RÉSUMÉ
Isoniazid (INH), a first-line drug in anti-tuberculosis therapy, is known to be potentially harmful and is associated with numerous side effects especially in the blood and liver. In the course of our previous investigations, 1,2,3-thiadiazole containing hydrazone (compound 3) showed excellent antimycobacterial activity against a referent strain M. tuberculosis H37Rv (MIC value 0.39 µM), low cytotoxicity, and did not have toxic effects when administered by oral or intraperitoneal routes to experimental animals (selectivity index SI > 1979, LD50>2000 mg/kg b.w.) what revealed its suitability for further exploration. In the present study compound 3 was chosen to determine its effects on the liver and kidney functions in female mice. The compound was administered orally for 14 days at three doses (100, 200, and 400 mg/kg b.w.). The quantity of malondialdehyde (MDA), the level of reduced glutathione (GSH), blood hematological and biochemical parameters were assessed, and urine analysis was carried out. As a positive control INH was used orally at a dose of 50 mg/kg b.w. The investigated compound 3 did not affect the urine and serum hematological and biochemical parameters as INH did, compared to those of the control mice. The new compound did not affect significantly the MDA quantity and maintained its level near to the control values, though lower by 36% (p < 0.05) than in the INH treated animals. At the higher doses, 200 and 400 mg/kg, it depleted the GSH content by 25% (p < 0.05), compared to the control. However, its level remained 47% (p < 0.05) higher than in the INH treated animals.
Sujet(s)
Antibactériens , Thiadiazoles , Animaux , Antituberculeux/toxicité , Femelle , Hydrazones/toxicité , Isoniazide/toxicité , Foie , Souris , Thiadiazoles/toxicitéRÉSUMÉ
Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b-12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b-12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.
Sujet(s)
Antiprotozoaires/toxicité , Thiadiazoles/toxicité , Toxoplasma/effets des médicaments et des substances chimiques , Antiprotozoaires/synthèse chimique , Lignée cellulaire , Prolifération cellulaire , Humains , Thiadiazoles/synthèse chimique , Toxoplasma/physiologieRÉSUMÉ
Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Overexpression of BCL2, an antiapoptotic protein, provides the advantage of prolonged survival to cancer cells. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential. However, most of them were abolished before clinical use due to their side effects. Previously, we had identified and characterized a novel BCL2 inhibitor, Disarib, with the potential to eliminate tumor cells in a BCL2 specific manner leading to reduction in tumor burden in multiple mouse models. Notably, a head-to-head comparison of Disarib to ABT199, the only FDA approved BCL2 inhibitor revealed that Disarib is as potent as ABT199. Recent studies using mice revealed that Disarib did not invoke significant side effects in mice. In the present study, we have investigated the acute toxicity of Disarib in Wistar rats. The bioavailability studies following exposure of Disarib in Wistar rats revealed its maximum availability in serum at 24 h following oral administration. Acute toxicity analysis revealed that even a dose as high as 2000 mg/kg of Disarib did not cause significant toxicity in rats. There was no significant variation in blood parameters or kidney and liver functions following administration of Disarib. Histological analysis of different tissues from Disarib treated groups revealed standard architecture with no observable cellular damage. Importantly, exposure to Diasrib did not result in genotoxicity as determined by micronucleus assay. Further, solubility assays revealed that besides DMSO, Disarib is also soluble in alcohol. While the high acidic condition can increase the solubility of Disarib, even a lower percentage of alcohol with acidic conditions can improve its solubility. Thus, the toxicological profile in the current study revealed no significant side effects when Disarib was administered orally to rats.
Sujet(s)
Indoles/toxicité , Protéines proto-oncogènes c-bcl-2/antagonistes et inhibiteurs , Thiadiazoles/toxicité , Animaux , Biodisponibilité , Indoles/pharmacocinétique , Rein/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Rat Wistar , Thiadiazoles/pharmacocinétique , Tests de toxicité aigüeRÉSUMÉ
Reaction of piperazine with chloroacetylchloride in dry acetone yield compound 1: , which on reaction with hydrazine hydrate yielded compound 2: , which was further reacted with various substituted phenylisothiocyanates in absolute alcohol to afford compounds 3-8: i. e. 2-(carbazolylacetyl)-N-(substitutedphenyl)-hydrazinepiperazinothioamides. Compounds 3-8: on reaction with aqueous NaOH, ethanolic NaOH and conc. H2SO4 afford triazoles 9-14: , oxadiazoles 15-20: and thiadiazoles 21-26: respectively. Twenty four newly synthesized compounds were evaluated for their anticonvulsant activity and acute toxicity. The structures of these compounds were established on the basis of analytical and spectral data.
Sujet(s)
Anticonvulsivants/administration et posologie , Crises épileptiques/traitement médicamenteux , Animaux , Anticonvulsivants/synthèse chimique , Anticonvulsivants/toxicité , Modèles animaux de maladie humaine , Femelle , Humains , Mâle , Souris , Oxadiazoles/administration et posologie , Oxadiazoles/synthèse chimique , Oxadiazoles/toxicité , Pipérazine/administration et posologie , Pipérazine/synthèse chimique , Pipérazine/toxicité , Rats , Crises épileptiques/diagnostic , Crises épileptiques/étiologie , Relation structure-activité , Thiadiazoles/administration et posologie , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicité , Tests de toxicité aigüe , Triazoles/administration et posologie , Triazoles/synthèse chimique , Triazoles/toxicitéRÉSUMÉ
In a previous study, 3-amino-4-[4-(dimethylamino)phenyl]-4,5-dihydro-1,2,5-thiadiazole 1,1-dioxide (DPTD), which is five-membered cyclosulfamide, was synthesized and structurally characterized. The aim of this study was to investigate the cytotoxic and genotoxic effects of DPTD on cultured human lymphocytes in the presence and absence of a metabolic activation system (S9 mix). The cytotoxicity and genotoxicity of DPTD in human peripheral blood lymphocytes were examined in vitro by using chromosomal aberration (CA) and micronucleus (MN) tests. Mitomycin-C (MMC) for cultures without S9 mix and cyclophosphamide monohydrate (CP) for cultures with S9 mix were used as positive controls. The cultures were treated with DPTD (45, 90, and 180 µg/mL) in the absence and presence of S9 mix. The cells were also co-treated with DPTD together with MMC or CP. DPTD showed cytotoxic activity due to decreases in mitotic index (MI) and nuclear division index (NDI) in the absence and presence of S9 mix. DPTD also increased the CAs, aberrant cells with CAs and MN values in cultures with and without S9 mix. When DPTD and MMC or CP were used together, lower MI and NDI values and higher CA and MN values were found than those DPTD treated alone. Both DPTD and its metabolites have cytotoxic, cytostatic and genotoxic potential on human peripheral blood lymphocyte cultures under the experimental conditions. Furthermore, co-treatment of DPTD and MMC or CP can cause more cytotoxicity and genotoxicity. Our results indicated that the use of DPTD with other chemotherapeutic drugs may display more effective results.
Sujet(s)
Mutagènes , Thiadiazoles , Cellules cultivées , Aberrations des chromosomes , Humains , Lymphocytes , Tests de micronucleus , Index mitotique , Mutagènes/toxicité , Échange de chromatides soeurs , Thiadiazoles/toxicitéRÉSUMÉ
Acibenzolar-S-methyl (ASM) is one of the most effective plant resistance activators and protects against a broad spectrum of fungal, bacterial and viral pathogens. A rapid, efficient and high-throughput analysis method for ASM and its metabolite acibenzolar acid in fruits and vegetables was developed using potato, garlic, cabbage, grape and tomato as representative commodities by modified QuEChERS and UPLC-MS/MS. The modified procedure showed satisfying recoveries (70-108%) fortified in the range of 0.01-1 mg/kg with relative standard deviations (RSDs) lower than 17.7%. With the established analytical method, the dietary risk of ASM in fruits and vegetables from Chinese markets were further monitored using risk quotient (RQ) method. The RQ value based on ASM residue in China are far less than 1, elucidating that the potential health risk induced by ASM ingestion for Chinese population is not significant. Comparing the residue and risk assessment results of ASM in agricultural products in China to those in Codex, the maximum residue limits (MRLs) for ASM on garlic, cabbage and tomato established by CAC (Codex Alimentarius Commission) can be safely adopted in China, whereas the MRLs on potato and grape in China should be proposed as 0.01 mg/kg.
Sujet(s)
Anti-infectieux/toxicité , Thiadiazoles/toxicité , Brassica , Chine , Chromatographie en phase liquide/méthodes , Exposition alimentaire , Fruit/composition chimique , Ail , Solanum lycopersicum , Appréciation des risques , Solanum tuberosum , Spectrométrie de masse en tandem/méthodes , Légumes/composition chimique , VitisRÉSUMÉ
Holm oak trees (Quercus ilex L.) mortality is increasing worryingly in the Mediterranean area in the last years. To a large degree this mortality is caused by the oomycete Phytophthora spp., which is responsible for forest decline and dieback in evergreen oak forest areas of the southwestern Iberian Peninsula. This study is based on the possibility of applying chemical elicitors or filtered oomycete extracts to holm oak somatic embryos (SE) in order to induce epigenetic memory, priming, that may increase tolerance to the pathogen in future infections. To this end, we first examined the effect of priming treatments on SE development and its oxidative stress state, to avoid elicitors that may cause damage to embryogenic tissues. Both, the sterile oomycete extracts and the chemical elicitor methyl jasmonate (MeJA) did not produce any detrimental effect on SE growth and development, unlike the elicitors benzothiadiazole (BTH) and p-aminobenzoic acid (PABA) that reduced the relative weight gain and resulted in necrotic and deformed SE when were applied at high concentrations (25 µM BTH or 50 µM PABA) in accordance with their high malondialdehyde content. No significant differences among elicitation treatments were found in dual culture bioassays, although those SEs elicited with 50 µM MeJA increased H2O2 production after challenged against active oomycete indicating the activation of stress response. Since this elicitation treatment did not produce any adverse effect in the embryogenic process we suggest that could be used in further priming experiments to produce holm oak plants adapted to biotic stress.
Sujet(s)
Phytophthora/pathogénicité , Maladies des plantes/microbiologie , Maladies des plantes/prévention et contrôle , Quercus/embryologie , Quercus/microbiologie , Acide 4-amino-benzoïque/toxicité , Acétates/pharmacologie , Cyclopentanes/pharmacologie , Forêts , Interactions hôte-microbes/effets des médicaments et des substances chimiques , Peroxyde d'hydrogène/métabolisme , Malonaldéhyde/métabolisme , Oxylipines/pharmacologie , Phytophthora/composition chimique , Protéines/pharmacologie , Quercus/effets des médicaments et des substances chimiques , Graines/effets des médicaments et des substances chimiques , Graines/embryologie , Graines/métabolisme , Espagne , Thiadiazoles/toxicitéRÉSUMÉ
In this study, a number of 2,5-disubstituted 1,3,4-thiadiazoles were synthesized using an appropriate synthetic route, and their anticonvulsant activity was determined by the maximal electroshock seizure (MES) test and their neurotoxicity was evaluated by the rotarod test. Additionally, their hypnotic activity was tested using the pentobarbital-induced sleep test. Compounds 7 (ED50 = 1.14 and 2.72 µmol/kg in the MES and sleep tests, respectively) and 11 (ED50 = 0.65 and 2.70 µmol/kg in the MES and sleep tests, respectively) were the most potent ones in the sleep test and anticonvulsant test, showing a comparable activity with diazepam as the reference drug. The results of in vivo studies, especially the antagonistic effects of flumazenil, and also the radioligand-binding assay confirmed the involvement of benzodiazepine (BZD) receptors in the anticonvulsant and hypnotic activity of compounds 7 and 11. Finally, the docking study of compound 11 in the BZD-binding site of the GABAA (gamma-aminobutyric acid) receptor confirmed the possible binding of the compound to the BZD receptors. We concluded that the novel 1,3,4-thiadiazole derivatives with appropriate substitution at positions 2 and 5 of the heterocyclic ring had a good affinity to BZD receptors and showed significant efficacy in the pharmacological tests.
Sujet(s)
Anticonvulsivants/pharmacologie , Hypnotiques et sédatifs/pharmacologie , Récepteurs GABA-A/effets des médicaments et des substances chimiques , Crises épileptiques/prévention et contrôle , Sommeil/effets des médicaments et des substances chimiques , Thiadiazoles/pharmacologie , Animaux , Anticonvulsivants/synthèse chimique , Anticonvulsivants/métabolisme , Anticonvulsivants/toxicité , Sites de fixation , Modèles animaux de maladie humaine , Conception de médicament , Stimulation électrique , Hypnotiques et sédatifs/synthèse chimique , Hypnotiques et sédatifs/métabolisme , Hypnotiques et sédatifs/toxicité , Mâle , Souris , Simulation de docking moléculaire , Structure moléculaire , Activité motrice/effets des médicaments et des substances chimiques , Liaison aux protéines , Dosage par compétition , Récepteurs GABA-A/métabolisme , Test du rotarod , Crises épileptiques/métabolisme , Crises épileptiques/physiopathologie , Relation structure-activité , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicitéRÉSUMÉ
Aim: To evaluate the activity, cytotoxicity and efflux pumps inhibition of a series of 12 novels (-)-camphene-based 1,3,4-thiadiazoles (TDZs) against Mycobacterium tuberculosis (Mtb). Materials & methods: The minimum inhibitory concentration (MIC), cytotoxicity for three cell lines, ethidium bromide accumulation and checkerboard methods were carried out. Results: Compounds (6a, 6b, 6c, 6g, 6h and 6j) showed significant anti-Mtb activity (MIC 3.9-7.8 µg/ml) and no antagonism with anti-TB drugs already used in the TB treatment. Selectivity index (SI) was also determined, with values reaching 42.9 for H37Rv strain and 97.1 for clinical isolate. Five compounds also showed bacterial efflux pumps inhibition and one showed modulator effect with three drugs. Conclusion: These six TDZs should be considered as new scaffolds to develop anti-TB drugs.
Sujet(s)
Antituberculeux/pharmacologie , Mycobacterium tuberculosis/effets des médicaments et des substances chimiques , Thiadiazoles/pharmacologie , Animaux , Protéines de la membrane externe bactérienne/effets des médicaments et des substances chimiques , Cellules sanguines/effets des médicaments et des substances chimiques , Chlorocebus aethiops , Découverte de médicament , Synergie des médicaments , Humains , Macrophages/effets des médicaments et des substances chimiques , Tests de sensibilité microbienne , Ovis/sang , Terpènes/pharmacologie , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicité , Tuberculose/traitement médicamenteux , Cellules Vero/effets des médicaments et des substances chimiquesRÉSUMÉ
Thiazole-Zn is a systemic fungicide synthesized and developed in China that has been used for the prevention and treatment of bacterial and fungal diseases on fruits and vegetables. Thiazole-Zn is a new thyroid disruptor chemical. The purpose of this study was to clarify the thyroid-disrupting property of thiazole-Zn and the mechanism responsible for thyroid hormone (TH) biosynthesis inhibition in male rats induced by thiazole-Zn. First, the effects of different thiazole-Zn doses and exposure times on the thyroid weights, thyroid morphology and serum hormone levels of rats were investigated. The results showed that thiazole-Zn increased thyroid weights and serum thyroid-stimulating hormone (TSH) levels and induced thyroid cell hypertrophy and hyperplasia in a dose-related and time-related manner. Furthermore, measurement of thyroid radioiodine uptake in vivo in rats confirmed that thiazole-Zn inhibited active iodide uptake into the thyroid, which reduced circulating levels of serum T3 and T4. Decreases in circulating THs resulted in a compensatory increase in serum TSH levels through a negative feedback system. Subsequently, sustained excessive stimulation of the thyroid gland by TSH led to thyroid follicular cell hypertrophy and hyperplasia. In addition, thiazole-Zn increased sodium/iodide symporter (NIS) expression in the rat thyroid, and the increased NIS expression promoted and restored iodide uptake into the thyroids of rats. The risk of iodine intake inhibition by thiazole-Zn to humans, especially susceptible individuals, such as children and pregnant women, warrants additional attention.
Sujet(s)
Complexes de coordination/toxicité , Fongicides industriels/toxicité , Thiadiazoles/toxicité , Glande thyroide/effets des médicaments et des substances chimiques , Glande thyroide/anatomopathologie , Animaux , Chine , Hyperplasie , Hypertrophie , Iode/métabolisme , Radio-isotopes de l'iode , Mâle , Rats , Rat Sprague-Dawley , Symporteurs/métabolisme , Glande thyroide/métabolisme , Hormones thyroïdiennes/sang , Thyréostimuline/sangRÉSUMÉ
Traditional organic fluorophores generally have hydrophobic conjugated backbones and exhibit an aggregation-caused quenching emission property, which limits greatly their applications in the biological field. Aggregation-induced emission (AIE) fluorophores can breakthrough this shortcoming and are more promising in biological imaging. In this paper, we synthesized three novel donor-acceptor-donor-type second near-infrared (NIR-II) fluorophores and studied their geometric and electronic structures and photophysical properties by both theoretical and experimental studies. All the three fluorophores had typical AIE characteristics, and their emission wavelength spanned the traditional near-infrared and NIR-II regions. They exhibited much stronger fluorescence after being encapsulated in polymer nanoparticles (NPs) than in solutions, and the fluorophore-loaded NPs had desirable biosafety and significant tumor accumulation, indicating that they have great application potentials in tumor detection.
Sujet(s)
Colorants fluorescents/composition chimique , Phénothiazines/composition chimique , Quinoxalines/composition chimique , Thiadiazoles/composition chimique , Animaux , Lignée cellulaire tumorale , Colorants fluorescents/synthèse chimique , Colorants fluorescents/toxicité , Humains , Mâle , Souris de lignée ICR , Souris nude , Micelles , Tumeurs/imagerie diagnostique , Imagerie optique , Phénothiazines/synthèse chimique , Phénothiazines/toxicité , Poloxamère/composition chimique , Quinoxalines/synthèse chimique , Quinoxalines/toxicité , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicitéRÉSUMÉ
Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 µg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 µg/mL vs. 1-64 µg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
Sujet(s)
Antibactériens/pharmacologie , Quinolinone/pharmacologie , Thiadiazoles/pharmacologie , Animaux , Antibactériens/synthèse chimique , Antibactériens/toxicité , DNA gyrase/métabolisme , Conception de médicament , Enterococcus faecalis/effets des médicaments et des substances chimiques , Enterococcus faecium/effets des médicaments et des substances chimiques , Femelle , Cellules HepG2 , Cellules endothéliales de la veine ombilicale humaine , Humains , Mâle , Staphylococcus aureus résistant à la méticilline/effets des médicaments et des substances chimiques , Staphylococcus aureus résistant à la méticilline/enzymologie , Souris , Tests de sensibilité microbienne , Simulation de docking moléculaire , Structure moléculaire , Quinolinone/synthèse chimique , Quinolinone/toxicité , Staphylococcus epidermidis/effets des médicaments et des substances chimiques , Relation structure-activité , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicité , Inhibiteurs de la topoisomérase-II/synthèse chimique , Inhibiteurs de la topoisomérase-II/pharmacologie , Inhibiteurs de la topoisomérase-II/toxicitéRÉSUMÉ
Multifunctional nanoparticles were simply synthesized by mixing a TICT+AIE featured molecule (TPAPP-CHO) with PBS solution. The fluorescent (FL) dots entered the cells via energy-related endocytosis and were located in lysosome emitting green FL. This indicated that the nanoparticles were dissociated in the lysosome. Moreover, the synthesized nanoparticles (NPs) demonstrate potent cytotoxicity against human U87 glioblastoma cells by inducing cell apoptosis via triggering intracellular ROS overproduction.
Sujet(s)
Dérivés de l'aniline/toxicité , Apoptose/effets des médicaments et des substances chimiques , Benzaldéhydes/toxicité , Colorants fluorescents/composition chimique , Boîtes quantiques/toxicité , Thiadiazoles/toxicité , Dérivés de l'aniline/composition chimique , Dérivés de l'aniline/usage thérapeutique , Benzaldéhydes/composition chimique , Benzaldéhydes/usage thérapeutique , Lignée cellulaire tumorale , Humains , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologie , Boîtes quantiques/composition chimique , Boîtes quantiques/usage thérapeutique , Espèces réactives de l'oxygène/métabolisme , Thiadiazoles/composition chimique , Thiadiazoles/usage thérapeutiqueRÉSUMÉ
This study was aimed to evaluate the effect of a mixture of flufenacet + isoxaflutole on counts of microorganisms, ecophysiological diversity index (EP), colony development index (CD) and on the enzymatic activity of soil and maize growth. The experiment was conducted with sandy clay, to which the tested herbicide was administered in doses of: 0.25, 5.0, 10, 20, 40, 80 and 160 mg/kg. Soil without the addition of the mixture served as the control. Results demonstrated that the tested mixture contributed to a decrease in numbers of Azotobacter, organotrophic bacteria, actinobacteria and fungi. The negative effect of the herbicide could also be noticed in the case of the enzymatic activity of soil. Soil contamination contributed to suppressed activities of dehydrogenases, catalase, urease, alkaline phosphatase and arylsulfatase. In turn, the initial increase in the activity of ß-glucosidase was followed by its decline observed with time. The flufenacet + isoxaflutole mixture affected also maize plant growth, reducing maize dry matter yield when used at doses from 5.0 to 160 mg/kg. In summary, it may be concluded that mixture evokes a negative effect on the microbiological and biochemical activity of soil and that their excess in the soil leads to plant decay as at the seeding stage.
Sujet(s)
Acétamides/toxicité , Herbicides/toxicité , Isoxazoles/toxicité , Microbiologie du sol , Polluants du sol/toxicité , Thiadiazoles/toxicité , Zea mays/croissance et développement , Actinobacteria/effets des médicaments et des substances chimiques , Bactéries/effets des médicaments et des substances chimiques , Enzymes/métabolisme , Champignons/effets des médicaments et des substances chimiques , Oxidoreductases/métabolisme , Sol/composition chimique , Urease/métabolismeRÉSUMÉ
BACKGROUND: Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES: To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi. METHODS: The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS: Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS: Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.
Sujet(s)
Nitroimidazoles/toxicité , Trypanocides/toxicité , Cellules sanguines/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Test des comètes/méthodes , Altération de l'ADN , Humains , Tests de micronucleus/méthodes , Nifurtimox/composition chimique , Nifurtimox/toxicité , Nitroimidazoles/composition chimique , Valeurs de référence , Reproductibilité des résultats , Thiadiazoles/composition chimique , Thiadiazoles/toxicité , Facteurs temps , Trypanocides/composition chimique , Trypanosoma cruzi/effets des médicaments et des substances chimiquesRÉSUMÉ
A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 µM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 µM and could be a promising antiproliferative agent.
Sujet(s)
Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Sulfonamides/composition chimique , Thiadiazoles/synthèse chimique , Thiadiazoles/pharmacologie , Agents antiVIH/composition chimique , Agents antiVIH/toxicité , Lignée cellulaire , Techniques de chimie synthétique , Humains , Stéréoisomérie , Relation structure-activité , Thiadiazoles/composition chimique , Thiadiazoles/toxicitéRÉSUMÉ
The metallic complexes µ-chloro-µ-[2,5-bis (2-pyridyl)-1,3,4-thiadiazole] aqua chlorocopper (II) dichlorocopper (II) (abbreviated 2PTH-Cu2-Cl4); aquabis [2,5-bis (2-pyridyl)-1,3,4-thiadiazole-κ2N2,N3] (trifluoromethane-sulfonato-κO) copper(II) trifluoro metrhanesulfonate (2PTH-Cu-tF) and bis[(2,5-bis(pyridine-2-yl)-1,3,4-thiadiazole-di-azido copper(II)] (2PTH-Cu-Az) were compared for their antimicrobial activities in vitro, and their aptitude to control Verticillium wilt and crown gall diseases development of tomato in the greenhouse. Results showed that the complex 2PTH-Cu-Az inhibited drastically the growth of V. dahliae in vitro. 2PTH-Cu2-Cl4 and 2PTH-Cu-tF did not display any noticeable antimicrobial activity in vitro against all of the pathogens tested. However, in planta evaluation revealed that the three complexes protected tomato against crown gall similarly. They also reduced Verticillium wilt disease severity, although the complex 2PTH-Cu-Az was the most efficient. When compared to other complexes, 2PTH-Cu-Az triggered only a weak oxidative burst as revealed by H2O2 measurement and the activity of ascorbate peroxidase and catalase. These results suggest that the superiority of 2PTH-Cu-Az against V. dahliae rely on its direct antifungal activity and its ability to modulate H2O2 accumulation.
Sujet(s)
Antifongiques/toxicité , Cuivre/toxicité , Maladies des plantes/prévention et contrôle , Pseudomonas syringae/effets des médicaments et des substances chimiques , Solanum lycopersicum/microbiologie , Thiadiazoles/toxicité , Verticillium/effets des médicaments et des substances chimiques , Agrobacterium tumefaciens/effets des médicaments et des substances chimiques , Agrobacterium tumefaciens/croissance et développement , Ascorbate peroxidases/métabolisme , Catalase/métabolisme , Erwinia amylovora/effets des médicaments et des substances chimiques , Erwinia amylovora/croissance et développement , Peroxyde d'hydrogène/métabolisme , Solanum lycopersicum/métabolisme , Pseudomonas syringae/croissance et développement , Verticillium/croissance et développementRÉSUMÉ
The quality of kiwifruit became worse as a result of the abuse of plant growth regulators (PGRs). The safety of the fruits treated with PGRs also worried consumers. Therefore, the present study analyzed the structure of thidiazuron [TDZ, (1-phenyl-3-(1,2,3-thidiazol-5-yl)-urea)] (1) and its metabolites of biotransformation in kiwifruits using liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LC-IT-TOF-MS). Standard compounds were also synthesized and used for structural identification of those metabolites. In addition, cytotoxicity of TDZ and its metabolites was tested through sulforhodamine B assays against normal Chinese hamster ovary (CHO) cells. Four metabolites were identified. They were 4-hydroxy-thidiazuron (2), 3-hydroxy-thidiazuron (3), thidiazuron-4-O-ß-d-glucoside (4), and thidiazuron-3-O-ß-d-glucoside (5). Values of IC50 of compounds 1, 2, and 3 to CHO cells were 18.3 ± 1.8, 37.56 ± 1.5, and 23.36 ± 1.59 µM, respectively. Compounds 4 and 5 had no effect on CHO cells.
Sujet(s)
Actinidia/composition chimique , Fruit/composition chimique , Phénylurées/composition chimique , Facteur de croissance végétal/composition chimique , Thiadiazoles/composition chimique , Animaux , Cellules CHO , Survie cellulaire/effets des médicaments et des substances chimiques , Chromatographie en phase liquide à haute performance , Cricetinae , Cricetulus , Spectrométrie de masse , Structure moléculaire , Phénylurées/synthèse chimique , Phénylurées/métabolisme , Phénylurées/toxicité , Facteur de croissance végétal/synthèse chimique , Facteur de croissance végétal/métabolisme , Facteur de croissance végétal/toxicité , Thiadiazoles/synthèse chimique , Thiadiazoles/métabolisme , Thiadiazoles/toxicitéRÉSUMÉ
1,3,4-Thiadiazole and sugar-derived molecules have proven to be promising agrochemicals with growth promoting, insecticidal and fungicidal activities. In the research field of agricultural fungicide, applying union of active group we synthesized a new set of 1,3,4-thiadiazole xylofuranose derivatives and all of the compounds were characterized by 1H NMR and HRMS. In precise toxicity measurement, some of compounds exhibited more potent fungicidal activities than the most widely used commercial fungicide Chlorothalonil, promoting further research and development. Based on our experimental data, 3D-QSAR (three-dimensional quantitative structure-activity relationship) was established and investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques, helping to better understand the structural requirements of lead compounds with high fungicidal activity and environmental compatibility.
Sujet(s)
Fongicides industriels/composition chimique , Hétérosides/composition chimique , Nucléosides/composition chimique , Relation quantitative structure-activité , Thiadiazoles/composition chimique , Champignons/classification , Champignons/effets des médicaments et des substances chimiques , Champignons/croissance et développement , Fongicides industriels/synthèse chimique , Fongicides industriels/toxicité , Hétérosides/synthèse chimique , Hétérosides/toxicité , Liaison hydrogène , Interactions hydrophobes et hydrophiles , Tests de sensibilité microbienne , Modèles chimiques , Modèles moléculaires , Structure moléculaire , Nucléosides/synthèse chimique , Nucléosides/toxicité , Spectroscopie par résonance magnétique du proton , Spécificité d'espèce , Électricité statique , Thiadiazoles/synthèse chimique , Thiadiazoles/toxicitéRÉSUMÉ
The first hyperbranched BODIPY-based conjugated polymer dots (Pdots) were reported. The Pdots showed quantum yields of as high as 22%, which is 40% higher than their linear counterparts. The Pdots were successfully applied in cell-labelling applications. These results demonstrated that hyperbranched polymers are a very promising material for biological imaging and applications.