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1.
Eur J Med Chem ; 194: 112255, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32244098

RESUMO

Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.


Assuntos
4-Quinolonas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonucleosídeos/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-Atividade
2.
Curr Top Med Chem ; 20(3): 244-255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995008

RESUMO

4-Oxoquinoline derivatives constitute an important family of biologically important substances, associated with different bioactivities, which can be synthesized by different synthetic methods, allowing the design and preparation of libraries of substances with specific structural variations capable of modulating their pharmacological action. Over the last years, these substances have been extensively explored by the scientific community in efforts to develop new biologically active agents, with greater efficiency for the treatment of a variety of diseases. Viral infections have been one of the targets of these studies, although to a lesser extent than other diseases such as cancer and bacterial infections. Nevertheless, the literature provides examples that corroborate with the fact that these substances may act on different pharmacological targets in different viral pathogens. This review provides a compilation of some of the major studies published in recent years showing the discovery and/or development of new antiviral oxoquinoline agents, highlighting, whenever possible, their mechanisms of action.


Assuntos
4-Quinolonas/farmacologia , Antivirais/farmacologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , Antivirais/síntese química , Antivirais/química , Desenvolvimento de Medicamentos , Humanos , Estrutura Molecular
3.
Photochem Photobiol Sci ; 18(8): 1910-1922, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328761

RESUMO

New porphyrin/4-oxoquinoline conjugates were synthesized from the Heck coupling reaction of a ß-brominated porphyrin with 1-allyl-4-oxoquinoline derivatives, followed by demetallation and deprotection affording the promising photosensitizers 9a-e. Singlet oxygen studies have demonstrated that all the porphyrin/4-oxoquinoline conjugates 9a-e were capable of producing cytotoxic species and found to be excellent photosensitizing agents in the inactivation of S. aureus by the antimicrobial photodynamic therapy (aPDT) protocol.


Assuntos
4-Quinolonas/farmacologia , Antibacterianos/farmacologia , Fotoquimioterapia , Porfirinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , 4-Quinolonas/química , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Porfirinas/química
4.
Microbiome ; 7(1): 93, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208456

RESUMO

BACKGROUND: Marine bacteria form complex relationships with eukaryotic hosts, from obligate symbioses to pathogenic interactions. These interactions can be tightly regulated by bioactive molecules, creating a complex system of chemical interactions through which these species chemically communicate thereby directly altering the host's physiology and community composition. Quorum sensing (QS) signals were first described in a marine bacterium four decades ago, and since then, we have come to discover that QS mediates processes within the marine carbon cycle, affects the health of coral reef ecosystems, and shapes microbial diversity and bacteria-eukaryotic host relationships. Yet, only recently have alkylquinolone signals been recognized for their role in cell-to-cell communication and the orchestration of virulence in biomedically relevant pathogens. The alkylquinolone, 2-heptyl-4-quinolone (HHQ), was recently found to arrest cell growth without inducing cell mortality in selected phytoplankton species at nanomolar concentrations, suggesting QS molecules like HHQ can influence algal physiology, playing pivotal roles in structuring larger ecological frameworks. RESULTS: To understand how natural communities of phytoplankton and bacteria respond to HHQ, field-based incubation experiments with ecologically relevant concentrations of HHQ were conducted over the course of a stimulated phytoplankton bloom. Bulk flow cytometry measurements indicated that, in general, exposure to HHQ caused nanoplankton and prokaryotic cell abundances to decrease. Amplicon sequencing revealed HHQ exposure altered the composition of particle-associated and free-living microbiota, favoring the relative expansion of both gamma- and alpha-proteobacteria, and a concurrent decrease in Bacteroidetes. Specifically, Pseudoalteromonas spp., known to produce HHQ, increased in relative abundance following HHQ exposure. A search of representative bacterial genomes from genera that increased in relative abundance when exposed to HHQ revealed that they all have the genetic potential to bind HHQ. CONCLUSIONS: This work demonstrates HHQ has the capacity to influence microbial community organization, suggesting alkylquinolones have functions beyond bacterial communication and are pivotal in driving microbial community structure and phytoplankton growth. Knowledge of how bacterial signals alter marine communities will serve to deepen our understanding of the impact these chemical interactions have on a global scale.


Assuntos
4-Quinolonas/farmacologia , Bactérias/metabolismo , Microbiota , Fitoplâncton/efeitos dos fármacos , Percepção de Quorum , Transdução de Sinais , Bactérias/classificação , Proteínas de Bactérias/genética , Clorofila/análise , Recifes de Corais , Oceanos e Mares , Fitoplâncton/microbiologia , Água do Mar/microbiologia
5.
Antiviral Res ; 162: 101-109, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582937

RESUMO

Antiretroviral therapy (ART) against HIV-1 infection offers the promise of controlling disease progression and prolonging the survival of HIV-1-infected patients. However, even the most potent ART regimens available today cannot cure HIV-1. Because patients will be exposed to ART for many years, physicians and researchers must anticipate the emergence of drug-resistant HIV-1, potential adverse effects of the current drugs, and need for future drug development. In this study, we screened a small-molecule compound library using cell-based anti-HIV-1 assays and discovered a series of novel anti-HIV-1 compounds, 4-oxoquinolines. These compounds exhibited potent anti-HIV-1 activity (EC50 < 0.1 µM) with high selectivity indexes (CC50/EC50 > 2500) and favorable pharmacokinetic profiles in mice. Surprisingly, our novel compounds have a chemical backbone similar to the clinically used integrase (IN) strand transfer inhibitor (INSTI) elvitegravir, although they lack the crucial 3-carboxylate moiety needed for the common INSTI diketo motif. Indeed, the new 4-oxoquinoline derivatives have no detectable INSTI activity. In addition, various drug-resistant HIV-1 strains did not display cross resistance to these compounds. Interestingly, time-of-addition experiments indicated that the 4-oxoquinoline derivative remains its anti-HIV-1 activity even after the viral integration stage. Furthermore, the compounds significantly suppressed p24 antigen production in HIV-1 latently infected cells exposed with tumor necrosis factor alpha. These findings suggest that our 4-oxoquinoline derivatives with no 3-carboxylate moiety may become novel lead compounds in the development of anti-HIV-1 drugs.


Assuntos
4-Quinolonas/farmacologia , 4-Quinolonas/farmacocinética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , HIV-1/efeitos dos fármacos , Animais , Descoberta de Drogas , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Bibliotecas de Moléculas Pequenas
6.
Eur J Med Chem ; 143: 710-723, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220792

RESUMO

Gram-positive bacteria are responsible for a broad range of infectious diseases, and the emergency and wide spread of drug-resistant Gram-positive pathogens including MRSA and MRSE has caused great concern throughout the world. 4-Quinolones which are exemplified by fluoroquinolones are mainstays of chemotherapy against various bacterial infections including Gram-positive pathogen infections, and their value and role in the treatment of bacterial infections continues to expand. However, the resistance of Gram-positive organisms to 4-quinolones develops rapidly and spreads widely, making them more and more ineffective. To overcome the resistance and reduce the toxicity, numerous of 4-quinolone derivatives were synthesized and screened for their in vitro and in vivo activities against Gram-positive pathogens, and some of them exhibited excellent potency. This review aims to outlines the recent advances made towards the discovery of 4-quinolone-based derivatives as anti-Gram-positive pathogens agents and the critical aspects of design as well as the structure-activity relationship of these derivatives. The enriched SAR paves the way to the further rational development of 4-quinolones with a unique mechanism of action different from that of the currently used drugs to overcome the resistance, well-tolerated and low toxic profiles.


Assuntos
4-Quinolonas/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 141: 335-345, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031077

RESUMO

The emergence and wide-spread of drug-resistant bacteria including multi-drug resistant and pan-drug resistant pathogens which are associated with considerable mortality, represent a significant global health threat. 4-Quinolones which are exemplified by fluoroquinolones are the second largest chemotherapy agents used in clinical practice for the treatment of various bacterial infections. However, the resistance of bacteria to 4-quinolones develops rapidly and spreads widely throughout the world due to the long-term, inappropriate use and even abuse. To overcome the resistance and improve the potency, several strategies have been developed. Amongst them, molecular hybridization, which is based on the incorporation of two or more pharmacophores into a single molecule with a flexible linker, is one of the most practical approaches. This review aims to summarize the recent advances made towards the discovery of 4-quinolone hybrids as potential antibacterial agents as well as their structure-activity relationship (SAR). The enriched SAR may pave the way for the further rational development of 4-quinolone hybrids with excellent potency against both drug-susceptible and drug-resistant bacteria.


Assuntos
4-Quinolonas/farmacologia , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade
8.
Rev. esp. quimioter ; 30(1): 1-8, feb. 2017. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-159552

RESUMO

Las fluoroquinolonas son agentes quimioterapéuticos con potente actividad biológica siendo la estructura de los ácidos 4-quinolona-3-carboxílicos privilegiada ya que contiene diferentes sitios para la funcionalización, permitiendo ampliar su uso en la práctica clínica por sus actividades antifúngicas, antivirales y anticancerosas. Las variaciones estructurales en quinolonas ha resultado en una primera, segunda, tercera y cuarta generación de fármacos por lo que es recomendable continuar modificando estructuras existentes en formas novedosas para generar compuestos con propiedades biológicas y farmacológicas deseables (AU)


Fluoroquinolones are a class of well-established chemotherapeutic agents with a potent biological activity being the structure of 4-quinolone-3-carboxilic acids privileged because it contains different sites for functionalization allowing expand its use in clinical practice for their antifungal, antiviral and anticancer activities. Quinolones structural changes have resulted in a first, second, third and fourth generation of drugs so it is advisable to continue modifying existing structures in new ways to generate compounds with desirable biological and pharmacological properties (AU)


Assuntos
Humanos , Masculino , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , 4-Quinolonas/farmacologia , Ácidos Carboxílicos/farmacologia , Antineoplásicos/uso terapêutico , Antifúngicos/uso terapêutico , Neoplasias/tratamento farmacológico , HIV , Candida albicans , Aspergillus fumigatus , Fungos
9.
Mol Divers ; 21(1): 37-52, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27670880

RESUMO

A series of 4-quinolone-3-carboxylic acid-containing spirooxindole-pyrrolidine derivatives was synthesized via multicomponent 1,3-dipolar cycloaddition reactions of azomethine ylides with new (E)-4-oxo-6-(3-phenyl-acryloyl)-1,4-dihydroquinoline-3-carboxylic acids in good yields with high regioselectivity. The cycloadducts were characterized by analytical and spectral data including [Formula: see text], [Formula: see text], 2D NMR and mass spectroscopy. The structure of one of the compounds (8a) was investigated theoretically by computational techniques. DFT studies support the proposed mechanism for this cycloaddition reaction. Furthermore, antibacterial activities of the new compounds were evaluated against Gram-positive and Gram-negative bacterial strains. Compounds 8f, 8m and 8p showed potent inhibition activities against selected bacteria. The in vitro cytotoxicity of spirooxindole derivatives (8a-r) was evaluated against MCF-7 breast cancer cell line. Among the various compounds tested, compound 8f [Formula: see text] showed significant cytotoxic activity compared to the standard drug doxorubicin [Formula: see text].


Assuntos
4-Quinolonas/síntese química , 4-Quinolonas/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Indóis/química , Pirrolidinas/química , 4-Quinolonas/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Ácidos Carboxílicos/química , Técnicas de Química Sintética , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Oxindois , Teoria Quântica , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 126: 408-420, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27907877

RESUMO

New and convenient methods for the functionalization of the 4-quinolone scaffold at positions C-1, C-3 and C-6 were developed. The 4-quinolone derivatives were evaluated for their inhibitory potential on alkaline phosphatase isozymes. Most of the compounds exhibit excellent inhibitory activity and moderate selectivity. The IC50 values on tissue non-specific alkaline phosphatase (TNAP) were in the range of 1.34 ± 0.11 to 44.80 ± 2.34 µM, while the values on intestinal alkaline phosphatase (IAP) were in the range of 1.06 ± 0.32 to 192.10 ± 3.78 µM. The most active derivative exhibits a potent inhibition on IAP with a ≈14 fold higher selectivity as compared to TNAP. Furthermore, molecular docking calculations were performed for the most potent inhibitors to show their binding interactions within the active site of the respective enzymes.


Assuntos
4-Quinolonas/síntese química , 4-Quinolonas/farmacologia , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , 4-Quinolonas/química , 4-Quinolonas/metabolismo , Fosfatase Alcalina/química , Domínio Catalítico , Técnicas de Química Sintética , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Relação Estrutura-Atividade
11.
Antimicrob Agents Chemother ; 60(10): 5894-905, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27458231

RESUMO

A rapid decline in the development of new antimicrobial therapeutics has coincided with the emergence of new and more aggressive multidrug-resistant pathogens. Pathogens are protected from antibiotic activity by their ability to enter an aggregative biofilm state. Therefore, disrupting this process in pathogens is a key strategy for the development of next-generation antimicrobials. Here, we present a suite of compounds, based on the Pseudomonas aeruginosa 2-heptyl-4(1H)-quinolone (HHQ) core quinolone interkingdom signal structure, that exhibit noncytotoxic antibiofilm activity toward the fungal pathogen Candida albicans In addition to providing new insights into what is a clinically important bacterium-fungus interaction, the capacity to modularize the functionality of the quinolone signals is an important advance in harnessing the therapeutic potential of signaling molecules in general. This provides a platform for the development of potent next-generation small-molecule therapeutics targeting clinically relevant fungal pathogens.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Pseudomonas aeruginosa/química , Bibliotecas de Moléculas Pequenas/farmacologia , 4-Quinolonas/química , 4-Quinolonas/farmacologia , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Candida albicans/fisiologia , Linhagem Celular , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Glicoproteínas de Membrana/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Quinolonas/química , Quinolonas/farmacologia , Bibliotecas de Moléculas Pequenas/química
12.
Bioorg Med Chem Lett ; 26(2): 613-617, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26646219

RESUMO

A series of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives were prepared through multistep synthesis. The key step in the synthesis was to obtain the C-7 fatty amide derivative. The azide was selectively formed at C-7 position using sodium azide at 60°C. Subsequently, the azide was reduced under mild conditions using zinc and ammonium chloride to form the corresponding amine. The synthesized derivatives were further subjected to biological evaluation studies like cytotoxicity against a panel of cancer cell lines such as DU145, A549, SKOV3, MCF7 and normal lung cells, IMR-90 as well as with antimicrobial and antioxidant activities. It was observed that the carboxylated quinolone derivatives with hexanoic (8a), octanoic (8b), lauric (8d) and myristic (8e) moieties exhibited promising cytotoxicity against all the tested cancer cell lines. The results also suggested that hexanoic acid-based fatty amide carboxylated quinolone derivative (8a) exhibited promising activity against both bacterial and fungal strains and significant antibacterial activity was observed against Staphylococcus aureus MTCC 96 (MIC value of 3.9µg/mL). The compound 8a also showed excellent anti-biofilm activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121 with MIC values of 2.1 and 4.6µg/mL, respectively.


Assuntos
4-Quinolonas/química , Anti-Infecciosos/química , Antineoplásicos/química , Antioxidantes/química , 4-Quinolonas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Fungos/efeitos dos fármacos , Halogenação , Humanos , Micoses/tratamento farmacológico , Neoplasias/tratamento farmacológico
13.
J Enzyme Inhib Med Chem ; 31(5): 796-809, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26226179

RESUMO

The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63-3.09 µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI50; 22.60 µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 µM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.


Assuntos
4-Quinolonas/síntese química , 4-Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ciprofloxacino/química , Simulação por Computador , Norfloxacino/química , 4-Quinolonas/química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células , Humanos , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Relação Estrutura-Atividade
14.
Org Biomol Chem ; 13(19): 5537-41, 2015 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-25880413

RESUMO

The sharp rise in antimicrobial resistance has been matched by a decline in the identification and clinical introduction of new classes of drugs to target microbial infections. Thus new approaches are being sought to counter the pending threat of a post-antibiotic era. In that context, the use of non-growth limiting small molecules, that target virulence behaviour in pathogens, has emerged as a solution with real clinical potential. We have previously shown that two signal molecules (HHQ and PQS) from the nosocomial pathogen Pseudomonas aeruginosa have modulatory activity towards other microorganisms. This current study involves the synthesis and evaluation of analogues of HHQ towards swarming and biofilm virulence behaviour in Bacillus atrophaeus, a soil bacterium and co-inhibitor with P. aeruginosa. Compounds with altered C6-C8 positions on the anthranilate-derived ring of HHQ, display a surprising degree of biological specificity, with certain candidates displaying complete motility inhibition. In contrast, anti-biofilm activity of the parent molecule was completely lost upon alteration at any position indicating a remarkable degree of specificity and delineation of phenotype.


Assuntos
4-Quinolonas/farmacologia , Bacillus/fisiologia , Pseudomonas aeruginosa/química , Percepção de Quorum/efeitos dos fármacos , 4-Quinolonas/química , Bacillus/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Movimento/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
15.
J Agric Food Chem ; 63(1): 68-74, 2015 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-25494674

RESUMO

The methanol extract of the aerial part of Triumfetta grandidens (Tiliaceae) was highly active against Meloidogyne incognita, with second-stage juveniles (J2s) mortality of 100% at 500 µg/mL at 48 h post-exposure. Two 4-quinolone alkaloids, waltherione E (1), a new alkaloid, and waltherione A (2), were isolated and identified as nematicidal compounds through bioassay-guided fractionation and instrumental analysis. The nematicidal activities of the isolated compounds against M. incognita were evaluated on the basis of mortality and effect on egg hatching. Compounds 1 and 2 exhibited high mortalities against J2s of M. incognita, with EC50 values of 0.09 and 0.27 µg/mL at 48 h, respectively. Compounds 1 and 2 also exhibited a considerable inhibitory effect on egg hatching, which inhibited 91.9 and 87.4% of egg hatching, respectively, after 7 days of exposure at a concentration of 1.25 µg/mL. The biological activities of the two 4-quinolone alkaloids were comparable to those of abamectin. In addition, pot experiments using the crude extract of the aerial part of T. grandidens showed that it completely suppressed the formation of gall on roots of plants at a concentration of 1000 µg/mL. These results suggest that T. grandidens and its bioactive 4-quinolone alkaloids can be used as a potent botanical nematicide in organic agriculture.


Assuntos
4-Quinolonas/farmacologia , Antinematódeos/farmacologia , Componentes Aéreos da Planta/química , Triumfetta/química , Tylenchoidea/efeitos dos fármacos , 4-Quinolonas/química , 4-Quinolonas/isolamento & purificação , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Antinematódeos/química , Antinematódeos/isolamento & purificação , Estrutura Molecular , Agricultura Orgânica , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Extratos Vegetais/farmacologia
16.
Org Biomol Chem ; 12(42): 8555-61, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25245989

RESUMO

A new strategy was developed to synthesize 1,2-disubstituted 4-quinolones in good yield starting from 1,3-bisaryl-monothio-1,3-diketone substrates. The synthesized compounds were evaluated for antimalarial activity using Plasmodium falciparum strains. All compounds, except for two, showed good activity. Of these, seven compounds exhibited an excellent antimalarial activity (IC50, <2 µM). More importantly, all seven compounds were equally effective in inhibiting the growth of both chloroquine-sensitive and chloroquine-resistant strains. The cytotoxicity assessment using carcinoma and non-carcinoma human cell lines revealed that almost all synthesized compounds were minimally cytotoxic (IC50, >50 µM).


Assuntos
4-Quinolonas/síntese química , 4-Quinolonas/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , 4-Quinolonas/química , Antimaláricos/química , Linhagem Celular , Linhagem Celular Tumoral , Humanos
17.
Bioorg Med Chem ; 22(14): 3670-83, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24906513

RESUMO

Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.


Assuntos
4-Quinolonas/farmacologia , Ácidos Carboxílicos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , 4-Quinolonas/síntese química , 4-Quinolonas/química , Animais , Células CHO , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade
18.
Oncotarget ; 5(2): 326-37, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24504118

RESUMO

Intravesical instillation of chemotherapeutic agents is a well-established treatment strategy to decrease recurrence following transurethral resection in non-muscle invasive bladder cancer. Gemcitabine is a recently developed treatment option. However, the curative effects of gemcitabine are far from satisfactory due to de novo or acquired drug resistance. In a previous study, we reported that intravesical administration of the c-Myc inhibitor KSI-3716 suppresses tumor growth in an orthotopic bladder cancer model. Here, we explored whether KSI-3716 inhibits gemcitabine-resistant bladder cancer cell proliferation. As expected from the in vitro cytotoxicity of gemcitabine in several bladder cancer cell lines, gemcitabine effectively suppressed the growth of KU19-19 xenografts in nude mice, although all mice relapsed later. Long-term in vitro exposure to gemcitabine induced gemcitabine-specific resistance. Gemcitabine-resistant cells, termed KU19-19/GEM, formed xenograft tumors even in the presence of 2 mg/kg gemcitabine. Interestingly, KU19-19/GEM cells up-regulated c-Myc expression in the presence of the gemcitabine and resisted to the gemcitabine, however was suppressed by the KSI-3716. The sequential addition of gemcitabine and KSI-3716 inhibited gemcitabine-resistant cell proliferation to a great extent than each drug alone. These results suggest that sequential treatment with gemcitabine and KSI-3716 may be beneficial to bladder cancer patients.


Assuntos
4-Quinolonas/farmacologia , Compostos de Anilina/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Nat Prod ; 77(1): 183-7, 2014 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-24392742

RESUMO

The methanol extract of Melochia odorata yielded three 4-quinolone alkaloids including waltherione A (1) and two new alkaloids, waltherione C (2) and waltherione D (3). Waltheriones A and C showed significant activities in an in vitro anti-HIV cytoprotection assay at concentrations of 56.2 and 0.84 µM and inhibition of HIV P24 formation of more than 50% at 1.7 and 0.95 µM, respectively. The structures of the alkaloids were established by spectroscopic data interpretation.


Assuntos
4-Quinolonas/isolamento & purificação , Alcaloides/isolamento & purificação , Fármacos Anti-HIV/isolamento & purificação , Malvaceae/química , 4-Quinolonas/química , 4-Quinolonas/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Relação Dose-Resposta a Droga , Proteína do Núcleo p24 do HIV/antagonistas & inibidores , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Papua Nova Guiné , Caules de Planta/química , Quinolinas
20.
Bioorg Med Chem Lett ; 24(4): 1214-7, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24468411

RESUMO

Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C-N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 µM.


Assuntos
4-Quinolonas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
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