RESUMO
BACKGROUND: Fungal infections are highly prevalent and are responsible for high rates of morbidity and mortality. In this context, the search for new treatment alternatives is very relevant. OBJECTIVES: Analyse chemical compounds for antifungal potential against dermatomycosis fungi. METHODS: The antifungal activity of 121 compounds, intermediates or derivatives of 1,3-bis(aryloxy)propane substituted at C-2 (111 compounds) and isothiouronium derivatives (10 compounds) was investigated through susceptibility tests, mechanism of action, toxicity and hydrogel incorporation. RESULTS: The compound 1,3-bis(3,4-dichlorophenoxy)propan-2-aminium chloride (2j) was the most active fungicide against dermatophytes and Candida spp., at very low concentrations (0.39-3.12 µg/mL), including action on resistant and multidrug-resistant clinical strains. Compound 2j has presented a promising toxicity profile, showing selectivity index >10, relative to human lymphocytes. The compound was classified as non-irritant by the HET-CAM test and did not cause histopathological alterations in pig ear skin, thus presenting an excellent perspective for topical application. 2j targets the fungal cell wall, which was confirmed by scanning electron microscopy, which also indicated the additional ability of 2j to inhibit the Candida albicans pseudohyphae formation and biofilm of Microsporum canis. Compound 2j was incorporated in a hydrogel with bioadhesive potential. The results of the human skin permeation showed that 2j remained significantly in the epidermis, ideally for the dermatomycosis treatment. CONCLUSIONS: Therefore, the compound 2j demonstrated the potential for antifungal drug development, with a action mechanism elucidated and already applied in a semisolid formulation as a new therapeutic option for fungal skin infections.
Assuntos
Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Candida/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Propano/análogos & derivados , Animais , Antifúngicos/química , Sobrevivência Celular , Células Cultivadas , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Orelha Externa/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Ergosterol/metabolismo , Feminino , Citometria de Fluxo , Humanos , Hidrogéis , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Masculino , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Propano/química , Propano/farmacologia , Reologia , Relação Estrutura-Atividade , SuínosRESUMO
Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.
Assuntos
Antineoplásicos Fitogênicos/química , Propano/análogos & derivados , Pirróis/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Propano/química , Ligação Proteica , Rutaceae/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
3-hydroxypropionaldehyde (3-HPA) and 1,3-propanediol (1,3-PD) are subproducts of glycerol degradation and of economical interest as they are used for polymers synthesis, such as polyesters and polyurethanes. Some few characterized bacterial species (mostly from Firmicutes and Gamma-proteobacteria groups) are able to catabolize these monomers from glycerol using the gene products from the dha regulon. To expand our knowledge and direct further experimental studies on the regulon and related genes for the anaerobic glycerol metabolism, an extensive genomic screening was performed to identify the presence of the dha genes in fully sequenced prokaryotic genomes. Interestingly, this work shows that although only few bacteria species are known to produce 3-HPA or 1,3-PD, the incomplete regulon is found in more than 100 prokaryotic genomes. However, the complete pathway is found only in a few dozen species belonging to five different taxonomic groups, including one Archaea species, Halalkalicoccus jeotgali. Phylogenetic analysis and conservation of both gene synteny and primary sequence similarity reinforce the idea that these genes have a common origin and were possibly acquired by lateral gene transfer (LGT). Besides the evolutionary aspect, the identification of homologs from several different organisms may predict potential alternative targets for faster or more efficient biological synthesis of 3-HPA or 1,3-PD.
Assuntos
Archaea/genética , Bactérias/genética , Evolução Molecular , Gliceraldeído/análogos & derivados , Propano/química , Propilenoglicóis/química , Regulon , Aerobiose , Algoritmos , Sequência de Aminoácidos , Fermentação , Transferência Genética Horizontal , Genoma Arqueal , Genoma Bacteriano , Genômica , Gliceraldeído/química , Glicerol/química , Glicerol/metabolismo , Funções Verossimilhança , Dados de Sequência Molecular , Filogenia , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Flaxseed (Linum usitatissimum L.) oil was obtained via subcritical n-propane fluid extraction (SubFE) under different temperatures and pressures with an average yield of 28% and its composition, purity and oxidative stability were compared to oils obtained via conventional solvent extraction methods (SEMs). When the oxidative stability was measured by differential scanning calorimetry, the oil was found to be up to 5 times more resistant to lipid oxidation as compared to the SEM oils. Direct infusion electrospray ionization mass spectrometry (ESI-MS) analysis showed characteristic and similar TAG profiles for SubFE and SEMs oils but higher purity for the SubFE oil. The flaxseed oil content of ß-tocopherol, campesterol, stigmasterol and sitosterol were quantified via GC-MS. SubFE showed to be a promising alternative to conventional SEM since SubFE provides an oil with higher purity and higher oxidation stability and with comparable levels of biologically active components.
Assuntos
Fracionamento Químico/métodos , Óleo de Semente do Linho/análise , Óleo de Semente do Linho/química , Propano/química , Varredura Diferencial de Calorimetria , Colesterol/análogos & derivados , Colesterol/análise , Cromatografia Gasosa-Espectrometria de Massas , Óleo de Semente do Linho/normas , Oxirredução , Fitosteróis/análise , Pressão , Análise de Componente Principal , Sitosteroides/análise , Espectrometria de Massas por Ionização por Electrospray , Estigmasterol/análise , Temperatura , beta-Tocoferol/análiseRESUMO
In the title compound, C26H20ClNO3, the quinoline fragment is nearly orthogonal to the adjacent aryl ring, while the rest of the molecular skeleton is close to being planar. The crystal structure contains no hydrogen bonds of any sort, but there are two π-π stacking interactions present. One, involving the quinoline ring, links molecules related by inversion, while the other, involving the two nonfused aryl rings, links molecules related by translation, so together forming a ladder-type arrangement.
Assuntos
Propano/análogos & derivados , Quinolinas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , Propano/químicaRESUMO
Previously, we found that the nitrate synthesized from glycerin, 2-nitrate-1,3-dibuthoxypropan (NDBP), increased NO levels in rat aortic smooth muscle cells, inducing vasorelaxation in mesenteric artery. However, its effects on blood pressure and heart rate as well as on autonomic function were not investigated. This study evaluated the action of NDBP on these cardiovascular parameters in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats. We found that NDBP causes a biphasic response: hypotension and bradycardia followed by hypertension and tachycardia in WKY and SHR rats. Atropine (2mg/kg) blunted the hypotension induced by NDBP (15 mg/kg) in WKY and SHR (-75 ± 9 vs -12 ± 3 mmHg, n=6; -101 ± 6 vs -7 ± 2 bpm, n=6; respectively, p<0.05) and the pressor response to the compound was potentiated. Furthermore, vagotomy reduced the bradycardia in WKY and SHR (-136 ± 8 vs -17 ± 2, n=4, p<0.05; -141 ± 9 vs -8 ± 2, n=6, p<0.05). Moreover, hexamethonium (30 mg/kg) reduced both bradycardia (-278 ± 23 vs -48 ± 3 in WKY; -285 ± 16 vs -27 ± 19 in SHR, n=4; p<0.05) and pressor response (28 ± 8 vs -9 ± 5-WKY, n=6; 42 ± 7 vs -19 ± 8-SHR, n=5; p<0.05). In addition, administration of methylene blue (4 mg/kg) attenuated the hypotensive and bradycardic responses to the NDBP in all groups. In conclusion, NDBP induces bradycardia by direct vagal stimulation and pressor response by increasing sympathetic outflow to the periphery.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Propano/análogos & derivados , Ratos Endogâmicos SHR , Análise de Variância , Animais , Atropina/farmacologia , Inibidores Enzimáticos/farmacologia , Masculino , Azul de Metileno/farmacologia , Nitratos/química , Doadores de Óxido Nítrico/química , Parassimpatolíticos/farmacologia , Propano/química , Propano/farmacologia , Ratos , Ratos Endogâmicos WKY , Vagotomia , VigíliaRESUMO
The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30 µM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10 µM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20 mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1 mM), charybdotoxin-ChTX (B(KCa), 100 nM), glibenclamide (K(ATP), 1µM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10 µM) plus TEA (1 mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway.
Assuntos
Artérias Mesentéricas/efeitos dos fármacos , Nitratos/metabolismo , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Propano/análogos & derivados , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Sequestradores de Radicais Livres/farmacologia , Glicerol/química , Guanilato Ciclase/antagonistas & inibidores , Técnicas In Vitro , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Artérias Mesentéricas/citologia , Artérias Mesentéricas/fisiologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Nitratos/síntese química , Nitratos/química , Óxido Nítrico/biossíntese , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/metabolismo , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Propano/síntese química , Propano/química , Propano/metabolismo , Propano/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Guanilil Ciclase Solúvel , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/química , Vasodilatadores/metabolismoRESUMO
This study aimed at assessing the influence of different pressurized fluids treatment on the enzymatic activity and stability of a lyophilized ß-galactosidase. The effects of system pressure, exposure time and depressurization rate, using propane, n-butane, carbon dioxide and liquefied petroleum gas on the enzymatic activity were evaluated. The ß-galactosidase activity changed significantly depending on the experimental conditions investigated, allowing the selection of the proper compressed fluid for advantageous application of this biocatalyst in enzymatic reactions. The residual activity ranged from 32.1 to 93.8 % after treatment. The storage stability of the enzyme after high-pressure pre-treatment was also monitored, and results showed that the biocatalyst activity presents strong dependence of the fluid used in the pretreatment. The activity gradually decreases over the time for the enzyme treated with LGP and propane, while the enzyme treated with n-butane maintained 96 % of its initial activity until 120 days. For CO(2), there was a reduction of around 40 % in the initial activity 90 days of storage. The enzyme treated with n-butane also showed a better thermostability in terms of enzymatic half-life.
Assuntos
Proteínas Fúngicas/química , Kluyveromyces/enzimologia , Pressão , beta-Galactosidase/química , Butanos/química , Dióxido de Carbono/química , Estabilidade Enzimática , Propano/químicaRESUMO
The gas-phase thermal elimination of 2,2-diethoxypropane was found to give ethanol, acetone, and ethylene, while 1,1-diethoxycyclohexane yielded 1-ethoxycyclohexene and ethanol. The kinetics determinations were carried out, with the reaction vessels deactivated with allyl bromide, and the presence of the free radical suppressor cyclohexene and toluene. Temperature and pressure ranges were 240.1-358.3 °C and 38-102 Torr. The elimination reactions are homogeneous, unimolecular, and follow a first-order rate law. The rate coefficients are given by the following Arrhenius equations: for 2,2-diethoxypropane, log k(1) (s(-1)) = (13.04 ± 0.07) - (186.6 ± 0.8) kJ mol(-1) (2.303RT)(-1); for the intermediate 2-ethoxypropene, log k(1) (s(-1)) = (13.36 ± 0.33) - (188.8 ± 3.4) kJ mol(-1) (2.303RT)(-1); and for 1,1-diethoxycyclohexane, log k = (14.02 ± 0.11) - (176.6 ± 1.1) kJ mol(-1) (2.303RT)(-1). Theoretical calculations of these reactions using DFT methods B3LYP, MPW1PW91, and PBEPBE, with 6-31G(d,p) and 6-31++G(d,p) basis set, demonstrated that the elimination of 2,2-diethoxypropane and 1,1-diethoxycyclohexane proceeds through a concerted nonsynchronous four-membered cyclic transition state type of mechanism. The rate-determining factor in these reactions is the elongation of the C-O bond. The intermediate product of 2,2-diethoxypropane elimination, that is, 2-ethoxypropene, further decomposes through a concerted cyclic six-membered cyclic transition state mechanism.
Assuntos
Cicloexanos/química , Gases/química , Propano/análogos & derivados , Teoria Quântica , Cinética , Estrutura Molecular , Propano/químicaRESUMO
This work reports new experimental data and mathematical modeling of lipase-catalyzed biodiesel production using soybean oil and ethanol as substrates and pressurized n-propane as solvent. The experiments were carried out in a batch reactor, recording the reaction kinetics and evaluating the effects of temperature in the range of 45-70 degrees C, enzyme content from 1 to 20 wt% and oil to ethanol molar ratios of 1:3, 1:6, 1:9 and 1:15. The solvent to substrates mass ratio and pressure were set at 2:1 and 50 bar, respectively. Results showed that lipase-catalyzed alcoholysis in propane medium might be a potential alternative to conventional techniques for biodiesel production, since good conversions were obtained at mild temperature and pressure conditions. The semi-empirical mathematical model based on balance equations, adopted to describe the transesterification kinetics in pressurized n-propane, yielded relative deviations between experimental and calculated values lower than 10%, thus allowing a satisfactory representation of experimental results and a better understanding of the transesterification reaction.