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1.
J Med Chem ; 63(13): 7369-7391, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32515588

RESUMO

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).


Assuntos
Antiasmáticos/farmacologia , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , 4-Quinolonas/química , Animais , Antiasmáticos/química , Células CHO , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/farmacologia , Condrócitos/metabolismo , Condrócitos/patologia , Colforsina/farmacologia , Cricetulus , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ácido Iodoacético/toxicidade , Ligantes , Masculino , Camundongos , Células NIH 3T3 , Osteoartrite/induzido quimicamente , Ratos Wistar , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Relação Estrutura-Atividade , Caminhada
2.
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
3.
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
4.
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
5.
Molecules ; 24(2)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658415

RESUMO

Infection from multidrug resistant bacteria has become a growing health concern worldwide, increasing the need for developing new antibacterial agents. Among the strategies that have been studied, biofilm inhibitors have acquired relevance as a potential source of drugs that could act as a complement for current and new antibacterial therapies. Based on the structure of 2-alkyl-3-hydroxy-4-quinolone and N-acylhomoserine lactone, molecules that act as mediators of quorum sensing and biofilm formation in Pseudomonas aeruginosa, we designed, prepared, and evaluated the biofilm inhibition properties of long chain amide derivatives of 2-amino-4-quinolone in Staphylococcus aureus and P. aeruginosa. All compounds had higher biofilm inhibition activity in P. aeruginosa than in S. aureus. Particularly, compounds with an alkyl chain of 12 carbons exhibited the highest inhibition of biofilm formation. Docking scores and molecular dynamics simulations of the complexes of the tested compounds within the active sites of proteins related to quorum sensing had good correlation with the experimental results, suggesting the diminution of biofilm formation induced by these compounds could be related to the inhibition of these proteins.


Assuntos
4-Quinolonas/química , Amidas/síntese química , Amidas/farmacologia , Biofilmes/efeitos dos fármacos , Simulação por Computador , Amidas/química , Domínio Catalítico , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
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.
Methods Mol Biol ; 1673: 25-34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29130161

RESUMO

2-Alkyl-4-quinolones (AQs) such as 2-heptyl-3-hydroxy-4-quinolone (PQS) and 2-heptyl-4-hydroxyquinoline (HHQ) are quorum-sensing signal molecules. Here we describe two methods for AQ detection and quantification that employ thin-layer chromatography (TLC) and microtiter plate assays in combination with a lux-based Pseudomonas aeruginosa AQ biosensor strain. For TLC detection, organic solvent extracts of bacterial cells or spent culture supernatants are chromatographed on TLC plates, which are then dried and overlaid with the AQ biosensor. After detection by the bioreporter, AQs appear as both luminescent and green (from pyocyanin) spots. For the microtiter assay, either spent bacterial culture supernatants or extracts are added to a growth medium containing the AQ biosensor. Light output by the bioreporter correlates with the AQ content of the sample. The assays described are simple to perform, do not require sophisticated instrumentation, and are highly amenable to screening large numbers of bacterial samples.


Assuntos
4-Quinolonas/análise , Técnicas Biossensoriais/métodos , 4-Quinolonas/química , Cromatografia em Camada Delgada , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo
8.
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
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.
Bioorg Med Chem Lett ; 26(16): 3905-12, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27426300

RESUMO

Numerous potent P2X3 antagonists have been discovered and the therapeutic potential of P2X3 antagonism already comprises proof-of-concept data obtained in clinical trials with the most advanced compound. We have lately reported the discovery and optimization of thia-triaza-tricycle compounds with potent P2X3 antagonistic properties. This Letter describes the SAR of a back-up series containing a 4-oxo-quinazoline central ring. The discovery of the highly potent compounds 51 is presented.


Assuntos
4-Quinolonas/química , Antagonistas do Receptor Purinérgico P2X/química , Quinazolinonas/química , Receptores Purinérgicos P2X3/metabolismo , 4-Quinolonas/síntese química , 4-Quinolonas/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Concentração Inibidora 50 , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/metabolismo , Quinazolinonas/metabolismo , Receptores Purinérgicos P2X3/química , Relação Estrutura-Atividade
12.
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
13.
J Enzyme Inhib Med Chem ; 31(6): 1464-70, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26928712

RESUMO

Acetylcholinesterase inhibitors and compounds that trigger Aß amyloid oligomerization and fibrillization represent an opportunity to discover new drug candidates to treat Alzheimer's disease. In this work, we synthesized nine new acylhydrazones and a known one, both employing 3-carboethoxy-4-quinolone derivatives as starting materials with chemical yields ranging from 63% to 90%. We evaluated the effect of these compounds on the acetylcholinesterase (AChE) activity and the fibrillization of Aß42 peptide. Except for one acylhydrazone, the compounds exhibited good inhibitory effect on AChE (1.2 µM < IC50 values < 17 µM). They also showed a significant decrease in the thioflavin-T fluorescence emission, suggesting an inhibitory effect on the Aß42 fibril formation.


Assuntos
4-Quinolonas/química , Acetilcolinesterase/efeitos dos fármacos , Peptídeos beta-Amiloides/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Hidrazonas/farmacologia , Fragmentos de Peptídeos/efeitos dos fármacos , Peptídeos beta-Amiloides/química , Hidrazonas/química , Fragmentos de Peptídeos/química , Análise Espectral/métodos
14.
J Biol Chem ; 291(13): 6610-24, 2016 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-26811339

RESUMO

Pseudomonas aeruginosaproduces a number of alkylquinolone-type secondary metabolites best known for their antimicrobial effects and involvement in cell-cell communication. In the alkylquinolone biosynthetic pathway, the ß-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme PqsBC catalyzes the condensation of octanoyl-coenzyme A and 2-aminobenzoylacetate (2-ABA) to form the signal molecule 2-heptyl-4(1H)-quinolone. PqsBC, a potential drug target, is unique for its heterodimeric arrangement and an active site different from that of canonical FabH-like enzymes. Considering the sequence dissimilarity between the subunits, a key question was how the two subunits are organized with respect to the active site. In this study, the PqsBC structure was determined to a 2 Å resolution, revealing that PqsB and PqsC have a pseudo-2-fold symmetry that unexpectedly mimics the FabH homodimer. PqsC has an active site composed of Cys-129 and His-269, and the surrounding active site cleft is hydrophobic in character and approximately twice the volume of related FabH enzymes that may be a requirement to accommodate the aromatic substrate 2-ABA. From physiological and kinetic studies, we identified 2-aminoacetophenone as a pathway-inherent competitive inhibitor of PqsBC, whose fluorescence properties could be used forin vitrobinding studies. In a time-resolved setup, we demonstrated that the catalytic histidine is not involved in acyl-enzyme formation, but contributes to an acylation-dependent increase in affinity for the second substrate 2-ABA. Introduction of Asn into the PqsC active site led to significant activity toward the desamino substrate analog benzoylacetate, suggesting that the substrate 2-ABA itself supplies the asparagine-equivalent amino function that assists in catalysis.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , 4-Quinolonas/química , Acil Coenzima A/química , Aminobenzoatos/química , Proteínas de Bactérias/química , Pseudomonas aeruginosa/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , 4-Quinolonas/metabolismo , Acetofenonas/química , Acil Coenzima A/metabolismo , Sequência de Aminoácidos , Aminobenzoatos/metabolismo , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Ligação Competitiva , Biocatálise , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Escherichia coli/genética , Escherichia coli/metabolismo , Cinética , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Multimerização Proteica , Estrutura Secundária de Proteína , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Pseudomonas aeruginosa/enzimologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência
15.
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
16.
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
17.
Fitoterapia ; 105: 55-60, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26072041

RESUMO

Six extracts from the roots and the aerial parts of Waltheria indica L. (Malvaceae) were screened for their in vitro antitrypanosomal activity towards Trypanosoma brucei brucei STIB 427 strain, T. brucei rhodesiense STIB 900 and Trypanosoma cruzi Tulahuen C4. The dichloromethane extract from the roots showed the highest activity against T. cruzi (IC50=0.74 µg/mL) as well as a good selectivity index (SI value of 35). Based on these results, this extract was fractionated and led to the isolation of three alkaloids (adouetin X (1), waltheriones A (2) and C (3)) and three pentacyclic triterpene derivatives (betulinic acid (4), 3ß-acetoxy-27-trans-caffeoyloxyolean-12-en-28-oic acid methyl ester (5) and 3ß-acetoxy-27-cis-caffeoyloxyolean-12-en-28-oic acid methyl ester (6)) identified by 1D and 2D NMR, UV, IR and MS analyses. Among these, waltherione C exhibited the highest and selective antitrypanosomal activity towards T. cruzi (IC50=1.93 µM) with low cytotoxicity (IC50=101.23 µM), resulting in a selectivity index value of 52. Waltherione C conforms to hit activity criteria with respect to T. cruzi as required by the WHO/TDR.


Assuntos
Alcaloides/química , Antiprotozoários/química , Malvaceae/química , Triterpenos/química , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , 4-Quinolonas/química , 4-Quinolonas/isolamento & purificação , Alcaloides/isolamento & purificação , Animais , Antiprotozoários/isolamento & purificação , Linhagem Celular , Concentração Inibidora 50 , Estrutura Molecular , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Ratos , Triterpenos/isolamento & purificação
18.
Chem Biol ; 22(5): 611-8, 2015 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-25960261

RESUMO

Pseudomonas aeruginosa uses the alkylquinolones PQS (2-heptyl-3-hydroxy-4(1H)-quinolone) and HHQ (2-heptyl-4(1H)-quinolone) as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. The biosynthesis of HHQ is generally accepted to require the pqsABCD gene products. We now reconstitute the biosynthetic pathway in vitro, and demonstrate that in addition to PqsABCD, PqsE has a role in HHQ synthesis. PqsE acts as thioesterase, hydrolyzing the biosynthetic intermediate 2-aminobenzoylacetyl-coenzyme A to form 2-aminobenzoylacetate, the precursor of HHQ and 2-aminoacetophenone. The role of PqsE can be taken over to some extent by the broad-specificity thioesterase TesB, explaining why the pqsE deletion mutant of P. aeruginosa still synthesizes HHQ. Interestingly, the pqsE mutant produces increased levels of 2,4-dihydroxyquinoline, resulting from intramolecular cyclization of 2-aminobenzoylacetyl-coenzyme A. Overall, our data suggest that PqsE promotes the efficiency of alkylquinolone signal molecule biosynthesis in P. aeruginosa and balances the levels of secondary metabolites deriving from the alkylquinolone biosynthetic pathway.


Assuntos
4-Quinolonas/metabolismo , Proteínas de Bactérias/metabolismo , Pseudomonas aeruginosa/metabolismo , Tioléster Hidrolases/metabolismo , 4-Quinolonas/química , Acil Coenzima A/metabolismo , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Escherichia coli/metabolismo , Mutagênese , Pseudomonas aeruginosa/enzimologia , Quinolinas/química , Quinolinas/metabolismo , Percepção de Quorum , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Especificidade por Substrato , Tioléster Hidrolases/genética
19.
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
20.
Org Lett ; 17(5): 1268-71, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25700137

RESUMO

A novel, metal-free oxidative intramolecular Mannich reaction was developed between secondary amines and unmodified ketones, affording a simple and direct access to a broad range of 2-arylquinolin-4(1H)-ones through C(sp(3))-H activation/C(sp(3))-C(sp(3)) bond formation from readily available N-arylmethyl-2-aminophenylketones, using TEMPO as the oxidant and KO(t)Bu as the base.


Assuntos
4-Quinolonas/síntese química , Compostos de Anilina/química , Cetonas/química , Elementos de Transição/química , 4-Quinolonas/química , Catálise , Estrutura Molecular , Oxirredução
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