Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Más filtros











Intervalo de año de publicación
1.
ChemMedChem ; 19(20): e202400293, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-38924252

RESUMEN

This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42 e and 49 b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds.


Asunto(s)
Bencimidazoles , Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Relación Estructura-Actividad , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Enfermedad de Chagas/tratamiento farmacológico , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Humanos , Animales , Relación Dosis-Respuesta a Droga
2.
Int J Mol Sci ; 24(13)2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37446093

RESUMEN

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).


Asunto(s)
Productos Biológicos , Cannabinoides , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Productos Biológicos/farmacología , Cannabinoides/farmacología , Cannabinoides/química , Imidazoles , Receptor Cannabinoide CB2 , Receptor Cannabinoide CB1 , Relación Estructura-Actividad , Mamíferos
3.
J Fungi (Basel) ; 9(7)2023 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-37504741

RESUMEN

Chromoblastomycosis (CBM) is a neglected human implantation mycosis caused by several dematiaceous fungal species. Currently available therapy is usually associated with physical methods, especially surgery, and with high refractoriness. Therefore, drug discovery for CBM is essential. Drug repositioning is a strategy used to facilitate the discovery of new treatments for several diseases. The aim of this study was to discover substances with antifungal activity against CBM agents from a collection of drugs previously approved for use in human diseases. A screening was performed with the NIH Clinical Collection against Fonsecaea pedrosoi. Ten substances, with clinical applicability in CBM, inhibited fungal growth by at least 60%. The minimum inhibitory concentration (MIC) of these substances was determined against other CBM agents, and the benzimidazoles albendazole, mebendazole and thiabendazole presented the lowest MIC values. The selectivity index, based on MIC and cytotoxicity of these substances, revealed albendazole to be more selective. To investigate a possible synergism of this benzimidazole with itraconazole and terbinafine, the chequerboard method was used. All interactions were classified as indifferent. Our current results suggest that benzimidazoles have repositioning potential against CBM agents. Albendazole seems to be the most promising, since it presented the highest selectivity against all dematiaceous fungi tested.

4.
Pathogens ; 12(1)2023 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-36678472

RESUMEN

Goat production in Mexico is an important economic activity that is affected by different gastrointestinal nematode (GIN) species. GINs resistant to commercial anthelmintics have been reported. Plant extracts or agro-industrial by-products, such as coffee pulp, have been proposed as control alternatives, given their secondary metabolite content. The aim of the present study was to determine the anthelmintic activity of the hydroalcoholic extract of coffee pulp against benzimidazole-resistant GINs. Stool samples were collected from goats, from which GIN eggs were identified and quantified. Molecular techniques confirmed the genus of GINs and their benzimidazole resistance profile. The percentage of egg hatching inhibition (% EHI) and larval mortality (% LM) with the hydroalcoholic extract of coffee pulp was determined at concentrations from 200 to 0.39 mg/mL. The genera Haemonchus spp. and Trichostrongylus spp. were identified, and the presence of the ß-tubulin gene mutation, associated with benzimidazole (BZ) resistance, was determined. Hydroalcoholic extract of coffee pulp inhibited 100% of egg hatching at 200 and 100 mg/mL, with no larvicidal effect at the evaluated concentrations.

5.
Molecules ; 27(19)2022 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-36234805

RESUMEN

Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported 13C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole-pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.


Asunto(s)
Bencimidazoles , Tionas , Bencimidazoles/química , Ligandos , Piridinas , Pirroles
6.
Parasitol Res ; 121(9): 2623-2632, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35779120

RESUMEN

The spread of anthelmintic resistance (AR) in nematode populations threatens the viability of sheep production systems worldwide, and warrants the adoption of sensitive, practical, and standardized tests to detect AR. The aim of this study was to characterize the replacement of an Haemonchus contortus population resistant to benzimidazoles (BZDs) by a susceptible one, by means of both phenotypic and genotypic techniques. Phenotypic methods to assess BZD resistance included in vivo tests, such as the fecal egg count reduction test (FECRT), and in vitro tests, such as the egg hatch assay (EHA). Additionally, genotypification of polymorphisms associated with BZD resistance by sequencing a fragment of the isotype 1 ß-tubulin gene was carried out. The initial, BZD-resistant population (initial Balcarce population) exhibited an egg count reduction (ECR) of 59.3%. Following refugium replacement, the final population (final Balcarce population) exhibited an ECR of 95.2%. For the initial Balcarce population, the median effective dose (ED50) for the EHA was 0.607 µg thiabendazole (TBZ)/mL, with a rate of eclosion at a discriminating dose (EDD) of 0.1 µg TBZ/mL of 76.73%. For the final Balcarce population, ED50 was 0.02 µg TBZ/mL, and EDD was 1.97%. In the initial population, 93% of the analyzed individuals exhibited genotypic combinations associated with BZD resistance (53% Phe/Phe167-Tyr/Tyr200, 37% Phe/Tyr167-Phe/Tyr200, and 3% Phe/Tyr167-Glu/Leu198). Conversely, no combination associated with resistance was found in individuals from the final population. All of the tests were useful for detecting AR to BZDs. The results from the genetic and phenotypical studies were consistent, and the resulting information greatly aided in interpreting the outcomes of the population replacement and the potential impact of this strategy on management of AR.


Asunto(s)
Antihelmínticos , Hemoncosis , Haemonchus , Enfermedades de las Ovejas , Animales , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Bencimidazoles/farmacología , Resistencia a Medicamentos/genética , Hemoncosis/tratamiento farmacológico , Hemoncosis/veterinaria , Haemonchus/genética , Dinámica Poblacional , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/epidemiología , Tiabendazol/farmacología , Tiabendazol/uso terapéutico , Tubulina (Proteína)/genética
7.
Acta Trop ; 233: 106533, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35598651

RESUMEN

Hookworms represent a serious problem for human and animal health in different parts of the world. One of the suggested control strategies for parasitosis caused by members of the Ancylostomatidae family is mass drug aministration with benzimidazole compounds. This strategy has been proven to lead to the establishment of resistant strains in several nematodes related to SNPs at codons 167, 198 and 200 of the beta-tubulin isotype-1 gene. Through bioassay and in vivo analysis, we successfully isolated an albendazole-resistant A. ceylanicum strain by drug selective pressure. We observed a strong correlation between the presence of SNPs at codon 198 and drug resistance. We also described for the first time, in hookworms, the presence of SNP A200L, already described at low frequencies in ruminant nematodes. The results presented here are important for updating the current knowledge about anthelmintic resistance in hookworms. The answers and the new questions raised may provide a basis for the establishment of more effective control strategies.


Asunto(s)
Ancylostomatoidea , Antihelmínticos , Albendazol/farmacología , Ancylostoma/genética , Animales , Antihelmínticos/farmacología , Codón/farmacología , Resistencia a Medicamentos/genética , Humanos , Polimorfismo de Nucleótido Simple , Tubulina (Proteína)/genética
8.
Front Cell Infect Microbiol ; 12: 1044665, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36699729

RESUMEN

Introduction: Leishmaniasis is a neglected tropical disease, with approximately 1 million new cases and 30,000 deaths reported every year worldwide. Given the lack of adequate medication for treating leishmaniasis, drug repositioning is essential to save time and money when searching for new therapeutic approaches. This is particularly important given leishmaniasis's status as a neglected disease. Available treatments are still far from being fully effective for treating the different clinical forms of the disease. They are also administered parenterally, making it challenging to ensure complete treatment, and they are extremely toxic, in some cases, causing death. Triclabendazole (TCBZ) is a benzimidazole used to treat fasciolosis in adults and children. It presents a lower toxicity profile than amphotericin B (AmpB) and is administered orally, making it an attractive candidate for treating other parasitoses. The mechanism of action for TCBZ is not yet well understood, although microtubules or polyamines could potentially act as a pharmacological target. TCBZ has already shown antiproliferative activity against T. cruzi, T. brucei, and L. infantum. However, further investigations are still necessary to elucidate the mechanisms of action of TCBZ. Methods: Cytotoxicity assay was performed by MTT assay. Cell inhibition (CI) values were obtained according to the equation CI = (O.D treatment x 100/O.D. negative control). For Infection evaluation, fixated cells were stained with Hoechst and read at Operetta High Content Imaging System (Perkin Elmer). For growth curves, cell culture absorbance was measured daily at 600 nm. For the synergism effect, Fractional Inhibitory Concentrations (FICs) were calculated for the IC50 of the drugs alone or combined. Mitochondrial membrane potential (DYm), cell cycle, and cell death analysis were evaluated by flow cytometry. Reactive oxygen species (ROS) and lipid quantification were also determined by fluorimetry. Treated parasites morphology and ultrastructure were analyzed by electron microscopy. Results: The selectivity index (SI = CC50/IC50) of TCBZ was comparable with AmpB in promastigotes and amastigotes of Leishmania amazonensis. Evaluation of the cell cycle showed an increase of up to 13% of cells concentrated in S and G2, and morphological analysis with scanning electron microscopy showed a high frequency of dividing cells. The ultrastructural analysis demonstrated large cytoplasmic lipid accumulation, which could suggest alterations in lipid metabolism. Combined administration of TCBZ and AmpB demonstrated a synergistic effect in vitro against intracellular amastigote forms with cSFICs of 0.25. Conclusions: Considering that TCBZ has the advantage of being inexpensive and administrated orally, our results suggest that TCBZ, combined with AmpB, is a promising candidate for treating leishmaniasis with reduced toxicity.


Asunto(s)
Antiprotozoarios , Leishmania , Leishmaniasis , Niño , Humanos , Anfotericina B , Triclabendazol/farmacología , Triclabendazol/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Leishmaniasis/parasitología , Lípidos/farmacología
9.
Environ Sci Pollut Res Int ; 28(42): 59040-59049, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32207020

RESUMEN

Benzimidazoles are anthelmintics frequently used in sheep farming due to the high susceptibility of these animals to parasitic diseases. Sheep excreta are often disposed onto soils as a fertilizer, and they may contain benzimidazole residues that can contaminate soil and water. This work aimed to assess the leaching behavior of benzimidazole drugs (albendazole, fenbendazole, and thiabendazole) and their metabolites in two Brazilian soils of different textural classifications (sandy and clay), as well as sheep excreta-amended soils, following the OECD 312 Guidelines. Ewes received a single oral dose of 10 mg kg-1 b.w. of either albendazole or fenbendazole. The feces were collected at 24, 48, 72, 96, and 120 h post-dose, and the parent drugs and their metabolites extracted using the QuEChERS approach and quantified by UHPLC-MS/MS. For the leaching assays, a benzimidazole solution was directly applied onto the soil columns, or an amount of 5 g of the medicated sheep feces was distributed over the top of the soil columns. In soil samples, benzimidazoles were extracted by solid-liquid extraction and quantified by UHPLC-MS/MS. For the leaching studies, atrazine was used as a reference substance to determine the relative mobility factor of the analytes of interest. Benzimidazoles were considered slightly to moderately mobile in both soils tested, with a leaching distance of up to 25 cm in a 30-cm soil column. Approximately 3 to 6% of the benzimidazoles present in ewe feces were able to leach into the soil columns. This finding is of concern since benzimidazoles are persistent in soil and may pose a risk to soil biota and induce the development of resistant strains of parasites.


Asunto(s)
Contaminantes del Suelo , Suelo , Animales , Antiparasitarios , Bencimidazoles , Femenino , Ovinos , Espectrometría de Masas en Tándem
10.
J Inorg Biochem ; 201: 110842, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31536950

RESUMEN

Fourteen new complexes were obtained from Ln(III)(NO3)3∙n-H2O and the chromophores 2-(1H-benzo[d]imidazol-2-yl)-phenol (Bzp1) or 2-(5-methyl-1H-benzo[d]imidazol-2-yl)-phenol (Bzp2). The complete characterization allowed us to assign unequivocally the structures of all the complexes. The techniques used for this purpose were Ultraviolet-Visible (UV-Vis) and Fourier-Transform Infrared (FT-IR) spectroscopies, High-Resolution Mass Spectrometry (HRMS), Magnetic Susceptibility (MS), Elemental Analysis (EA) and Molar Conductivity (MC). HRMS allowed us to find the molecular ion and its isotopic pattern. The FT-IR spectral data suggested that benzimidazolyl-phenol ligands coordinate with Ln(III) ions through iminic nitrogen and phenolic oxygen. Thermogravimetric Analysis (TGA) studies of NdBzp1 and GdBzp2 complexes indicate the presence of lattice water along with three nitrates and two benzimidazolyl-phenol ligands; the thermal decomposition was consistent with the minimal formula suggested by EA. The coordination type of the benzimidazolyl-phenol ligands, the geometry and the structural organization of these coordination complexes have been interpreted by Density Functional Theory (DFT) calculations, and they coincided with the physicochemical data suggesting a coordination number eight for the Ln(III) ions. The cytotoxicity of the chromophores and their coordination complexes was tested against a cancer cell line (HeLa), as compared with structure/support cells (NIH-3T3) and defense cells (J774A.1), revealing that three coordination complexes showed moderate cytotoxicity against the cell lines studied.


Asunto(s)
Bencimidazoles/química , Elementos de la Serie de los Lantanoides/química , Compuestos Organometálicos/síntesis química , Fenoles/química , Células 3T3 , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Eritrocitos/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Células HeLa , Humanos , Ratones , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/toxicidad
11.
Eur J Med Chem ; 165: 1-10, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30641409

RESUMEN

Currently, only two drugs (i.e. benznidazole (BZN) and nifurtimox (NFX)) have been approved for the treatment of Trypanosoma cruzi (Tc) infection, the etiological agent causing Chagas disease. Since both drugs exhibit severe side effects, patients frequently abandon therapy, resulting in an inefficient pharmacotherapeutic treatment. In this context, there is an urgent need to develop new, safer and optimised anti-Tc agents. In this report, we present the synthesis and biological activity of 11 novel and 3 already reported N-arylsulfonyl-benzimidazole derivatives (NBSBZD,1-14) currently in development as potential anti-Tc compounds. These compounds were designed as part of a library of synthetic arylsulfonyl heterocycle derivatives constructed from privileged structures exhibiting drug-like properties. Based on bioactivity assays against Tc, (in both the extracellular and intracellular forms), we observed that 10 compounds exhibited bioactivity against the epimastigote form, while six of them exhibited activity against the amastigote counterpart. Also, the compounds showed less cytotoxicity compared to the reference drug BZN as measured in Vero cell culture. In order to elucidate the potential mechanism of action, metabolite excretion profiles studies were performed, and complemented with molecular modeling studies performed over known Tc druggable targets. Consistency was observed between experimental and theoretical findings, with metabolic profiles showing that compounds 1, 2, 9, 12 and 14 interfered with the normal glycolysis cycle of Tc, while molecular modeling studies were able to establish a solid structure-activity relationship towards the inhibition of 6-phospho-1-fructokinase, a key enzyme involved in the parasite glycolytic cascade. Overall, the present study constitutes a multidisciplinary contribution to the development of new anti-Chagas compounds.


Asunto(s)
Bencimidazoles/farmacología , Diseño de Fármacos , Tripanocidas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Animales , Bencimidazoles/síntesis química , Bencimidazoles/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Chlorocebus aethiops , Simulación del Acoplamiento Molecular , Tripanocidas/farmacología , Células Vero
12.
Expert Rev Anti Infect Ther ; 17(1): 51-56, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30501436

RESUMEN

INTRODUCTION: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelminthic action. A very limited number of drugs are available for the treatment of some zoonotic helminth infections, such as neurocysticercosis and echinococcosis. More recent work has expanded oxfendazole's nonclinical safety profile and demonstrated its safety and bioavailability in healthy human volunteers, thus advancing the possibility of a new and greatly needed option for antiparasitic treatment of geohelminths and tissue parasites. Areas covered: The present article reviews evidence supporting the safety and efficacy of oxfendazole against both gut and tissue dwelling helminths in animals, as well as more recent safety and pharmacokinetic data supporting its potential for use in human parasitoses. Expert commentary: The pharmacokinetics, safety, and wide spectrum of efficacy of oxfendazole are consistently demonstrated in intestinal helminth infections of animals as well as in tissue dwelling larval cestode and trematode infections in diverse animal species. Now supported by first-in-human safety and pharmacokinetic data, oxfendazole becomes a promising alternative to the limited portfolio of antiparasitic drugs available to treat helminthic diseases of humans.


Asunto(s)
Antihelmínticos/uso terapéutico , Bencimidazoles/uso terapéutico , Helmintiasis/tratamiento farmacológico , Animales , Antihelmínticos/efectos adversos , Antihelmínticos/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Semivida , Helmintiasis/parasitología , Helmintiasis Animal/tratamiento farmacológico , Helmintiasis Animal/parasitología , Humanos , Zoonosis/tratamiento farmacológico , Zoonosis/parasitología
13.
Braz. J. Pharm. Sci. (Online) ; 55: e17776, 2019. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1039048

RESUMEN

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, ß-cyclodextrin increased the solubility of albendazole from 0.4188 to ~93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-ß-cyclodextrin, on the other hand, increased solubility to ~443.06 µg mL-1 (1058×) for albendazole and ~159.36 µg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (~591.22 µg mL-1) for albendazole and 1373× (~144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-ß-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates


Asunto(s)
Bencimidazoles/administración & dosificación , Ciclodextrinas/farmacocinética , Disolución/clasificación , Solubilidad , Preparaciones Farmacéuticas , Albendazol/análisis , Fenbendazol/análisis , Antiparasitarios/análisis
14.
J Biol Inorg Chem ; 23(7): 1165-1183, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30076466

RESUMEN

Four copper(II) coordination compounds from 2-benzimidazole propionic acid (Hbzpr) and 4-(benzimidazol-2-yl)-3-thiobutanoic acid (Hbztb) were synthesized and fully characterized by elemental analyses, electronic spectroscopy, FT-IR and mass spectrometry. The molecular structure for the four complexes was confirmed by single-crystal X-ray crystallography. The DNA-interacting properties of the two trinuclear and two mononuclear compounds were investigated using different spectroscopic techniques including absorption titration experiments, fluorescence spectroscopy and circular dichroism spectroscopy. Trinuclear [Cu3(bzpr)4(H2O)2](NO3)2·3H2O·CH3OH (2) and [Cu3(bzpr)4Cl2]·3H2O (3) bind to DNA through non-intercalative interactions, while for mononuclear [Cu(bzpr)2(H2O)]·2H2O (1) and [Cu(bztb)2]·2H2O (4), at minor concentrations in relation to the DNA, a groove binding interaction is favored, while at higher concentrations an intercalative mode is preferred. The nuclease properties of all complexes were studied by gel electrophoresis, which showed that they were able to cleave supercoiled plasmid DNA (form I) to the nicked form (form II). Compound 4 is even capable of generating linear form III (resulting from double-strand cleavage). The proposed mechanism of action involves an oxidative pathway (Fenton-type reaction), which produces harmful reactive species, like hydroxyl radicals.


Asunto(s)
Bencimidazoles/farmacología , Complejos de Coordinación/farmacología , Cobre/farmacología , ADN/efectos de los fármacos , Bencimidazoles/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cobre/química , Cristalografía por Rayos X , División del ADN , Ligandos , Modelos Moleculares , Estructura Molecular , Plásmidos
15.
Mol Divers ; 22(4): 779-790, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29748853

RESUMEN

Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold. Our analysis revealed that a limited number of studies had investigated the antileishmanial effects of benzimidazoles. Among this limited number, L. major was the species most commonly used to evaluate the antileishmanial effects of these compounds, whereas L. amazonensis and L. braziliensis were used least often in the reported studies. The antileishmanial activities of benzimidazole derivatives were notably variable, a fact that may depend on the substitution pattern of the scaffold. In addition, we investigated the effects of a benzimidazole derivative on promastigotes and amastigotes of L. infantum and L. amazonensis using a novel fluorometric method. Significant antileishmanial effects were observed on both species, with L. amazonensis being the most sensitive. To the best of our knowledge, this chemoinformatic analysis represents the first attempt to determine the relevance of benzimidazole scaffolds for antileishmanial drug discovery using the ChEMBL database. The present findings will provide relevant information for future structure-activity relationship studies and for the investigation of benzimidazole-derived drugs as potential treatments for leishmaniasis.


Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Leishmania/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Leishmania/crecimiento & desarrollo , Relación Estructura-Actividad
16.
Rev. méd. Urug ; 33(4): 269-273, dic. 2017. ilus
Artículo en Español | LILACS | ID: biblio-875878

RESUMEN

La hidatidosis o equinococosis quística es una enfermedad zoonótica que tiene presentaciones clínicas muy heterogéneas. Los quistes sintomáticos y complicados habitualmente son resueltos mediante cirugía siguiendo las reglas de la WHO-IWGE. Sin embargo, en las formas transicionales (CE3) los criterios terapéuticos continúan en discusión. Asimismo, en quistes asintomáticos y en pacientes con alto riesgo quirúrgico, la opción del tratamiento médico con benzoimidazólicos y su combinación con la estrategia de vigilar y esperar puede ser una alternativa terapéutica segura. Se presenta un caso de hidatidosis hepática CE3b con características clínico-evolutivas excepcionales y alto riesgo quirúrgico en que se adoptó un manejo de vigilancia clínica y tratamiento con albendazol. Se analizan los beneficios y riesgos de esta terapéutica.


Cystic echinococcosis is a zoonotic disease with very heterogeneous clinical presentations. The possibility of symptomatic hepatic cysts be solved by surgery is the conduct of election. However, in asymptomatic cysts and in patients with high surgical risk, medical treatment with benzimidazolic combined with the strategy of watch and wait, may be an option to take into account. In the present work, we take as an example a case of hepatic hydatid disease with high surgical risk and analyze the potential benefits of establishing such therapeutic conduct and monitoring.


A hidatidose ou equinococose cística é uma doença zoonótica com apresentações clínicas muito heterogêneas heterogêneas. Os cistos sintomáticos e complicados de maneira geral são tratados por cirurgia de acordo com as indicações da WHO- IWGE. No entanto, nos casos de formas transicionais (CE3) os critérios terapêuticos continuam em discussão. Nos cistos assintomáticos e em pacientes com alto risco cirúrgico a opção do tratamento médico com benzoimidazolicos e sua combinação com a estratégia de vigilar e esperar, pode ser uma alternativa terapêutica segura. Apresenta-se um caso de hidatidose hepática CE3b, com características clínico-evolutivas excepcionais e alto risco cirúrgico, no qual utilizou- se um manejo de vigilância clínica e tratamento com albendazol. Os benefícios e os riscos desta terapêutica são analisados.


Asunto(s)
Humanos , Equinococosis Hepática/terapia , Vigilancia en Desastres
17.
Braz. j. biol ; Braz. j. biol;77(3)July-Sept. 2017.
Artículo en Inglés | LILACS-Express | LILACS, VETINDEX | ID: biblio-1468383

RESUMEN

Abstract The fast anthelmintic resistance development has shown a limited efficiency in the control of animals endoparasitosis and has promoted research using alternative control methods. The use of chemicals in animal anthelmintic treatment, in association with nematophagous fungi used for biological control, is a strategy that has proven to be effective in reducing the nematode population density in farm animals. This study aims to verify the in vitro susceptibility of the nematophagous fungi Arthrobotrys oligospora, Duddingtonia flagrans and Paecilomyces lilacinus against the antiparasitic drugs albendazole, thiabendazole, ivermectin, levamisole and closantel by using the Minimum Inhibitory Concentration (MIC). MICs ranged between 4.0 and 0.031 µg/mL for albendazole, thiabendazole and ivermectin, between 0.937 and 0.117 µg/mL for levamisole, and between 0.625 and 0.034 µg/mL for closantel. The results showed that all antiparasitic drugs had an in vitro inhibitory effect on nematophagous fungi, which could compromise their action as agents of biological control. D. flagrans was the most susceptible species to all drugs.


Resumo O desenvolvimento rápido da resistência anti-helmíntica demonstrou a eficiência limitada no controle de endoparasitoses em animais, e promoveu a investigação em métodos de controles alternativos. O uso de produtos químicos no tratamento anti-helmíntico animal, em associação com fungos nematófagos utilizados para o controlo biológico, é uma estratégia que tem provado ser eficaz na redução da densidade da população de nematódeos em animais agrícolas. Este estudo teve como objetivo verificar a suscetibilidade in vitro dos fungos nematófagos Arthrobotrys oligospora, Duddingtonia flagrans e Paecilomyces lilacinus frente aos antiparasitários albendazol, tiabendazol, ivermectina, levamisol e closantel, usando a concentração inibitória mínima (MIC). Os MICs variaram entre 4,0 e 0,031 g/mL para albendazol, tiabendazol e ivermectina, entre 0,937 e 0,117 g/mL para o levamisol, e entre 0,625 e 0,034 g/mL para closantel. Os resultados mostraram que todos os antiparasitários tiveram um efeito inibidor in vitro sobre os fungos nematófagos, o que poderia comprometer suas atividades como agentes de controle biológico. D. flagrans foi a espécie mais sensível a todas as drogas.

18.
Braz. j. biol ; Braz. j. biol;77(3): 476-479, July-Sept. 2017. tab
Artículo en Inglés | LILACS | ID: biblio-888788

RESUMEN

Abstract The fast anthelmintic resistance development has shown a limited efficiency in the control of animal's endoparasitosis and has promoted research using alternative control methods. The use of chemicals in animal anthelmintic treatment, in association with nematophagous fungi used for biological control, is a strategy that has proven to be effective in reducing the nematode population density in farm animals. This study aims to verify the in vitro susceptibility of the nematophagous fungi Arthrobotrys oligospora, Duddingtonia flagrans and Paecilomyces lilacinus against the antiparasitic drugs albendazole, thiabendazole, ivermectin, levamisole and closantel by using the Minimum Inhibitory Concentration (MIC). MICs ranged between 4.0 and 0.031 µg/mL for albendazole, thiabendazole and ivermectin, between 0.937 and 0.117 µg/mL for levamisole, and between 0.625 and 0.034 µg/mL for closantel. The results showed that all antiparasitic drugs had an in vitro inhibitory effect on nematophagous fungi, which could compromise their action as agents of biological control. D. flagrans was the most susceptible species to all drugs.


Resumo O desenvolvimento rápido da resistência anti-helmíntica demonstrou a eficiência limitada no controle de endoparasitoses em animais, e promoveu a investigação em métodos de controles alternativos. O uso de produtos químicos no tratamento anti-helmíntico animal, em associação com fungos nematófagos utilizados para o controlo biológico, é uma estratégia que tem provado ser eficaz na redução da densidade da população de nematódeos em animais agrícolas. Este estudo teve como objetivo verificar a suscetibilidade in vitro dos fungos nematófagos Arthrobotrys oligospora, Duddingtonia flagrans e Paecilomyces lilacinus frente aos antiparasitários albendazol, tiabendazol, ivermectina, levamisol e closantel, usando a concentração inibitória mínima (MIC). Os MICs variaram entre 4,0 e 0,031 μg/mL para albendazol, tiabendazol e ivermectina, entre 0,937 e 0,117 μg/mL para o levamisol, e entre 0,625 e 0,034 μg/mL para closantel. Os resultados mostraram que todos os antiparasitários tiveram um efeito inibidor in vitro sobre os fungos nematófagos, o que poderia comprometer suas atividades como agentes de controle biológico. D. flagrans foi a espécie mais sensível a todas as drogas.


Asunto(s)
Animales , Hongos Mitospóricos/efectos de los fármacos , Antiparasitarios/farmacología , Salicilanilidas/farmacología , Ivermectina/farmacología , Albendazol/farmacología , Control Biológico de Vectores , Levamisol/farmacología
19.
Talanta ; 171: 307-320, 2017 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-28551144

RESUMEN

A quantitative and confirmatory multiresidue method for determining the presence of avermectins, benzimidazoles and nitroimidazoles in bovine muscle tissue by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was developed, optimized and validated, using a QuEChERS extraction. The evaluated performance parameters were linearity, selectivity, matrix effect, decision limits (CCα), detection capability (CCß), limits of detection (LOD), limits of quantification (LOQ), accuracy, precision and robustness. The validated method exhibited linearity with coefficient of determination (R2) higher than 0.90 in the working range from 0.5 to 2.0 times the maximum residue limit (MRL) or the minimum required performance level (MRPL) for the studied analytes, except for closantel, for which the linear study range was defined from 50 to 200µgkg-1. The method was selective in the presence of macrolides and lincosamides for all the studied analytes. The LOD varied from 0.007 to 66.715µgkg-1, whereas LOQ values ranging from 0.011 to 113.674µgkg-1 were found. The results of the evaluation of the accuracy and precision were satisfactory for all the studied analytes, and according to the assessment of the robustness, the method was not robust only for the analytes abamectin, moxidectin, doramectin fenbendazole sulfone, closantel, thiabendazole, hydroxyl-metronidazole and ronidazole. The performance parameters demonstrated total method adequacy for the detection and quantification of avermectins, benzimidazoles and nitroimidazoles residues in bovine muscle tissues.


Asunto(s)
Bencimidazoles/análisis , Bencimidazoles/aislamiento & purificación , Ivermectina/análogos & derivados , Músculos/química , Nitroimidazoles/análisis , Nitroimidazoles/aislamiento & purificación , Métodos Analíticos de la Preparación de la Muestra , Animales , Bovinos , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Residuos de Medicamentos/análisis , Residuos de Medicamentos/aislamiento & purificación , Ivermectina/análisis , Ivermectina/aislamiento & purificación , Límite de Detección , Espectrometría de Masas en Tándem
20.
Front Microbiol ; 8: 535, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28400768

RESUMEN

Cryptococcus neoformans is the most lethal pathogen of the central nervous system. The gold standard treatment of cryptococcosis, a combination of amphotericin B with 5-fluorocytosine, involves broad toxicity, high costs, low efficacy, and limited worldwide availability. Although the need for new antifungals is clear, drug research and development (R&D) is costly and time-consuming. Thus, drug repurposing is an alternative to R&D and to the currently available tools for treating fungal diseases. Here we screened a collection of compounds approved for use in humans seeking for those with anti-cryptococcal activity. We found that benzimidazoles consist of a broad class of chemicals inhibiting C. neoformans growth. Mebendazole and fenbendazole were the most efficient antifungals showing in vitro fungicidal activity. Since previous studies showed that mebendazole reaches the brain in biologically active concentrations, this compound was selected for further studies. Mebendazole showed antifungal activity against phagocytized C. neoformans, affected cryptococcal biofilms profoundly and caused marked morphological alterations in C. neoformans, including reduction of capsular dimensions. Amphotericin B and mebendazole had additive anti-cryptococcal effects. Mebendazole was also active against the C. neoformans sibling species, C. gattii. To further characterize the effects of the drug a random C. gattii mutant library was screened and indicated that the antifungal activity of mebendazole requires previously unknown cryptococcal targets. Our results indicate that mebendazole is as a promising prototype for the future development of anti-cryptococcal drugs.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA