidez , Quinolinas/química
7.
Food Chem ; 324: 126898, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32361096

RESUMO

Reactions involving reactive carbonyls, creatinine, and ammonia-producing compounds were investigated in order to clarify the formation of the heterocyclic aromatic amine (HAA) 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ). Obtained results showed that MeIQ was only produced when 2-butenal (crotonaldehyde) was present. Reaction yields depended on the pH, with a maximum around pH 6.5, and on concentrations of crotonaldehyde and creatinine. Ammonia was also required for MeIQ formation, but ammonia was produced by creatinine decomposition. The amount of MeIQ formed increased with reaction time, temperature, and oxygen content in the reaction atmosphere. Activation energy for MeIQ formation from crotonaldehyde, creatinine, and glutamine was 72.2 ± 0.4 kJ·mol-1. A reaction pathway that explains MeIQ formation is proposed. Obtained results suggest a main role of reactive carbonyls formed in foods (the food carbonylome) on HAA formation. In addition, they provide scientific basis for the understanding of how HAAs are formed and could be mitigated.


Assuntos
Aldeídos/química , Creatinina/química , Quinolinas/química , Amônia/química , Cromatografia Líquida de Alta Pressão , Compostos Heterocíclicos/química , Concentração de Íons de Hidrogênio , Oxigênio/química , Quinolinas/análise , Espectrometria de Massas em Tandem , Temperatura
8.
Cancer Sci ; 111(5): 1774-1784, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112605

RESUMO

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival and invasion. Aberrant STAT3 has been demonstrated in various malignant cancers. YHO-1701 is a novel quinolinecarboxamide derivative generated from STX-0119. Here, we examined the effect of YHO-1701 on STAT3 and evaluated antitumor activity of YHO-1701 as a single agent and in combination. YHO-1701 inhibited STAT3-SH2 binding to phospho-Tyr peptide selectively and more potently than STX-0119 in biochemical assays. Molecular docking studies with STAT3 suggested more stable interaction of YHO-1701 with the SH2 domain. YHO-1701 exhibited approximately 10-fold stronger activity than STX-0119 in abrogating the STAT3 signaling pathway of human oral cancer cell line SAS. YHO-1701 also blocked multi-step events by inhibiting STAT3 dimerization and suppressed STAT3 promoter activity. As expected, YHO-1701 exerted strong antiproliferative activity against human cancer cell lines addicted to STAT3 signaling. Orally administered YHO-1701 showed statistically significant antitumor effects with long exposure to high levels of YHO-1701 at tumor sites in SAS xenograft models. Moreover, combination regimen with sorafenib led to significantly stronger antitumor activity. In addition, the suppression level of survivin (a downstream target) was superior for the combination as compared with monotherapy groups within tumor tissues. Thus, YHO-1701 had a favorable specificity for STAT3 and pharmacokinetics after oral treatment; it also contributed to the enhanced antitumor activity of sorafenib. The evidence presented here provides justification using for this approach in future clinical settings.


Assuntos
Antineoplásicos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Interleucina-6/sangue , Camundongos , Simulação de Acoplamento Molecular , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Multimerização Proteica/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Domínios de Homologia de src
9.
Ecotoxicol Environ Saf ; 192: 110328, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078840

RESUMO

In this study pillar[5]arene (P5) and a quinoline-functionalized pillar[5]arene (P5-6Q) which is used for detecting radioactive element, gas adsorption and toxic ions were synthesized. These materials were characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FTIR), elemental analysis, melting point, Mass Spectroscopy, Scanning Electron Microscopy (SEM) and Zeta Potential. The cytotoxic and genotoxic potential of P5 and P5-6Q at distinct concentrations of 12.5, 25, 50, and 100 µg/mL were also investigated by Allium ana-telophase and comet assays on Allium cepa roots and Drosophila melanogaster haemocytes. P5 and P5-6Q showed dose dependent cytotoxic effect by decreasing mitotic index (MI) and genotoxic effect by increasing chromosomal aberrations (CAs such as disturbed anaphase-telophase, polyploidy, stickiness, chromosome laggards and bridges) and DNA damage at the exposed concentrations. These changes in P5-6Q were lower than P5. Further research is necessary to clarify the cytotoxic and genotoxic action mechanisms of P5 and P5-6Q at molecular levels.


Assuntos
Calixarenos/toxicidade , Dano ao DNA , Drosophila melanogaster/efeitos dos fármacos , Cebolas/efeitos dos fármacos , Anáfase/efeitos dos fármacos , Animais , Calixarenos/química , Aberrações Cromossômicas , Ensaio Cometa , Citotoxinas/química , Citotoxinas/toxicidade , Drosophila melanogaster/genética , Hemócitos/efeitos dos fármacos , Índice Mitótico , Cebolas/genética , Raízes de Plantas/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Telófase/efeitos dos fármacos
10.
Top Curr Chem (Cham) ; 378(2): 22, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030596

RESUMO

Heterocyclic compounds having a nitrogen atom in the ring exhibit very interesting biological activities. Indole is the core structure of many bioactive compounds owing to its high affinity to bind with most biological targets. Indole is an electron-rich compound and generally prefers electrophilic rather than nucleophilic substitution. Hence, many important indole derivatives are difficult to synthesize through the conventional reactivity of indole. This limitation can be avoided by using the umpolung, from the German word meaning polarity inversion. In umpolung, the indole molecule, especially the C2 and C3 positions, behave as an electrophile. As C2-functionalized indoles have substantial importance in synthetic and pharmaceutical chemistry, this review focuses on the C2 umpolung of indoles via the indirect approach which is less explored. Unlike direct approaches of indole umpolung, indirect methods have several advantages and therefore a number of research articles have been published in this field. But no review is available up till now. This is the first review on this topic and we believe that it will surely motivate the readers to work in this area further.


Assuntos
Carbono/química , Indóis/química , Alcaloides/síntese química , Alcaloides/química , Catálise , Ciclização , Iodo/química , Quinolinas/síntese química , Quinolinas/química , Ácidos Sulfínicos/química
11.
J Fluoresc ; 30(2): 347-356, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32040795

RESUMO

A novel fluorescence chemosensor XYQ for detecting Zn(II) was synthesized. XYQ showed fluorescence turn-on to Zn(II) with high sensitivity and selectivity in aqueous media among 19 metal ions. Its binding structure was demonstrated by ESI-MS, Job plot, and 1H NMR titration. The detection limit of XYQ to Zn(II) was 0.53 µM. It is much below WHO drinking water standard (76.0 µM). XYQ could be applied successfully to the test kit and real samples. The fluorescence turn-on process was possibly explained as a chelation-enhanced fluorescence (CHEF) effect with theoretical calculations.


Assuntos
Corantes Fluorescentes/química , Quinolinas/química , Zinco/análise , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Íons/análise , Estrutura Molecular , Quinolinas/síntese química , Espectrometria de Fluorescência
12.
Artigo em Inglês | MEDLINE | ID: mdl-32053035

RESUMO

Quinoline Yellow (QY, Colour Index No. 47005) is internationally used as a colour additive in foods, drugs, and cosmetics. The manufacture of QY requires sulphonating quinophthalone, and depending on the degree of sulphonation, various forms of QY result, containing different proportions of quinophthalone mono-, di-, and trisulfonic acid sodium salts (monoSA, diSA, and triSA, respectively). Regulations on the specific composition and uses of QY differ across countries with associated differences in names for QY. The QY form certified for use in the U.S. in drugs and cosmetics is known as D&C Yellow No. 10 (Y10). The Code of Federal Regulations (CFR) specifies that Y10 and its lakes consist of predominantly monoSA's, the sum of whose levels is ≥ 75%, and that the sum level of diSA's is ≤ 15%, with one of them (6'8'diSA) at ≤ 3%. The present work reports the development of an HPLC method for determining those CFR-specified values and the level of a non-CFR-specified component, 6'8'5triSA. The selected analytes, 6'SA, 6'5diSA, 6'8'diSA, and 6'8'5triSA, were quantified by using five-point-calibration curves (R2 > 0.999) with data-point ranges of 9.96-96.53%, 0.54-21.69%, 0.10-5.00%, and 0.11-5.53% by weight, respectively. The method was found to be precise (relative standard deviation values, 0.55-0.80%) and accurate (recovery values, 91.07-99.45%). LOD and LOQ values, respectively, were as follows: 1.23 and 3.70%, 6'SA; 0.42 and 1.26%, 6'5diSA; 0.11 and 0.34%, 6'8'diSA; and 0.01 and 0.04%, 6'8'5triSA. The HPLC method was applied successfully to the analysis of 20 Y10 and eight Y10 lake samples. It can be extended to other QY forms such as E104 and Yellow 203 because it enables analysis of 6'8'5triSA. This paper also addresses the implications of the varying structure depictions and CAS numbers of the QY components that are due to the existence of three tautomeric forms of quinophthalone.


Assuntos
Corantes/análise , Análise de Alimentos , Contaminação de Alimentos/análise , Indenos/análise , Quinolinas/análise , Quinolinas/química , Cromatografia Líquida de Alta Pressão
13.
Chem Commun (Camb) ; 56(12): 1859-1862, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31950954

RESUMO

We present the design and synthesis of water-soluble quinoline-indole-based derivatives (IM-1, IM-2, and IM-3) with three-photon absorption activity. IM-3 can specifically target DNA and RNA accompanied by an obvious three-photon fluorescence enhancement in the second near-infrared window (1000-1700 nm). The in vitro experiments demonstrate that IM-3 can simultaneously stain mitochondria and the nucleolus both in living and fixed cells. The organelle-specific targeting behaviour is successfully visualized under stimulated emission depletion (STED) nanoscopy.


Assuntos
DNA Mitocondrial/análise , Corantes Fluorescentes/química , Indóis/química , Fótons , Quinolinas/química , RNA Neoplásico/análise , Nucléolo Celular/química , Células Hep G2 , Humanos , Estrutura Molecular , Imagem Óptica , Solubilidade , Água/química
14.
J Enzyme Inhib Med Chem ; 35(1): 584-597, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31992093

RESUMO

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to 1.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Quinolinas/síntese química , Quinolinas/química , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
15.
J Enzyme Inhib Med Chem ; 35(1): 432-459, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899980

RESUMO

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Desenho de Fármacos , Quinolinas/química , Quinolinas/farmacologia , Antiprotozoários/síntese química , Células Hep G2 , Humanos , Leishmania donovani/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-31915110

RESUMO

A novel, precise, accurate and rapid HPLC-UV method was developed, optimised and fully validated for simultaneous estimation of pitavastatin (PIT) and candesartan (CAN) in rat plasma using telmisartan as an internal standard. Following liquid-liquid extraction of the analytes from plasma, chromatographic separation was accomplished on a Waters Reliant C18 column (4.6 × 250 mm, 5 µm) using ACN-5 mM Sodium acetate buffer (80:20, v/v; pH adjusted to 3.5 with acetic acid) as mobile phase at a flow rate of 0.8 mL/min and wavelength of 234 nm. The calibration curves were linear over the concentration ranges of 2-400 ng/mL and 3-400 ng/mL for pitavastatin and candesartan respectively. The method when validated as per US-FDA guidelines was found to be precise as well as accurate. Extraction recovery observed for both analytes was above 90% as well as reproducible and consistent. Stability studies showed the samples to be stable over a long period covering from sample collection to final analysis. The method was successfully applied to investigate pharmacokinetic interaction between PIT and CAN in wistar rats. The mean plasma concentration-time curves of PIT and CAN showed that single PIT as well as CAN show similar pharmacokinetic properties to those obtained when co-administrated with each other (P value >0.05). Hence, there is no evidence for a potential drug-drug interaction between PIT and CAN. This information provides evidence for clinical rational use of CAN and PIT in cardiovascular patients.


Assuntos
Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Quinolinas/sangue , Quinolinas/farmacocinética , Tetrazóis/sangue , Tetrazóis/farmacocinética , Animais , Benzimidazóis/química , Interações Medicamentosas , Modelos Lineares , Quinolinas/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , Tetrazóis/química
17.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936488

RESUMO

Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.


Assuntos
Antineoplásicos/química , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Quinolinas/química , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/ultraestrutura , Interface Usuário-Computador
18.
Molecules ; 25(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947824

RESUMO

Herein, we design and synthesize an array of benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-c]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.


Assuntos
Antineoplásicos , Desenho de Fármacos , Leucemia , Quinolinas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia
19.
Org Biomol Chem ; 18(6): 1214-1220, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31996880

RESUMO

Boric acid promoted transfer hydrogenation of substituted quinolines to synthetically versatile 1,2,3,4-tetrahydroquinolines (1,2,3,4-THQs) was described under mild reaction conditions using a Hantzsch ester as a mild organic hydrogen source. This methodology is practical and efficient, where isolated yields are excellent and reducible functional groups are well tolerated in the N-heteroarene moiety. The reaction parameters and tentative mechanistic pathways are demonstrated by various control experiments and NMR studies. The present work can also be scaled up to obtain gram quantities and the utility of the developed process is illustrated by the transformation of 1,2,3,4-THQs into a series of biologically important molecules including the antiarrhythmic drug nicainoprol.


Assuntos
Ácidos Bóricos/química , Quinolinas/química , Catálise , Estrutura Molecular , Oxirredução , Quinolinas/síntese química , Estereoisomerismo
20.
Eur J Med Chem ; 188: 111983, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911292

RESUMO

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Descoberta de Drogas , Malária/tratamento farmacológico , Paclitaxel/farmacologia , Quinolinas/farmacologia , Animais , Antimaláricos/química , Artemisininas/química , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Estrutura Molecular , Paclitaxel/química , Quinolinas/química
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