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1.
Inorg Chem ; 58(13): 8800-8819, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247881

RESUMO

Very few inorganic antineoplastic drugs have entered the clinic in the last decades, mainly because of toxicity issues. Because copper is an essential trace element of ubiquitous occurrence, decreased side effects could be expected in comparison with the widely used platinum anticancer compounds. In the present work, two novel hydrazonic binucleating ligands and their µ-hydroxo dicopper(II) complexes were prepared and fully characterized. They differ by the nature of the aromatic group present in their aroylhydrazone moieties: while H3L1 and its complex, 1, possess a thiophene ring, H3L2 and 2 contain the more polar furan heterocycle. X-ray diffraction indicates that both coordination compounds are very similar in structural terms and generate dimeric arrangements in the solid state. Positive-ion electrospray ionization mass spectrometry analyses confirmed that the main species present in a 10% dimethyl sulfoxide (DMSO)/water solution should be [Cu2(HL)(OH)]+ and the DMSO-substituted derivative [Cu2(L)(DMSO)]+. Scattering techniques [dynamic light scattering (DLS) and small-angle X-ray scattering] suggest that the complexes and their free ligands interact with bovine serum albumin (BSA) in a reversible manner. The binding constants to BSA were determined for the complexes through fluorescence spectroscopy. Moreover, to gain insight into the mechanism of action of the compounds, calf thymus DNA binding studies by UV-visible and DLS measurements using plasmid pBR322 DNA were also performed. For the complexes, DLS data seem to point to the occurrence of DNA cleavage to Form III (linear). Both ligands and their dicopper(II) complexes display potent antiproliferative activity in a panel of four cancer cell lines, occasionally even in the submicromolar range, with the complexes being more potent than the free ligands. Our data on cellular models correlate quite well with the DNA interaction experiments. The results presented herein show that aroylhydrazone-derived binucleating ligands, as well as their dinuclear µ-hydroxodicopper(II) complexes, may represent a promising structural starting point for the development of a new generation of highly active potential antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Hidrazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , DNA/química , Clivagem do DNA/efeitos dos fármacos , Cães , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/toxicidade , Isomerismo , Ligantes , Células Madin Darby de Rim Canino , Camundongos , Plasmídeos/química , Multimerização Proteica/efeitos dos fármacos , Soroalbumina Bovina/metabolismo
2.
Eur J Med Chem ; 178: 13-29, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173968

RESUMO

The oncogenic Epstein-Barr virus (EBV) evades the immune system through limiting the expression of its highly antigenic and essential genome maintenance protein, EBNA1, to the minimal level to ensure viral genome replication, thereby also minimizing the production of EBNA1-derived antigenic peptides. This regulation is based on inhibition of translation of the virally-encoded EBNA1 mRNA, and involves the interaction of host protein nucleolin (NCL) with G-quadruplex (G4) structures that form in the glycine-alanine repeat (GAr)-encoding sequence of the EBNA1 mRNA. Ligands that bind to these G4-RNA can prevent their interaction with NCL, leading to disinhibition of EBNA1 expression and antigen presentation, thereby interfering with the immune evasion of EBNA1 and therefore of EBV (M.J. Lista et al., Nature Commun., 2017, 8, 16043). In this work, we synthesized and studied a series of 20 cationic bis(acylhydrazone) derivatives designed as G4 ligands. The in vitro evaluation showed that most derivatives based on central pyridine (Py), naphthyridine (Naph) or phenanthroline (Phen) units were efficient G4 binders, in contrast to their pyrimidine (Pym) counterparts, which were poor G4 binders due to a significantly different molecular geometry. The influence of lateral heterocyclic units (N-substituted pyridinium or quinolinium residues) on G4-binding properties was also investigated. Two novel compounds, namely PyDH2 and PhenDH2, used at a 5 µM concentration, were able to significantly enhance EBNA1 expression in H1299 cells in a GAr-dependent manner, while being significantly less toxic than the prototype drug PhenDC3 (GI50 > 50 µM). Antigen presentation, RNA pull-down and proximity ligation assays confirmed that the effect of both drugs was related to the disruption of NCL-EBNA1 mRNA interaction and the subsequent promotion of GAr-restricted antigen presentation. Our work provides a novel modular scaffold for the development of G-quadruplex-targeting drugs acting through interference with G4-protein interaction.


Assuntos
Hidrazonas/farmacologia , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fosfoproteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Quadruplex G , Herpesvirus Humano 4/genética , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Ligantes , Camundongos , RNA Mensageiro/genética
3.
Carbohydr Polym ; 216: 63-71, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047083

RESUMO

The effect of hydrazide linkers on the formation and mechanical properties of hyaluronan hydrogels was intensively evaluated. The reaction kinetics of hydrazone formation was monitored by NMR spectroscopy under physiological conditions where polyaldehyde hyaluronan (unsaturated: ΔHA-CHO, saturated: HA-CHO) was reacted with various hydrazides to form hydrogels. Linear (adipic, oxalic dihydrazide) and branched (N,N´,N´´-tris(hexanoylhydrazide-6-yl)phosphoric triamide and 4-arm-PEG hydrazide) hydrazides were compared as crosslinking agents. The mechanical properties of hydrogels were also modified by attaching a hydrophobic chain to HA-CHO; however, it was found that this modification did not lead to an increase in hydrogel stiffness. Cytotoxicity tests showed that all tested hydrazide crosslinkers reduced the viability of cells only slightly, and that the final hyaluronan hydrogels were non-toxic materials.


Assuntos
Reagentes para Ligações Cruzadas/química , Ácido Hialurônico/análogos & derivados , Hidrazinas/química , Hidrazonas/química , Hidrogéis/química , Acilação , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/toxicidade , Módulo de Elasticidade , Ácido Hialurônico/síntese química , Ácido Hialurônico/toxicidade , Hidrazinas/síntese química , Hidrazinas/toxicidade , Hidrazonas/síntese química , Hidrazonas/toxicidade , Hidrogéis/síntese química , Hidrogéis/toxicidade , Concentração de Íons de Hidrogênio , Cinética , Camundongos , Células Swiss 3T3
4.
Eur J Med Chem ; 177: 153-170, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132531

RESUMO

The eukaryotic initiation factor 4E (eIF4E) is an emerging anticancer drug target for specific anticancer therapy as a promising approach to overcome drug resistance and promote chemotherapy antitumor efficacy. A series of bromophenol-thiazolylhydrazone hybrids were designed, synthesized and evaluated for their antitumor activities. Among of them, the most potent compound 3e (EGPI-1) could inhibit the eIF4E/eIF4G interaction. Further mechanism study demonstrated EGPI-1 played an antitumor role in multiple modes of action including regulating the activity of eIF4E by inhibiting the phosphorylation of eIF4E and 4EBP1, disrupting mitochondrial function through the mTOR/4EBP1 signaling pathway, and inducing autophagy, apoptosis and ROS generation. Moreover, EGPI-1 showed good safety and favorable pharmacokinetic properties in vivo. These observations demonstrate that EGPI-1 may serve as an excellent lead compound for the development of new anticancer drugs that target the eIF4E/eIF4G interface and as a chemical genetic probe to investigate the role of the eIF4E in biological processes and human diseases.


Assuntos
Antineoplásicos/farmacologia , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4G em Eucariotos/antagonistas & inibidores , Hidrazonas/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Hidrazonas/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Fosforilação , Ligação Proteica , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Eur J Med Chem ; 174: 45-55, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31026746

RESUMO

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry. This represents a novel application of combinatorial chemistry focusing on the improvement of physicochemical properties, rather than on potency. This strategy allowed us to efficiently screen 44 reaction mixtures of different hydrazides and our previously reported indole aldehyde core structure, without the need for individual synthesis of all possible combinations of building blocks. Our approach afforded three new inhibitors with IC50 values in the nanomolar range and improved lipophilic ligand efficiency.


Assuntos
Hidrazonas/química , Indóis/química , Inibidores de Lipoxigenase/química , Araquidonato 15-Lipoxigenase/química , Técnicas de Química Combinatória , Descoberta de Drogas , Humanos , Hidrazonas/síntese química , Indóis/síntese química , Ligantes , Inibidores de Lipoxigenase/síntese química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
6.
Chemistry ; 25(35): 8229-8235, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-30969447

RESUMO

Aggregation-induced-emission luminogens (AIEgens) have gained considerable attention as interesting tools for several biomedical applications, especially for bioimaging due to their brightness and photostability. Numerous AIEgens have been developed for lighting up the subcellular organelles to understand their forms and functions not only healthy but also unhealthy states, such as in cancer cells. However, there is lack of easily synthesizable, biocompatible small molecules for illuminating mitochondria (powerhouses) inside cells. To address this issue, an easy and short synthesis of new biocompatible hydrazide-hydrazone-based small molecules with remarkable aggregation-induced emission (AIE) properties is described. These small-molecule AIEgens showed hitherto unobserved AIE properties due to dual intramolecular H-bonding confirmed by theoretical calculation, pH- and temperature-dependent fluorescence and X-ray crystallographic studies. Confocal microscopy showed that these AIEgens were internalized into the HeLa cervical cancer cells without showing any cytotoxicity. One of the AIEgens was tagged with a triphenylphosphine (TPP) moiety, which successfully localized in the mitochondria of HeLa cells in a selective way compared to L929 noncancerous fibroblast cells. These unique hydrazide-hydrazone-based biocompatible AIEgens can serve as powerful tools to illuminate multiple subcellular organelles to elucidate their forms and functions in cancer cells for next-generation biomedical applications.


Assuntos
Materiais Biocompatíveis/química , Corantes Fluorescentes/química , Hidrazonas/química , Mitocôndrias/metabolismo , Linhagem Celular , Sobrevivência Celular , Simulação por Computador , Fibroblastos/citologia , Células HeLa , Humanos , Hidrazonas/síntese química , Mitocôndrias/ultraestrutura , Imagem Óptica , Compostos Organofosforados/química
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 216: 375-384, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30921660

RESUMO

A novel hydrazone, (E)-Ethyl-4-(2-(furan-2-ylmethylene)hydrazinyl)benzoate (EFHB), has been synthesized and characterized by FT-IR, NMR and Mass spectroscopy, and X-ray diffraction; compound crystallized as translucent light yellow thin plates. EFHB was studied for their binding to human serum albumin (HSA) using the fluorescence quench titration method. Molecular docking was also performed to get a more detailed insight into their interaction with HSA at the binding site. Addition of this hydrazone to HSA produced significant fluorescence quenching and splitting of emission spectra of HSA through static quenching mechanism with binding constants of about 104 M-1 at 292.15, 298.15, 304.15 and 310.15 K. According to the synchronous fluorescence, tryptophan and tyrosine residues of the protein are most perturbed by the binding process. Thermodynamic parameters ΔG, ΔH, and ΔS were got and the main sort of acting force between EFHB and HSA was studied. Results of molecular docking have shown that EFHB binds to subdomain IIA of HSA mainly by hydrophobic interaction, energy binding are in good agreement with those obtained by fluorescence study (ΔGthe = -7.32 ±â€¯0.09 kcal mol-1 and ΔGexp = -6.76 ±â€¯0.03 kcal mol-1).


Assuntos
Benzoatos/química , Benzoatos/metabolismo , Hidrazonas/química , Hidrazonas/metabolismo , Albumina Sérica Humana/metabolismo , Benzoatos/síntese química , Sítios de Ligação , Técnicas de Química Sintética , Cristalografia por Raios X , Humanos , Hidrazonas/síntese química , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana/química , Termodinâmica
8.
J Enzyme Inhib Med Chem ; 34(1): 597-612, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30727777

RESUMO

A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.


Assuntos
Antioxidantes/farmacologia , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Tiazóis/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Tiazóis/síntese química , Tiazóis/química
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 212: 146-154, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30622039

RESUMO

A simple asymmetric hydrazone 1 based on salicylaldehyde was designed and prepared, and exhibited an evident aggregation-induced emission (AIE) at a long wavelength of 570 nm in aqueous medium. Probe 1 can selectively sense Al3+ in CH3OH solution through the chelation-enhanced fluorescence mechanism and also recognize Cu2+ via fluorescence quenching in H2O solution through the Cu2+-induced assembly of aggregates. In addition, the probe can be applied for detecting Cu2+ in biological samples.


Assuntos
Aldeídos/química , Alumínio/análise , Cobre/análise , Hidrazonas/química , Solventes/química , Aldeídos/síntese química , Difusão Dinâmica da Luz , Fluorescência , Células HeLa , Humanos , Hidrazonas/síntese química , Íons , Conformação Molecular , Espectroscopia de Prótons por Ressonância Magnética , Soluções , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Fatores de Tempo , Água/química
10.
Luminescence ; 34(1): 90-97, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30575272

RESUMO

Four novel salicyloylhydrazone derivatives and their terbium(III) complexes were synthesized and characterized. The thermal analysis results showed that the terbium(III) complexes possessed good thermal stability. The fluorescence research results showed that the terbium(III) complex substituted by phenyl possessed the best fluorescence intensity among them, and its fluorescence quantum yield was also the highest. The exploration of the electrochemical properties indicated that the introduction of electron-donating groups to the ligand can increase the highest occupied molecular orbital (HOMO) energy levels and decrease the oxidation potential of the corresponding terbium(III) complexes. The introduction of electron-withdrawing groups to the ligand can reduce their HOMO energy levels and increase their oxidation potential. The results showed that the terbium(III) complexes are good candidates for luminescent material.


Assuntos
Hidrazonas/química , Substâncias Luminescentes/química , Térbio/química , Eletroquímica/métodos , Hidrazonas/síntese química , Ligantes , Substâncias Luminescentes/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Espectrometria de Fluorescência , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
11.
Curr Top Med Chem ; 18(26): 2256-2265, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30569857

RESUMO

A series of substituted oxopropanylindole hydrazone derivatives was synthesized and evaluated for anti-oxidant and anti-dyslipidemic activity. Of the 12 tested, 3 compounds (6c, 7b and 7d) showed good anti-oxidant activity, compound 6c attenuated LDL oxidation by 32%. The compounds 6c and 7d also showed good anti-dyslipidemic activity by reducing serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). These two compounds were further evaluated for antiadipogenic and anti-hyperglycemic activity, where 6c showed 44% reduction in lipid accumulation and 20.5% and 24.3% reduction in blood glucose at 5h and 24h respectively, as compared to standard drug metformin. Thus, compounds 6c and 7d with balanced anti-oxidant and anti-dyslipidimic activities may be excellent candidates for lead optimization and drug development for the treatment of metabolic disorders.


Assuntos
Antioxidantes/uso terapêutico , Hidrazonas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Indóis/uso terapêutico , Lipoproteínas LDL/uso terapêutico , Células 3T3-L1 , Animais , Antioxidantes/síntese química , Antioxidantes/química , Glicemia/efeitos dos fármacos , Células Cultivadas , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Radical Hidroxila/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Indóis/síntese química , Indóis/química , Lipoproteínas LDL/química , Masculino , Camundongos , Oxigênio/química , Ratos , Ratos Sprague-Dawley
12.
Org Lett ; 20(24): 8082-8085, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30532977

RESUMO

Reactions of thermally generated benzynes with diaziridines are reported. These trapping reactions follow the same pathway as reported earlier by Heine and co-workers with electron-deficient alkynes. The resulting N-arylhydrazones were obtained efficiently in a single step. The preference for the mode of addition of the nucleophilic diaziridine nitrogen atom to the more electrophilic benzyne carbon was consistent with what is predicted on the basis of distortion analysis. The feasibility of converting the hydrazone into a Fisher-indole adduct was demonstrated.


Assuntos
Aziridinas/química , Derivados de Benzeno/química , Hidrazonas/síntese química , Hidrazonas/química , Estrutura Molecular
13.
Chem Commun (Camb) ; 54(85): 12010-12013, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30204171

RESUMO

Using the conformational restraint strategy, we developed a hydrazonate-derived coumarin into a lysosome targeting probe for imaging native formaldehyde at the subcellular level. Using this probe, we observed the overproduction of formaldehyde in lysosomes when cells were treated with endoplasmic reticulum (ER) stress inducers, suggesting the involvement of formaldehyde in protein misfolding.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Formaldeído/metabolismo , Hidrazonas/química , Lisossomos/metabolismo , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/toxicidade , Estresse do Retículo Endoplasmático , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Formaldeído/análise , Humanos , Hidrazonas/síntese química , Hidrazonas/toxicidade , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Conformação Molecular , Dobramento de Proteína/efeitos dos fármacos
14.
Eur J Med Chem ; 158: 247-258, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30218910

RESUMO

A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/metabolismo
15.
Eur J Med Chem ; 156: 118-125, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006157

RESUMO

New benzofuranhydrazones 3-12 were easily prepared and assayed for their radical-scavenging ability. Hydrazones 3-12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11. Furthermore, hydrazones 3-12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3-12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5, 7 and 11 correlated to their high antiproliferative activity.


Assuntos
Antineoplásicos/química , Antioxidantes/química , Benzofuranos/química , Desenho de Drogas , Hidrazonas/química , Protetores Solares/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Leucemia Eritroblástica Aguda/tratamento farmacológico , Melanoma/tratamento farmacológico , Relação Estrutura-Atividade , Protetores Solares/síntese química , Protetores Solares/farmacologia
16.
Molecules ; 23(7)2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30037021

RESUMO

In this study, a series of novel pyrazole-hydrazone derivatives containing an isoxazole moiety were synthesized. Antiviral bioassays indicated that some of the title compounds exhibited better in vivo antiviral activities against tobacco mosaic virus (TMV). In particular, compounds 6a, 6c and 6q exhibited the best curative activity, protection activity, and inactivation activity against TMV, respectively, which were superior to those of Ningnanmycin. This study demonstrated that this series of novel pyrazole-hydrazone derivatives containing an isoxazole amide moiety could effectively control TMV.


Assuntos
Antivirais/química , Hidrazonas/química , Isoxazóis/química , Pirazóis/química , Antivirais/síntese química , Antivirais/farmacologia , Técnicas de Química Sintética , Desenho de Drogas , Hidrazonas/síntese química , Hidrazonas/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
17.
J Enzyme Inhib Med Chem ; 33(1): 1181-1193, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30044647

RESUMO

In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-ß inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC50 values of 3.1 and 3.8 µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors.


Assuntos
Hidrazonas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/química , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Modelos Moleculares , Difração de Pó , Análise Espectral/métodos
18.
An Acad Bras Cienc ; 90(1 Suppl 2): 1073-1088, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29873669

RESUMO

N-acylhydrazone is an interesting privileged structure that has been used in the molecular design of a myriad of bioactive compounds. In order to identify new antinociceptive drug candidates, we described herein the design, synthesis, X-ray diffraction study and the pharmacological evaluation of a series of 3-amino-4-methylthiophene-2-acylcarbohydrazone derivatives (8a-t). Compounds were prepared in good overall yields through divergent synthesis from a common key intermediate and were characterized by classical spectroscopy methods. X-ray diffraction study was employed for unequivocal determination of the imine double bond stereochemistry. 8a-t were evaluated in vivo through oral administration using the classical writhing test in mice. N-acylhydrazone derivatives 8j and 8l displayed relative potency similar to dipyrone, highlighting them as promising analgesic lead-candidates for further investigation.


Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Hidrazonas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Desenho de Drogas , Hidrazonas/farmacologia , Espectrometria de Massas , Camundongos , Difração de Raios X
19.
Acta Crystallogr C Struct Chem ; 74(Pt 6): 703-714, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29870006

RESUMO

Two chalcones were synthesized by the aldolic condensation of enolizable aromatic ketones with substituted benzaldehydes under Claisen-Schmidt reaction conditions and then treated with 2,4-dinitrophenylhydrazine to yield their corresponding hydrazones. The two (E,Z)-2,4-dinitrophenylhydrazone structures, namely (Z)-1-(2,4-dinitrophenyl)-2-[(E)-3-(4-methylphenyl)-1-phenylallylidene]hydrazine, C22H18N4O4, (H1), and (Z)-1-[(E)-3-(4-chlorophenyl)-1-(naphthalen-1-yl)allylidene]-2-(2,4-dinitrophenyl)hydrazine, C25H17ClN4O4, (H2), were isolated by recrystallization and characterized by FT-IR, UV-Vis, single-crystal and powder X-ray diffraction methods. The UV-Vis spectra of the hydrazones have been studied in two organic solvents of different polarity. It was found that (H2) has a molar extinction coefficient larger than 40000. Single-crystal X-ray diffraction analysis reveals that the molecular zigzag chains of (H1) and (H2) are interconnected through noncovalent contacts. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. All the synthesized chalcones and hydrazones were evaluated for their antibacterial and antioxidant activities. Results indicate that the studied compounds show significant activity against Gram negative Escherichia coli strain and the chalcone 3-(4-methylphenyl)-1-phenylprop-2-en-1-one, (C1), was the most effective. In addition, only hydrazone (H1) displayed a moderate DPPH (2,2-diphenyl-1-picryl hydrazyl) scavenging efficiency.


Assuntos
Antibacterianos/síntese química , Benzaldeídos/química , Compostos de Bifenilo/química , Chalcona/síntese química , Hidrazinas/química , Hidrazinas/síntese química , Hidrazonas/síntese química , Cetonas/química , Antibacterianos/química , Chalcona/química , Cristalografia por Raios X , Hidrazonas/química , Ligações de Hidrogênio , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Int J Mol Sci ; 19(7)2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949884

RESUMO

Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 μM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Hidrazonas/síntese química , Hidrazonas/farmacologia , Níquel/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/química , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Humanos , Hidrazonas/química , Concentração Inibidora 50 , Espaço Intracelular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Soluções
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