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1.
Chem Commun (Camb) ; 56(3): 415-418, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821393

RESUMO

We report a novel 1,2-catechol based radioiodinated precursor for radioiodination of bicyclo[6.1.0]nonyne (BCN) installed biologically active molecules using a strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition reaction (SPOCQ) under ambient conditions. Compared to the reported methodologies, the new strategy demonstrates some clear advantages, including high in vitro and in vivo stability, high radiochemical yield, and exceptionally fast reaction kinetics at micro-molar concentration.


Assuntos
Reação de Cicloadição , Quinonas/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Catecóis/química , Coração/diagnóstico por imagem , Radioisótopos do Iodo/química , Marcação por Isótopo , Cinética , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
2.
Molecules ; 24(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234360

RESUMO

Volatile terpenes represent the largest group of Cannabis sativa L. components and they are responsible for its aromatic properties. Even if many studies on C. sativa have been focused on cannabinoids, which are terpenophenolics, little research has been carried out on its volatile terpenic compounds. In the light of all the above, the present work was aimed at the chemical characterization of seventeen essential oils from different fibre-type varieties of C. sativa (industrial hemp or hemp) by means of GC-MS and GC-FID techniques. In total, 71 compounds were identified, and the semi-quantitative analysis revealed that α- and ß-pinene, ß-myrcene and ß-caryophyllene are the major components in all the essential oils analysed. In addition, a GC-MS method was developed here for the first time, and it was applied to quantify cannabinoids in the essential oils. The antibacterial activity of hemp essential oils against some pathogenic and spoilage microorganisms isolated from food and food processing environment was also determined. The inhibitory effects of the essential oils were evaluated by both the agar well diffusion assay and the minimum inhibitory concentration (MIC) evaluation. By using the agar diffusion method and considering the zone of inhibition, it was possible to preliminarily verify the inhibitory activity on most of the examined strains. The results showed a good antibacterial activity of six hemp essential oils against the Gram-positive bacteria, thus suggesting that hemp essential oil can inhibit or reduce bacterial proliferation and it can be a valid support to reduce microorganism contamination, especially in the food processing field.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cannabis/química , Óleos Voláteis/farmacologia , Antibacterianos/química , Bactérias/patogenicidade , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/isolamento & purificação , Canabinoides/química , Cromatografia Gasosa-Espectrometria de Massas , Testes de Sensibilidade Microbiana , Monoterpenos/química , Monoterpenos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Terpenos/química
3.
Chempluschem ; 84(5): 493-497, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31245251

RESUMO

Fluorogenic bioorthogonal reactions enable visualization of biomolecules with excellent signal-to-noise ratio. A bicyclononyne-tetrazine ligation that produces fluorescent pyridazine products has been developed. In stark contrast to previous approaches, the formation of the dye is an inherent result of the chemical reaction and no additional fluorophores are needed in the reagents. The crucial structural elements that determine dye formation are electron-donating groups present in the starting tetrazine unit. The newly formed pyridazine fluorophores show interesting photophysical properties the fluorescence intensity increase in the reaction can reach an excellent 900-fold. Model imaging experiments demonstrate the application potential of this new fluorogenic bioorthogonal reaction.


Assuntos
Compostos Bicíclicos com Pontes/química , Corantes Fluorescentes/química , Piridazinas/química , Linhagem Celular Tumoral , Reação de Cicloadição , Compostos Heterocíclicos com 1 Anel/química , Humanos , Microscopia Confocal
4.
Chemistry ; 25(45): 10698-10709, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31149749

RESUMO

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N',N'-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of GaIII -based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68 Ga radiolabeling under truly physiological conditions (pH 7.4).


Assuntos
Compostos Bicíclicos com Pontes/química , Quelantes/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Teoria da Densidade Funcional , Radioisótopos de Gálio/química , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Cinética , Conformação Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Transferrina/química
5.
Org Biomol Chem ; 17(22): 5615-5632, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120090

RESUMO

Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.


Assuntos
Antibacterianos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Cisteína/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cisteína/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
6.
Pharmazie ; 74(3): 147-149, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961679

RESUMO

Mirogabalin, which is a novel ligand for the α2δ subunit of voltage-gated calcium channels, is being developed for treating neuropathic pain including diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique α2δ subunit binding characteristics and has potent and long-lasting analgesic effects in neuropathic pain models. In the present study, we investigated the effects of mirogabalin on N-type calcium channel currents of the rat dorsal root ganglion (DRG) culture neurons using the whole-cell patch clamp technique. Small or medium DRG neurons were isolated from Sprague-Dawley rats and were incubated for 20 to 24 h with mirogabalin or pregabalin. The DRG neurons were depolarised from a holding potential of -40 mV to +40 mV in steps of 10 mV for 220 ms, and elicited N-type calcium channel currents were recorded. The N-type calcium channel currents were verified by sensitivity to ω-conotoxin GVIA, a selective N-type calcium channel blocker. Mirogabalin inhibited the calcium channel currents of rat DRG neurons at 50 µM, and pregabalin inhibited them at 200 µM. Mirogabalin and pregabalin showed significant differences in the peak current densities at depolarisation to -20 and -10 mV when compared with that shown by the vehicle control. In conclusion, mirogabalin inhibits N-type calcium channel currents in rat DRG culture neurons. The potent and long-lasting analgesic effects of mirogabalin are thought to be associated with its potent and selective binding to α2δ-1 subunits and following functional inhibition of calcium channel currents.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Gânglios Espinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Compostos Bicíclicos com Pontes/química , Bloqueadores dos Canais de Cálcio/química , Células Cultivadas , Conotoxinas/farmacologia , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Neurônios/metabolismo , Técnicas de Patch-Clamp , Pregabalina/farmacologia , Ratos , Ratos Sprague-Dawley
7.
Bull Environ Contam Toxicol ; 102(6): 848-853, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989280

RESUMO

In this study, the detection power of a gas chromatography mass spectrometer (GC-MS) for procymidone and chlorflurenol was significantly enhanced using switchable solvent liquid phase microextraction (SS-LPME) as a preconcentration tool. This was achieved by a comprehensive optimization of significant parameters to the SS-LPME method such as switchable solvent amount, concentration and amount of sodium hydroxide, pH effect and mixing effect. The optimum experimental conditions obtained were used to determine analytical figures of merit for the analytes. The limits of detection obtained were 0.44 and 2.9 ng/mL for procymidone and chlorflurenol, respectively. The optimum method was applied to water sampled from an irrigation canal and two wastewater samples. The samples were spiked at two concentrations and the percent recovery results obtained ranged between 86 and 115% for both analytes. The recovery results together with the low standard deviations recorded validated the method as accurate and precise.


Assuntos
Compostos Bicíclicos com Pontes/análise , Fluorenos/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise , Irrigação Agrícola , Compostos Bicíclicos com Pontes/química , Fluorenos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Microextração em Fase Líquida/métodos , Solventes/química , Água/química
8.
ACS Chem Biol ; 14(5): 1011-1019, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30977996

RESUMO

The natural product sesquisabinene is a key component of the fragrant essential oil of the sandalwood tree, currently valued at $5,000/L. Sesquisabinene contains a highly strained [3.1.0] bicyclic ring system and is generated from farnesyl diphosphate in a reaction catalyzed by a class I terpenoid cyclase. To understand how the enzyme directs the formation of a strained hydrocarbon ring system, we now report the X-ray crystal structure of sesquisabinene synthase 1 (SQS1) from the Indian sandalwood tree ( Santalum album). Specifically, we report the structure of unliganded SQS1 at 1.90 Å resolution and the structure of its complex with three Mg2+ ions and the inhibitor ibandronate at 2.10 Å resolution. The bisphosphonate group of ibandronate coordinates to all three metal ions and makes hydrogen bond interactions with basic residues at the mouth of the active site. These interactions are similarly required for activation of the substrate diphosphate group to initiate catalysis, although partial occupancy binding of the Mg2+B ion suggests that this structure represents the penultimate metal coordination complex just prior to substrate activation. The structure of the liganded enzyme enables a precise definition of the enclosed active site contour that serves as a template for the cyclization reaction. This contour is very product-like in shape and readily fits an extended conformation of sesquisabinene and its precursor, the homobisabolyl cation. Structural comparisons of SQS1 with epi-isozizaene synthase mutants that also generate sesquisabinene suggest that [3.1.0] ring formation is not dependent on the isoprenoid tail conformation of the homobisabolyl cation.


Assuntos
Compostos Bicíclicos com Pontes/química , Carbono-Carbono Liases/química , Catálise , Domínio Catalítico , Ligações de Hidrogênio , Ácido Ibandrônico/química , Magnésio/química , Conformação Molecular
9.
Methods Mol Biol ; 1973: 1-13, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016692

RESUMO

Chemical modification of nucleic acids can be achieved by the enzymatic polymerization of modified nucleoside triphosphates (dN*TPs). This approach obviates some of the requirements and drawbacks imposed by the more traditional solid-phase synthesis of oligonucleotides. Here, we describe the protocol that is necessary to synthesize dN*TPs and evaluate their substrate acceptance by polymerases for their subsequent use in various applications including selection experiments to identify aptamers. The protocol is exemplified for a sugar-constrained nucleoside analog, 7',5'-bc-TTP.


Assuntos
Compostos Bicíclicos com Pontes/química , DNA/biossíntese , Nucleotídeos/química , Açúcares/química , DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Oligonucleotídeos/química , Técnicas de Síntese em Fase Sólida
10.
Methods Mol Biol ; 1973: 59-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016696

RESUMO

This chapter describes procedures for (1) the synthesis of six 2'-C,4'-C-ethyleneoxy-bridged thymidine phosphoramidites, i.e., methylene-EoDNA-T, (R)-Me-methylene-EoDNA-T, (S)-Me-methylene-EoDNA-T, EoDNA-T, (R)-Me-EoDNA-T, and (S)-Me-EoDNA-T phosphoramidites, (2) the introduction of the phosphoramidites into oligonucleotides, (3) UV-melting experiments of the duplexes of the modified oligonucleotides and complementary RNA, and (4) nuclease degradation experiments of the modified oligonucleotides.


Assuntos
Compostos Bicíclicos com Pontes/química , DNA/biossíntese , DNA/química , Desoxirribonucleases/metabolismo , Etilenos/química , Timina/química , Estabilidade Enzimática
11.
Electrophoresis ; 40(15): 1931-1940, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30710369

RESUMO

The present study investigated the separation of bicyclic ß-amino acids with bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane and cyclopenta[d][1,2]oxazole core structures by capillary electrophoresis using native cyclodextrins as well as neutral and charged derivatives as chiral selectors. The amino acids were derivatized with dansyl chloride to provide a UV chromophore. Separations were carried out at 20°C in a 48.5/40 cm, 50 µm fused-silica capillary at an applied voltage of 20 kV. Fifty millimolar sodium phosphate background electrolytes pH 2.5 and 7.2 containing either 5 or 30 mg/mL of the CDs were used. For the majority of the investigated CDs, enantioseparations could only be achieved at pH 2.5 when the analytes are positively charged. Successful enantioseparations as negatively charged analytes at pH 7.2 were only observed for few compounds. In the case of methyl-γ-cyclodextrin, opposite enantiomer migration order was observed in pH 2.5 or 7.2 background electrolytes. Dependence of the enantiomer migration order on the size of the cavity of the cyclodextrins was also found. Furthermore, the degree of methylation of ß-cyclodextrin derivatives affected the migration order of several analyte enantiomers.


Assuntos
Aminoácidos/isolamento & purificação , Compostos Bicíclicos com Pontes/química , Ciclodextrinas/química , Eletroforese Capilar/métodos , Octanos/química , Oxazóis/química , Aminoácidos/análise , Aminoácidos/química , Compostos de Dansil/química
13.
Molecules ; 24(2)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30634693

RESUMO

Here, we investigated the anti-oxidant and anti-melanogenic effects of pomelo peel essential oil (PPEO) from pomelo cv. Guan Xi. The volatile chemical composition of PPEO was analyzed with gas chromatography⁻mass spectrometry (GC/MS). The most abundant component of PPEO was limonene (55.92%), followed by ß-myrcene (31.17%), and ß-pinene (3.16%). PPEO showed strong anti-oxidant activities against 1,1-diphenyl-2-picryhydrazyl (DPPH) (,2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) (, and superoxide anion free radicals. Based on the B16 melanoma cell system, the effects of PPEO on the viability and morphology of B16 cells and the production of melanin were evaluated. The results revealed that PPEO at concentrations below 50 µg/mL could decrease the melanin content without affecting cell viability and morphology. Intracellular tyrosinase (TYR) activity and Western blot analysis showed that PPEO could down-regulate the expression level of TYR in B16 cells and dose-dependently inhibit TYR activity (by a maximum of 64.54%). Meanwhile, the main active components responsible for the effect are citral and ß-myrcene. In conclusion, PPEO has good anti-oxidant and anti-melanogenic activity, and thus can be widely used as a natural antioxidant in the food, pharmaceutical, and cosmetic industries.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Citrus/química , Melanoma/enzimologia , Óleos Voláteis/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Cromatografia Gasosa-Espectrometria de Massas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Limoneno/química , Limoneno/farmacologia , Melanoma/tratamento farmacológico , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Monoterpenos/química , Monoterpenos/farmacologia , Óleos Voláteis/química , Óleos Vegetais/química , Óleos Vegetais/farmacologia
14.
Org Biomol Chem ; 17(5): 1037-1052, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30620036

RESUMO

Natural products (NPs) have been shown to be an extraordinary source of bioactive compounds and three-dimensional complex frameworks that can be useful to produce high-value molecular collections that are able to address "undruggable" and difficult therapeutic targets. Bicyclic acetals are particularly relevant for these purposes, given their key role in several biological interactions and the structural and stereochemical diversity that comes from the many possible ring combinations. To investigate this topological diversity, we have systematically characterized in a systematic and detailed manner fused, spiro and bridged bicyclic acetals in a large set of NPs, highlighting the great potential of bicyclic acetals in Diversity-Oriented Synthesis (DOS). Accordingly, a summary of some recent efforts on the development of acetal-containing small molecule collections through DOS approaches is herein reported.


Assuntos
Acetais/química , Produtos Biológicos/química , Compostos Bicíclicos com Pontes/química , Produtos Biológicos/síntese química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
15.
ACS Chem Neurosci ; 10(1): 221-225, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30462482

RESUMO

While resveratrol protects organisms from the deleterious effects of oxidative stress, its multifarious mechanism of action limits its potential as a selective medicinal agent. To address this shortcoming, we have designed a molecular scaffold that we have termed a resveramorph. The structure of this compound class possesses much of the functional group characteristics of resveratrol but in a nonplanar molecular arrangement, and, in the present work, we probe the neuroprotective activities of two resveramorph analogues. These novel compounds were found to protect neurotransmission from hydrogen peroxide-induced oxidative stress. Our findings demonstrate that, at a subnanomolar level, one analogue, resveramorph 1, protects synaptic transmission from acute oxidative stress at the Drosophila neuromuscular junction. These results position resveramorphs as potential lead compounds in the development of new drugs for neurodegenerative diseases.


Assuntos
Antioxidantes/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Resveratrol/farmacologia , Transmissão Sináptica/fisiologia , Animais , Antioxidantes/química , Compostos Bicíclicos com Pontes/química , Drosophila melanogaster , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/química , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos
16.
Bioorg Med Chem ; 27(2): 338-342, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30545734

RESUMO

Isocarbacyclin is a valuable synthetic analogue of prostacyclin with potential neuroprotective effects for the treatment of ischemic stroke. Herein, we describe the synthesis of isocarbacyclin and bicyclic analogues in only 7-10 steps, with the ω-side chain diversified at a late stage. A combination of new reaction design, function-oriented synthesis, and late-stage diversification led to a series of compounds that were tested for their neuroprotective activities. Efforts toward the synthesis of tricyclic analogues of isocarbacyclin, using the same combination of metal-catalyzed reactions, is also described.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Epoprostenol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Epoprostenol/síntese química , Epoprostenol/química , Epoprostenol/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estereoisomerismo , Acidente Vascular Cerebral/tratamento farmacológico
17.
Chemistry ; 25(14): 3496-3500, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30589135

RESUMO

The PYR/PYL/RCAR protein families have recently emerged as receptors of the phytohormone abscisic acid (ABA, 1), which regulates plant responses to environmental stress. These families have multiple members with different physiological actions, and so selective agonists or antagonists are needed both as tools to elucidate functional differences and as lead compounds for agrochemicals. We previously identified RK460 (rac-3 a) as a PYR1-selective antagonist, and showed that it possesses five stereocenters on a 6,5-cis-bicyclo skeleton. Here, we synthesized all the stereoisomers of RK460 and evaluated their activity towards a panel of receptors. Relative stereochemistry as well as absolute stereochemistry was important for selective action.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/antagonistas & inibidores , Arabidopsis/efeitos dos fármacos , Compostos Bicíclicos com Pontes/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Reguladores de Crescimento de Planta/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Reguladores de Crescimento de Planta/síntese química , Reguladores de Crescimento de Planta/química , Receptores de Superfície Celular/metabolismo , Estereoisomerismo
18.
Bioorg Med Chem Lett ; 29(2): 248-251, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30501964

RESUMO

An innovative and efficient reagent- and scaffold-based diversity oriented synthesis (DOS) of a fragment set was developed for fragment-based drug discovery (FBDD) programs. Twelve diverse, functionalized and bicyclic scaffolds were rapidly accessed by adopting a convenient synthetic toolkit around three privileged azine cores in order to effectively modulate biomolecules. These structures are characterized by both key motifs for interacting with diverse biological targets via hydrogen bonds and useful points of growth for subsequent fragment optimization.


Assuntos
Compostos Azo/síntese química , Compostos Bicíclicos com Pontes/síntese química , Compostos Azo/química , Compostos Bicíclicos com Pontes/química , Descoberta de Drogas , Ligações de Hidrogênio , Estrutura Molecular
19.
Curr Top Med Chem ; 18(29): 2481-2490, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30430938

RESUMO

AIMS: The objective of this study was to investigate the effectiveness of (+)-ß-pinene inhibition on Candida spp. growth, aiming at elucidation of the mechanism of action; to determine fungal cell enzyme binding activity (through molecular docking simulations) and its effects on biofilm reduction. METHODS: Candida strains (n=25) from referenced and clinical origins, either susceptible or resistant to standard clinical antifungals, were tested for determination of Minimum Inhibitory Concentration (MIC); Minimum Fungicidal Concentration (MFC); and microbial death curves upon treatment with (+)-ß-pinene; the effects of (+)-ß-pinene on the cell wall (sorbitol assay), membrane ergosterol binding, and effects on biofilm were evaluated by microdilution techniques. We also evaluated the interactions between (+)-ß-pinene and cell wall and membrane enzymes of interest. RESULTS: The MIC values of (+)-ß-pinene ranged from <56.25 to 1800 µmol/L. The MIC of (+)-ß-pinene did not increase when ergosterol was added to the medium, however it did increase in the presence of sorbitol, leading to a doubled MIC for C. tropicalis and C. krusei. The results of the molecular docking simulations indicated better interaction with delta-14-sterol reductase (-51 kcal/mol). (+)-ß-pinene presents anti-biofilm activity against multiples species of Candida. CONCLUSION: (+)-ß-pinene has antifungal activity and most likely acts through interference with the cell wall; through molecular interaction with Delta-14-sterol reductase and, to a lesser extent, with the 1,3-ß- glucan synthase. This molecule was also found to effectively reduce Candida biofilm adhesion.


Assuntos
Antifúngicos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Candida/efeitos dos fármacos , Monoterpenos/farmacologia , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Compostos Bicíclicos com Pontes/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Monoterpenos/química , Estereoisomerismo
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