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1.
Int J Mol Sci ; 24(19)2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37834396

RESUMO

Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ's significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the ß-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the ß-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ's potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.


Assuntos
Antiprotozoários , Giardia lamblia , Giardíase , Animais , Camundongos , Albendazol/química , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Tubulina (Proteína) , Simulação de Acoplamento Molecular , Solubilidade
2.
Molecules ; 28(10)2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37241736

RESUMO

Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik-Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 µg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.


Assuntos
Micoses , Scedosporium , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Voriconazol/farmacologia , Micro-Ondas , Micoses/tratamento farmacológico , Testes de Sensibilidade Microbiana
3.
Molecules ; 28(17)2023 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-37687053

RESUMO

Salvia hispanica L., commonly known as chía, and its seeds have been used since ancient times to prepare different beverages. Due to its nutritional content, it is considered a dietary ingredient and has been reported with many health benefits. Chia seed components are helpful in cardiovascular disease (CVD) by reducing blood pressure, platelet aggregation, cholesterol, and oxidation. Still, its vasodilator effects on the vascular system were not reported yet. The hexanic (HESh), dichloromethanic (DESh), and methanolic (MESh) extracts obtained from chía seeds were evaluated on an aortic ring ex-vivo experimental model. The vasorelaxant efficacy and mechanism of action were determined. Also, phytochemical data was obtained through 13C NMR-based dereplication. The MESh extract showed the highest efficacy (Emax = 87%), and its effect was partially endothelium-dependent. The mechanism of action was determined experimentally, and the vasorelaxant curves were modified in the presence of L-NAME, ODQ, and potassium channel blockers. MESh caused a relaxing effect on KCl 80 mM-induced contraction and was less potent than nifedipine. The CaCl2-induced contraction was significantly decreased compared with the control curve. Phytochemical analysis of MESh suggests the presence of mannitol, previously reported as a vasodilator on aortic rings. Our findings suggest NO-cGMP pathway participation as a vasodilator mechanism of action of S. hispanica seeds; this effect can be attributed, in part, to the mannitol presence. S. hispanica could be used in future research focused on antihypertensive therapies.


Assuntos
Salvia hispanica , Vasodilatadores , Vasodilatadores/farmacologia , Óxido Nítrico , Nifedipino
4.
Microb Cell Fact ; 21(1): 96, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643468

RESUMO

Low-cost substrates are an exciting alternative for bioprocesses; however, their complexity can affect microorganism metabolism with non-desirable outcomes. This work evaluated banana peel extract (BPE) as a growth medium compared to commercial Yeast-Malt (YM) broth in the native and non-conventional yeast Rhodotorula mucilaginosa UANL-001L. The production of carotenoids, fatty acids, and exopolysaccharides (EPS) was also analyzed. Biomass concentration (3.9 g/L) and growth rate (0.069 g/h) of Rhodotorula mucilaginosa UANL-001L were obtained at 200 g/L of BPE. Yields per gram of dry biomass for carotenoids (317 µg/g) and fatty acids (0.55 g/g) showed the best results in 150 g/L of BPE, while 298 µg/g and 0.46 mg/g, respectively, were obtained in the YM broth. The highest yield of EPS was observed in 50 g/L of BPE, a two-fold increase (160.1 mg/g) compared to the YM broth (76.3 mg/g). The fatty acid characterization showed that 100 g/L of BPE produced 400% more unsaturated compounds (e.g., oleic and ricinoleic acid) than the YM broth. Altogether, these results indicate that BPE is a suitable medium for producing high-value products with potential industrial applications.


Assuntos
Musa , Rhodotorula , Carotenoides/metabolismo , Meios de Cultura/metabolismo , Ácidos Graxos/metabolismo , Rhodotorula/metabolismo , Leveduras
5.
Bioorg Med Chem Lett ; 70: 128804, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35598791

RESUMO

In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a set of three proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1-3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1-3 did it over PPARα. Compounds 1-3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1-3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects.


Assuntos
Hipoglicemiantes , PPAR gama , Animais , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Lipídeos , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos , Tiazolidinas/farmacologia
6.
Dis Aquat Organ ; 151: 11-22, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36047670

RESUMO

Panulirus argus virus 1 (PaV1) (Family Mininucleoviridae) causes chronic and systemic infection in wild juvenile spiny lobsters Panulirus argus (Latreille, 1804), ending in death by starvation and metabolic wasting. In marine decapods, the antennal gland is involved in osmoregulation and excretion. In this compact organ, fluid is filtered from the hemolymph, and ions are reabsorbed to produce a hypotonic urine. Although PaV1 is released with the urine in infected individuals, little is known regarding the metabolic effect of PaV1 in the antennal gland. The objective of this study was to perform a comparative evaluation of the metabolic profile of the antennal gland of clinically PaV1-infected lobsters versus those with no clinical signs of infection, using proton nuclear magnetic resonance analysis. Overall, 48 compounds were identified, and the most represented metabolites were those involved in carbohydrate, amino acid, energy, and nucleotide metabolism. Most of the metabolites that were down-regulated in the infected group were essential and non-essential amino acids. Some metabolites involved in the urea cycle and carbohydrate metabolism were also altered. This study represents a first approach to the metabolic evaluation of the antennal gland. We broadly discuss alterations in the content of several proteinogenic and non-proteinogenic amino acids and other key metabolites involved in energetic and nucleotide metabolism.


Assuntos
Crangonidae , Palinuridae , Aminoácidos , Animais , Região do Caribe , Vírus de DNA , Nucleotídeos
7.
Molecules ; 27(12)2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35745009

RESUMO

The Scedosporium genus is an emerging pathogen with worldwide prevalence and high mortality rates that gives multidrug resistance to antifungals; therefore, pharmacological alternatives must be sought for the treatment of diseases caused by this fungus. In the present project, six new α-aminophosphates were synthesized by the Kabachnik-Fields multicomponent reaction by vortex agitation, and six new monohydrolyzed α-aminophosphonic acids were synthesized by an alkaline hydrolysis reaction. Antifungal activity was evaluated using the agar diffusion method as an initial screening to determine the most active compound compared to voriconazole; then it was evaluated against 23 strains of the genus Scedosporium following the M38-A2 protocol from CLSI (activity range: 648.76-700 µg/mL). Results showed that compound 5f exhibited the highest antifungal activity according to the agar diffusion method (≤1 mg/mL). Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay and it was shown that compound 5f exhibits a lower toxicity in comparison to voriconazole at the same concentration (1000 µM). A docking study was conducted afterwards, showing that the possible mechanism of action of the compound is through the inhibition of allosteric 14-α-demethylase. Taking these results as a basis, 5f is presented as a compound with attractive properties for further studies.


Assuntos
Scedosporium , Ágar , Antifúngicos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Voriconazol/farmacologia
8.
Molecules ; 27(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36432034

RESUMO

Flavonoids are naturally occurring compounds widely distributed in the Citrus genus. These natural compounds have many health benefits, mainly for metabolic and cardiovascular diseases. In fact, some these compounds are components of drug products with approved indications for peripheral vascular insufficiency and hemorrhoids. However, information on pharmacological effects of these compounds remains disperse and there is scarce comprehensive analysis of whole data and evidence. These kinds of evidence analyses could be necessary in drug design and the development of novel and innovate drug products in diabetes and hypertension. We aimed to systematically search for evidence on the efficacy of citroflavonoids in diabetes and hypertension in in vivo models. We searched four literature databases based on a PICO strategy. After database curation, twenty-nine articles were retrieved to analyze experimental data. There was high heterogeneity in both outcomes and methodology. Naringenin and hesperetin derivates were the most studied citroflavonoids in both experimental models. More investigation is still needed to determine its potential for drug design and development.


Assuntos
Citrus , Diabetes Mellitus , Hipertensão , Hipertensão/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas , Flavonoides/farmacologia , Flavonoides/uso terapêutico
9.
Molecules ; 27(2)2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35056705

RESUMO

This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes' activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.


Assuntos
Disponibilidade Biológica
10.
Bull Environ Contam Toxicol ; 108(1): 93-98, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33954861

RESUMO

Degradation efficiency of a heavy crude oil by a marine microbial consortium was evaluated in this study, with and without the addition of a chemical dispersant (Nokomis 3-F4). 15.50% of total petroleum hydrocarbons (TPH) were removed after 15 days of incubation without dispersant, with a degradation rate of 2.39 ± 0.22 mg L-1 day-1. In contrast, the addition of Nokomis 3-F4 increased TPH degradation up to 30.81% with a degradation rate of 5.07 ± 0.37 mg L-1 day-1. 16S rRNA gene sequencing indicated a dominance of the consortium by Achromobacter and Alcanivorax. Nonetheless, significant increases in the relative abundance of Martelella and Ochrobactrum were observed with the addition of Nokomis 3-F4. These results will contribute to further environmental studies of the Gulf of Mexico, where Nokomis 3-F4 can be used as chemical dispersant.


Assuntos
Poluição por Petróleo , Petróleo , Poluentes Químicos da Água , Biodegradação Ambiental , Consórcios Microbianos , Poluição por Petróleo/análise , RNA Ribossômico 16S/genética , Água , Poluentes Químicos da Água/análise
11.
Bull Environ Contam Toxicol ; 108(3): 526-531, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33893519

RESUMO

We report the chemical characterisation and toxic effects of municipal solid waste landfill leachates on the embryonic development of Danio rerio. The results of the Fourier transform infrared spectroscopy (FTIR) revealed the presence of nitrogen-containing groups and aromatic functional groups associated with highly toxic pollutants such as ammonia and heavy metal-humic complexes. Mortalities of up to 93 and 100% were observed in 1:64 and 1:32 landfill leachate dilutions, v/v, respectively. The hatching percentages of the fish were also severely affected, with very low percentages ranging from 0 to 33.3% for 1:32, 1:64 and 1:128 dilutions, v/v. Morphologically, a developmental arrest was evident for all treatments. This study reveals the high toxicity of landfill leachates that could contaminate the aquifer of the Yucatan Peninsula and threaten the health of living organisms.


Assuntos
Eliminação de Resíduos , Poluentes Químicos da Água , Animais , Desenvolvimento Embrionário , México , Resíduos Sólidos , Instalações de Eliminação de Resíduos , Poluentes Químicos da Água/análise , Peixe-Zebra
12.
J Phycol ; 57(2): 655-663, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33294976

RESUMO

The genus Sargassum is well represented by benthic and pelagic species, some of which form massive aggregates that can travel long distances due to the force of the ocean currents. Although they constitute an essential habitat for fish and invertebrate species, large accumulations of Sargassum in coastal areas generate several economic, environmental, and health impacts. It is important to recognize the species forming these aggregates, and identify the metabolites they produce, allowing for its exploitation, and therefore, better management practices. NMR metabolic profiling is a technique that can discriminate samples while detecting their unique or differential chemical features, and has been successfully used in the study and classification of several algal species. The present investigation studied the metabolic profiling of Sargassum species found on strandings at Puerto Morelos (Quintana Roo) east coast of the Mexican Caribbean. PCA of the 1 H-NMR profiles corresponding to S. natans, S. natans (morphotype VIII), S. fluitans, and a benthic Sargassum buxifolium allowed the discrimination of samples amongst them. Furthermore, discrimination between the two forms of S. natans was also possible. The PCA loading plot revealed that glutamine and glutamate have the highest influence in the clustering of the benthic Sargassum, while a high abundance of lactate, Myo-inositol, and trimethylamine is a unique feature from the S. natans morphotype VIII. Additional PLS-DA models showed that a heat-drying process improved the extraction of metabolites. Maceration and microwave-assisted extraction with water-ethanol led to similar profiles and thus any of them could be used in future investigations.


Assuntos
Sargassum , Animais , Região do Caribe , Ecossistema , Meio Ambiente , México
13.
Molecules ; 26(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067744

RESUMO

The funerary rites of particular members of the pre-Hispanic Mayan society included the pigmentation of the corpse with a red color. In order to understand this ritual, it is first necessary to identify the constituents of the pigment mixture and then, based on its properties, analyze the possible form and moment of application. In the present approach, 1H-NMR analysis was carried to detect organic components in the funerary pigments of Xcambó, a small Maya settlement in the Yucatan Peninsula. The comparison of the spectra belonging to the pigment found in the bone remains of seven individuals, and those from natural materials, led to the identification of beeswax and an abietane resin as constituents of the pigment, thus conferring it agglutinant and aromatic properties, respectively. The 1H-NMR analysis also allowed to rule out the presence of copal, a resin found in the pigment cover from paramount chiefs from the Mayan society. Additionally, a protocol for the extraction of the organic fraction from the bone segment without visible signs of analysis was developed, thus broadening the techniques available to investigate these valuable samples.

14.
Molecules ; 26(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557136

RESUMO

Substituted phenylacetic (1-3), phenylpropanoic (4-6), and benzylidenethiazolidine-2,4-dione (7-9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.


Assuntos
Simulação por Computador , Desenho de Fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Simulação de Dinâmica Molecular , Técnicas de Química Sintética , Hipoglicemiantes/química , Terapia de Alvo Molecular , Conformação Proteica , Reprodutibilidade dos Testes
15.
Parasitol Res ; 119(3): 903-913, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32008065

RESUMO

The concentrations of polycyclic aromatic hydrocarbon metabolites (PAHm) and their bioconcentration factors (BCF) were determined in the larval stages of the cestode Oncomegas wageneri, recovered from the intestine of the Mexican flounder Cyclopsetta chittendeni, in the southern Gulf of Mexico. The PAHm concentrations in O. wageneri were measured using fixed-wavelength fluorescence spectrometry and compared with PAHm concentrations in host bile. Oncomegas wageneri PAHm concentrations were markedly higher than those in host tissues. The highest BCF values were obtained for 1-hydroxypyrene (OHP) and benzo(a)pyrene (BaP). Using a General Linear Model, a significant negative relationship was found between O. wageneri PAHm concentrations (as response variable) and the number of O. wageneri and oil well proximity. Low BCF values and PAHm concentrations in C. chittendeni correlated positively with O. wageneri PAHm concentrations. In contrast, high BCF values for PAHm concentrations in C. chittendeni had a negative association with O. wageneri PAHm concentrations. This study provides the first evidence of the presence of PAHm in intestinal larval cestodes of marine flatfishes, demonstrating levels of PAHm that were higher than levels in their hosts.


Assuntos
Cestoides/química , Doenças dos Peixes/parasitologia , Linguado/parasitologia , Larva/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Animais , Bioacumulação/fisiologia , Golfo do México , Espectrometria de Fluorescência
16.
Molecules ; 25(13)2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32630656

RESUMO

Sanitary landfill leachates usually have characteristics that depend on the region where they are generated and according to the age of the landfill, which is why a unique treatment for their sanitation has not been found. However, the adsorption preceded by the Fenton process has been proven to be highly efficient at removing contaminants. In this study, the adsorptive capacity of two types of activated carbon, granular and powdered, was analyzed to determine which was more efficient in the adsorption stage in the Fenton-adsorption process. Likewise, its behavior was analyzed using three isotherm models (Langmuir, Freundlich and Temkin), testing the raw leachate and the Fenton-treated one with both carbons. The adsorption that is carried out on the carbons is better adjusted to the Freundlich and Temkin models. It concludes that multilayers, through the physical adsorption, carry out the adsorption of pollutants on the surface of the carbons. The results show that, statistically, granular activated carbon is more efficient at removing chemical oxygen demand (COD), and powdered activated carbon removes color better. Finally, an adsorption column was designed for the Fenton-adsorption process that was able to remove 21.68 kgCOD/kg carbon. Removal efficiencies for color and COD were >99%.


Assuntos
Carvão Vegetal/química , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/química , Adsorção , Análise da Demanda Biológica de Oxigênio , México , Modelos Químicos , Tamanho da Partícula , Pós/química , Eliminação de Resíduos Líquidos/instrumentação
17.
Molecules ; 25(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339310

RESUMO

Many studies describe different pharmacological effects of flavonoids on experimental animals and humans. Nevertheless, few ones are confirming the safety of these compounds for therapeutic purposes. This study aimed to investigate the preclinical safety of naringenin, naringin, hesperidin, and quercetin by in vivo, in vitro, and in silico approaches. For this, an MTT-based cytotoxicity assay in VERO and MDCK cell lines was performed. In addition, acute toxicity was evaluated on Wistar rats by OECD Guidelines for the Testing of Chemicals (Test No. 423: Acute Oral Toxicity-Class Method). Furthermore, we used the ACD/Tox Suite to predict toxicological parameters such as hERG channel blockade, CYP450 inhibition, and acute toxicity in animals. The results showed that quercetin was slightly more cytotoxic on cell lines (IC50 of 219.44 ± 7.22 mM and 465.41 ± 7.44 mM, respectively) than the other citroflavonoids. All flavonoids exhibited an LD50 value > 2000 mg/kg, which classifies them as low-risk substances as OECD guidelines established. Similarly, predicted LD50 was LD50 > 300 to 2000 mg/kg for all flavonoids as acute toxicity assay estimated. Data suggests that all these flavonoids did not show significant toxicological effects, and they were classified as low-risk, useful substances for drug development.


Assuntos
Peso Corporal/efeitos dos fármacos , Flavonoides/farmacologia , Administração Oral , Animais , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Feminino , Flavanonas/química , Flavanonas/metabolismo , Flavanonas/farmacologia , Flavonoides/química , Flavonoides/metabolismo , Dose Letal Mediana , Células Madin Darby de Rim Canino , Medicina Tradicional , Quercetina/química , Quercetina/metabolismo , Quercetina/farmacologia , Ratos , Ratos Wistar , Células Vero
18.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059495

RESUMO

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.


Assuntos
Antiprotozoários/farmacologia , Carbamatos/química , Metronidazol/análogos & derivados , Metronidazol/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carbamatos/síntese química , Carbamatos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/patogenicidade , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Metronidazol/síntese química , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/patogenicidade
19.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540347

RESUMO

To elucidate interactions between the antifungal cyclic lipopeptides iturin A, fengycin, and surfactin produced by Bacillus bacteria and the microtubular protein ß-tubulin in plant pathogenic fungi (Fusarium oxysporum, Colletrotrichum gloeosporioides, Alternaria alternata, and Fusarium solani) in molecular docking and molecular dynamics simulations, we retrieved the structure of tubulin co-crystallized with taxol from the Protein Data Bank (PDB) (ID: 1JFF) and the structure of the cyclic lipopeptides from PubChem (Compound CID: 102287549, 100977820, 10129764). Similarity and homology analyses of the retrieved ß-tubulin structure with those of the fungi showed that the conserved domains shared 84% similarity, and the root mean square deviation (RMSD) was less than 2 Å. In the molecular docking studies, within the binding pocket, residues Pro274, Thr276, and Glu27 of ß-tubulin were responsible for the interaction with the cyclic lipopeptides. In the molecular dynamics analysis, two groups of ligands were formed based on the number of poses analyzed with respect to the RMSD. Group 1 was made up of 10, 100, and 500 poses with distances 0.080 to 0.092 nm and RMSDs of 0.10 to 0.15 nm. For group 2, consisting of 1000 poses, the initial and final distance was 0.1 nm and the RMSDs were in the range of 0.10 to 0.30 nm. These results suggest that iturin A and fengycin bind with higher affinity than surfactin to ß-tubulin. These two lipopeptides may be used as lead compounds to develop new antifungal agents or employed directly as biorational products to control plant pathogenic fungi.


Assuntos
Lipopeptídeos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos Cíclicos/química , Tubulina (Proteína)/química
20.
Bull Environ Contam Toxicol ; 103(4): 610-616, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468105

RESUMO

A growing concern exists over water contamination by veterinary pharmaceuticals from small pig farms in Yucatan, Mexico, where the anaerobic digesters installed as the wastewater treatment system are not operated properly. Therefore, considerable interest exists to develop analytical methods to detect these compounds and characterize their fate in the environment. In this study, the detection of three antibiotics (enrofloxacin, oxytetracycline and sulfamethoxazole) and a ß-agonist (ractopamine) was carried out using fluorescence spectrophotometry, with a semi-quantitative approach and a low environmental impact. Wastewater samples from 10 pig farms were analyzed, detecting concentrations of approximately 0.043 µg mL-1 for enrofloxacin, 1.427 µg mL-1 for oxytetracycline, and 9.748 µg mL-1 for sulfamethoxazole. The detection of these pharmaceuticals in the effluents of treated wastewater from the biodigesters of the pig farms suggests the need to optimize the system and prevent the entry of these compounds into the environment.


Assuntos
Monitoramento Ambiental/métodos , Espectrometria de Fluorescência/métodos , Drogas Veterinárias/análise , Poluentes Químicos da Água/análise , Animais , Antibacterianos , Fazendas , Química Verde , México , Fenetilaminas , Suínos , Águas Residuárias/análise , Águas Residuárias/química
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