sulfonamide Dotaz Zobrazit nápovědu
- MeSH
- biomedicínský výzkum MeSH
- diuretika MeSH
- lidé MeSH
- sulfonamidy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
Background: Increasing resistance has resulted in an urgent need for new antimicrobial drugs. A systematic me-too approach was chosen to modify clinically used sulfonamides to obtain their imines. Methods & results: Twenty-five compounds were synthesized and evaluated for their antibacterial activity. The most active compounds were also investigated against methicillin- and trimethoprim/sulfamethoxazole (SMX)-resistant Gram-positive species. Staphylococci shared the highest susceptibility including resistant strains with minimum inhibitory concentrations from 3.91 μM (≥2.39 μg ml-1). Crucially, the compounds inhibit MRSA and trimethoprim/SMX-resistant Staphylococci without any cross-resistance. Modification of parent sulfonamides turned a bacteriostatic effect into a bactericidal effect. Toxicity for HepG2 and hemolytic properties were also determined. Conclusions: The presence of a dihalogenated salicylidene moiety is required for optimal activity. Based on toxicity, promising derivatives for further investigation were identified.
- MeSH
- aldehydy chemie farmakologie MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- bakteriální léková rezistence účinky léků MeSH
- iminy chemie farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Staphylococcus účinky léků MeSH
- sulfonamidy chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Adsorption characteristics of high-silica zeolites (HSZSM-5) for two selected sulfonamide antibiotics (SAs) (sulfamethoxazole and sulfadiazine) were investigated. The SAs were almost completely (>90%) removed from the water by HSZSM-5. Adsorption followed second-order kinetics with liquid-film diffusion as the dominant mechanism. SA adsorption capacity on high-silica zeolites was examined in terms of pH, temperature, and the presence of natural organic matter (NOM). HSZSM-5 had better adsorption performance in acidic conditions, and the apparent distribution coefficient indicated that SA0 species were the major contribution to the overall adsorption at pH of 2-10. Adsorption of SAs on HSZSM-5 was a spontaneous and exothermic physisorption process. SA removal by HSZSM-5 was a mixed mechanism through ion-exchange and hydrophobic interaction. HSZSM-5 has potential application prospects in removing SAs from wastewater.
Sulfonamide antibiotics coming from both human and veterinary medicine are among the most common emerging pollutants in freshwater. The present paper shows the successful application of passive sampling using POCIS in combination with an immunochemical ELISA technique and HPLC/MS/MS analysis to study the distribution of sulfonamides in streams around small towns in the Czech Republic, as well as around a major agglomeration of the city of Brno, including its waste water treatment plant (WWTP). Results indicated the presence of sulfonamides at most studied sites with concentrations ranging from <20 up to 736 ng of sulfamethoxazole equivalents per POCIS. Very high levels were detected in both the influent and effluent of the Brno WWTP with maxima > 8000 ng SMX per POCIS. All samplers collected down-stream of the studied towns and WWTPs clearly showed an increase in sulfonamide drug residues. Higher concentrations were determined in rivers at the city of Brno agglomeration. In agreement with other available studies, these findings indicate low efficiency of conventional WWTPs to eliminate polar pharmaceuticals such as sulfonamides. Good performance and correlation with the LC/MS results, as well as ease of use, indicate good potential for the immunochemical ELISA technique to become the screening tool for sulfonamide determination in surface waters including passive samplers.
- MeSH
- antibakteriální látky analýza MeSH
- chemické látky znečišťující vodu analýza MeSH
- chemické znečištění vody statistika a číselné údaje MeSH
- ELISA MeSH
- monitorování životního prostředí metody MeSH
- odpad tekutý - odstraňování metody MeSH
- sulfonamidy analýza MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
We report a cluster of genes encoding two monooxygenases (SadA and SadB) and one FMN reductase (SadC) that enable Microbacterium sp. strain BR1 and other Actinomycetes to inactivate sulfonamide antibiotics. Our results show that SadA and SadC are responsible for the initial attack of sulfonamide molecules resulting in the release of 4-aminophenol. The latter is further transformed into 1,2,4-trihydroxybenzene by SadB and SadC prior to mineralization and concomitant production of biomass. As the degradation products lack antibiotic activity, the presence of SadA will result in an alleviated bacteriostatic effect of sulfonamides. In addition to the relief from antibiotic stress this bacterium gains access to an additional carbon source when this gene cluster is expressed. As degradation of sulfonamides was also observed when Microbacterium sp. strain BR1 was grown on artificial urine medium, colonization with such strains may impede common sulfonamide treatment during co-infections with pathogens of the urinary tract. This case of biodegradation exemplifies the evolving catabolic capacity of bacteria, given that sulfonamide bacteriostatic are purely of synthetic origin. The wide distribution of this cluster in Actinomycetes and the presence of traA encoding a relaxase in its vicinity suggest that this cluster is mobile and that is rather alarming.
- MeSH
- Actinobacteria účinky léků genetika růst a vývoj metabolismus MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální geny MeSH
- biodegradace účinky léků MeSH
- flavinmononukleotid metabolismus MeSH
- fylogeneze MeSH
- hydrochinony metabolismus MeSH
- multigenová rodina MeSH
- oxygenasy se smíšenou funkcí metabolismus MeSH
- radioizotopy uhlíku MeSH
- sulfonamidy metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 μM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 μM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 μM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 μM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie toxicita MeSH
- antitumorózní látky chemická syntéza chemie farmakologie toxicita MeSH
- buňky 3T3 MeSH
- chalkonoidy chemická syntéza chemie farmakologie toxicita MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- sulfonamidy chemická syntéza chemie farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie MeSH
- karbamáty chemická syntéza chemie MeSH
- katalytická doména MeSH
- lidé MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- sulfonamidy chemická syntéza chemie MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
- MeSH
- antitumorózní látky farmakologie chemie MeSH
- chalkon chemie farmakologie MeSH
- chalkonoidy chemie farmakologie MeSH
- glutathion-S-transferasa fí * antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů farmakologie chemie MeSH
- kumariny * chemie farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- simulace molekulového dockingu * MeSH
- sulfonamidy * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Simple molecular descriptors of extensive series of 1,3,5-triazinyl sulfonamide derivatives, based on the structure of sulfonamides and their physicochemical properties, were designed and calculated. These descriptors were successfully applied as inputs for artificial neural network (ANN) modelling of the relationship between the structure and biological activity. The optimized ANN architecture was applied to the prediction of the inhibition activity of 1,3,5-triazinyl sulfonamides against human carbonic anhydrase (hCA) II, tumour-associated hCA IX, and their selectivity (hCA II/hCA IX).
- MeSH
- antigeny nádorové metabolismus MeSH
- inhibitory karboanhydras chemie metabolismus MeSH
- karboanhydrasa II antagonisté a inhibitory metabolismus MeSH
- karboanhydrasa IX antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- neuronové sítě (počítačové) * MeSH
- racionální návrh léčiv MeSH
- sulfonamidy chemie metabolismus MeSH
- triaziny chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
