RESUMO
Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods & results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC50 = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R2 = 0.844; Q2 = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.
Assuntos
Doença de Chagas/tratamento farmacológico , Diaminas/farmacologia , Nitrilas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Diaminas/síntese química , Diaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Relação Quantitativa Estrutura-Atividade , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
The aim of this study was to synthesize and investigate the in vitro antifungal properties of 23 cinnamyl Schiff bases. In addition, cytotoxic effects of such cinnamyl Schiff bases against human lung, kidney or red blood cells were also checked. The compounds were synthesized in a single-step, 2 min of reaction under microwave irradiation produced up to 97% yield. Six of the 23 cinnamyl Schiff bases possessed antifungal activities against strains of Candida, Aspergillus, Fonsecaea and, particularly, Cryptococcus species. Indeed, cinnamyl Schiff bases 1 and 23 exhibited minimum inhibitory concentration (MIC) values more than twofold lower than fluconazole (FCZ) against all the Cryptococcus neoformans strains (MIC = 1·33, 1·4 and 5·2 µg ml-1 , respectively) and Cryptococcus gattii strains (MIC = 5·3, 2·8 and 9·2 µg ml-1 , respectively) (12 strains of each species) while cinnamyl Schiff base 11 was as potent as FCZ against all strains from both Cryptococcus species. No significant cytotoxic effects were observed for Schiff bases against human lung, kidney or red blood cells, all presenting selective indexes higher than 10. In conclusion, this study revealed cinnamyl Schiff bases, especially 1 and 23, as new lead anticryptococcal agents for the discovery of novel antifungal drugs. SIGNIFICANCE AND IMPACT OF THE STUDY: The occurrence and severity of fungal infections have increased in recent decades due to resistance to available antifungal drugs and the appearance of new emerging pathogens. Thus, the search for new antifungal agents is mandatory. From a series of 23 cinnamyl Schiff bases, two compounds (1 and 23) were interrogated as new anticryptococcal agents without significant cytotoxicity against human lung, kidney or red blood cells. In turns, these new Schiff bases are lead compounds for the discovery of novel antifungal drugs.
Assuntos
Antifúngicos/farmacologia , Micoses/tratamento farmacológico , Bases de Schiff/farmacologia , Antifúngicos/síntese química , Antineoplásicos/farmacologia , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Fonsecaea/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Bases de Schiff/síntese químicaRESUMO
A new series of Cu(II) complexes [bis[{(µ2-chloro)-2-MeO-Ph-CH2-(N=CH)-2,4-tert-butyl-2-OC6H2)}Cu(II)] (Cu1); bis[{(µ2-chloro)-2-MeS-Ph-CH2-(N=CH)-2,4-tert-butyl-2-(OC6H2)}Cu(II)] (Cu2); bis[{(µ2-chloro)-2-MeO-Ph-CH2-(N=CH)-2-(OC10H6)} Cu(II)] (Cu3); bis[{(µ2-chloro)-2-MeS-Ph-CH2-(N=CH)-2-(OC10H6)}Cu(II)] complex (Cu4); bis[{2-MeS-Ph-CH2-(N=CH)-2,4-tert-butyl-2-(OC6H2)}Cu(II)] (Cu5)] have been synthesized and characterized by elemental analysis, IR, UV-Visible and by X-ray crystallography for Cu1, Cu4 and Cu5. In the solid state, Cu1 features of a chloro-bridged dimer complex with κ2 coordination of the monoanionic phenoxy-imine ligand onto the copper center. On the other hand, the molecular structure of Cu4 reveals the naphthoxy-imine ligand with pendant S-group coordinated to the copper atom in tridentate meridional fashion. Treatment of [Cu(OAc)2·H2O] with two equiv. of [2-MeS-Ph-CH2-(N=CH)-2,4-tert-butyl-2-(HOC6H2)] led to a monomeric complex Cu5, with the ONS-donor Schiff base acting as a bidentate ligand. The redox behavior was explored by cyclic voltammetry. The reduction/oxidation potential of Cu(II) complexes depends on the structure and conformation of the central atom in the coordination compounds. Antioxidant activities of the complexes, Cu1 - Cu5, were determined by in vitro assays such as 1,1-diphenyl-2-picryl-hydrazyl free radicals (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radicals (ABTS+). The dinuclear compounds Cu1-Cu4, from the concentration of 5 µM, presented a good activity in scavenging DPPH radical. In addition, most of the Cu(II) complexes showed ABTS.+ radical-scavenging activity. The monomeric complex Cu5 at all concentrations tested showed antioxidant inability. The cytotoxicity of the Cu1 and Cu3 was determined in V79 cell line by reduction of 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay.
Assuntos
Complexos de Coordenação/farmacologia , Sequestradores de Radicais Livres/farmacologia , Bases de Schiff/farmacologia , Animais , Linhagem Celular , Complexos de Coordenação/síntese química , Cobre/química , Cricetulus , Cristalografia por Raios X , Eletroquímica , Sequestradores de Radicais Livres/síntese química , Ligantes , Estrutura Molecular , Oxirredução , Bases de Schiff/síntese química , Relação Estrutura-AtividadeRESUMO
Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including anti-inflammatory, antipyretic, and antimicrobial activities, among others. In this work, we have synthesized 12 Schiff base derivatives of 4-aminoantipyrine. In vitro antimicrobial, antioxidant, and cytotoxicity properties are analyzed, as well as in silico predictive adsorption, distribution, metabolism, and excretion (ADME) and bioactivity scores. Results identify two potential Schiff bases: one effective against E. faecalis and the other with antioxidant activity. Both have reasonable ADME scores and provides a scaffold for developing more effective compounds in the future. Initial studies are usually limited to laboratory in vitro approaches, and following these initial studies, much research is needed before a drug can reach the clinic. Nevertheless, these laboratory approaches are mandatory and constitute a first filter to discriminate among potential drug candidates and chemical compounds that should be discarded.
Assuntos
Ampirona/farmacologia , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Antiprotozoários/farmacologia , Bases de Schiff/farmacologia , Ampirona/síntese química , Ampirona/química , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antioxidantes/síntese química , Antioxidantes/química , Antiprotozoários/síntese química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Relação Estrutura-AtividadeRESUMO
Chitosans are versatile biopolymers recognized for their wide range of biological activities. However, the low solubility in neutral and basic solutions restricts the applications. Thus amphiphilic biopolymeric Schiff bases from chitosans, salicylaldehyde and glycidol were successfully synthesized and characterized using 1H-NMR, UV/Vis, FTIR, TG/DTG-DTA and tested for their antimicrobial activities against plant pathogenic microorganisms and human breast cancer cells (MCF-7). Overall, functionalization of chitosans with salicylaldehyde and glycidol with different molecular weight (Mw¯) was performed to improve the biological actives of chitosans. Thus the biological activity of the new amphiphilic compounds prepared in this work were evaluated regarding microorganisms with agricultural relevance and tumor cells. The biopolymeric amphiphilic Schiff bases showed significant effects against Pseudomonas syringae (IC50 < 5 µg mL-1) compared to the natural chitosans with medium Mw¯ (CHM 223 kDa) and low Mw¯ (CHL 64 kDa), which had IC50 values of 42 and 37 µg mL-1, respectively. In addition, they improved antitumor activity against tumor cells compared to the natural chitosan.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Quitosana , Fusarium/efeitos dos fármacos , Pseudomonas syringae/efeitos dos fármacos , Bases de Schiff , Animais , Células 3T3 BALB , Quitosana/análogos & derivados , Quitosana/química , Quitosana/farmacologia , Humanos , Células MCF-7 , Camundongos , Testes de Sensibilidade Microbiana/métodos , Peso Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , SolubilidadeRESUMO
Chagas disease is a major health problem not only in Latin America but also in Europe and North America due to the spread of this disease into nonendemic areas. In terms of global burden, this major tropical infection is considered to be one of the most neglected diseases, and there are currently only two available chemotherapies: benznidazole and nifurtimox. Unfortunately, although these chemotherapies are beneficial in the acute phase of the disease, benznidazole and nifurtimox lead to significant side effects, including hepatitis and neurotoxicity. Therefore, the search for and development of more effective, safe and inexpensive anti-Trypanosoma cruzi drugs are required. In this work, a series of 10 nitroaromatic Schiff bases bearing different (nitro) aromatic rings-was synthesized. Subsequently, the in vitro and in vivo anti-T. cruzi activities of the Schiff bases were investigated, as well as the in vivo toxicity and the biological effects. The basic structure of the most promising in vivo Schiff base, 10 would be useful in the synthesis of new compounds for Chagas disease treatment.
Assuntos
Hidrocarbonetos Aromáticos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Testes de Toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Administração Oral , Animais , Feminino , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Parasitemia/tratamento farmacológico , Bases de Schiff/química , Bases de Schiff/toxicidade , Tripanossomicidas/química , Tripanossomicidas/toxicidadeRESUMO
In an attempt to enhance chitosan biological activities, biopolymeric Schiff bases of chitosan and different salicylaldehydes and their palladium(II) and platinum(II) complexes were synthesized and tested. The chemical structures of these derivatives were characterized using ¹H-NMR, FTIR spectroscopy and XPRD. Thermal analysis was done through TGA/DTG-DTA. Electronic absorption spectra and surface morphologies were analyzed by SEM-EDAX. Chitosan and its derivatives were evaluated for their in vitro antimicrobial activity against two common bacterial and fungal plant pathogens Pseudomonas syringae pv. tomato and Fusarium graminearum, respectively, and for their antitumor activity against a human breast cancer cell line (MCF-7). It was found that, compared to the nonmodified chitosan, chitosan modified with Schiff bases and their complexes was highly toxic against the MCF-7 cell line and had antibacterial effects against P. syringea. However, the modified chitosan derivatives had less pronounced antifungal effects against F. graminearum compared to the nonmodified chitosan, suggesting different modes of action.
Assuntos
Aldeídos/química , Biopolímeros/química , Quitosana/química , Complexos de Coordenação/síntese química , Bases de Schiff/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Biopolímeros/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Paládio/química , Platina/química , Polimerização , Bases de Schiff/farmacologiaRESUMO
Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.
Assuntos
Antineoplásicos , Membrana Celular , Citotoxinas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias , Salicilatos , Vanadatos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Cisplatino/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/ultraestrutura , Salicilatos/síntese química , Salicilatos/química , Salicilatos/farmacocinética , Salicilatos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacocinética , Bases de Schiff/farmacologia , Vanadatos/síntese química , Vanadatos/química , Vanadatos/farmacocinética , Vanadatos/farmacologiaRESUMO
Two mononuclear MnIII complexes [Mn(3,5-F2salpn)(H2O)2][B(C6H5)4]·2H2O (1·2H2O) and [Mn(3,5-Cl2salpn)(OAc)(H2O)]·H2O (2·H2O), where H2salpn=1,3-bis(salicylidenamino)propane, have been prepared and characterized. The crystal structure of 1·H2O shows that this complex forms µ-aqua dimers with a short Mnâ¯Mn distance of 4.93Å. Under anaerobic conditions, the two complexes are stable in solution and possess trans-diaxial symmetry with the tetradentate Schiff base ligand symmetrically arranged in the equatorial plane. When left in air, these complexes slowly dimerize to yield high-valent [MnIV2(3,5-X2-salpn)2(µ-O)2] in which each X2-salpn ligand wraps the two Mn ions. This process is favored in basic medium where the deprotonation of the bound water molecule is concomitant with air oxidation. The two complexes catalyze the dismutation of superoxide (superoxide dismutase (SOD) activity) and peroxide (catalase (CAT) activity) in basic medium. The phenyl-ring substituents play an important role on the CAT reaction but have little effect on SOD activity. Kinetics and spectroscopic results indicate that 1 and 2 catalyze H2O2 disproportionation through a cycle involving MnIII2 and MnIV2 dimers, unlike related complexes with a more rigid and smaller chelate ring, which employ MnIII/MnVO monomers.
Assuntos
Antioxidantes , Catalase/química , Complexos de Coordenação , Hidrocarbonetos Clorados , Hidrocarbonetos Fluorados , Manganês/química , Superóxido Dismutase/química , Antioxidantes/síntese química , Antioxidantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Hidrocarbonetos Clorados/síntese química , Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Bases de Schiff/síntese química , Bases de Schiff/químicaRESUMO
Nitrone-containing compounds are commonly employed as spin traps of free radical species in chemical and biological studies. Some molecules as α-phenyl-N-t-butyl nitrone (PBN) and its derivatives have been tested as potential drugs to treat oxidative stress related diseases, as Alzheimer and stroke for example. In this work we report the design and the synthesis of α-aryl-N-aryl nitrones and their cytoprotection profile on human neuroblastoma cells (SH-SY5Y) under induced oxidative stress. All the nine synthesized nitrones showed a significant response at low micromolar concentration. The selected compound 8 (α-phenyl-N-phenyl nitrone) increased the reduced glutathione (GSH) levels by 65% and lowered the necrotic cell death from 25.8% to 3.8%. Based on our data, the designed highly conjugated nitrone double-bond skeleton can be considered as a good scaffold for further studies regarding oxidative stress-related diseases.