Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1

Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular-target-directed approach involving intervention of hexokinase activity—a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC50=9.1 μm), low mammalian cytotoxicity (IMR90 cells, EC50>25 μm), and no appreciable activity on whole bloodstream-form (BSF) parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50=0.28 μm; BSF, ED50=1.9 μm). Compounds in this series also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency than toward TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple disease-causing trypanosomatid protozoa

Analysis of norfloxacin ecotoxicity and the relation with its degradation by means of electrochemical oxidation using different anodes

[EN] In this work, ecotoxicological bioassays based on Lactuca sativa seeds and bioluminescent bacterium (Vibrio fischeri) have been carried out in order to quantify the toxicity of Norfloxacin (NOR) and sodium sulfate solutions, before and after treating them using electrochemical advanced oxidation. The effect of some process variables (anode material, reactor configuration and applied current) on the toxicity evolution of the treated solution has been studied. A NOR solution shows an EC50 (5 days) of 336 mg L-1 towards Lactuca sativa. This threshold NOR concentration decreases with sodium sulfate concentration, in solutions that contain simultaneously Norfloxacin and sodium sulfate. In every case considered in this work, the electrochemical advanced oxidation process increased the toxicity (towards both Lactuca sativa and Vibrio fischeri) of the solution. This toxicity increase is mainly due to the persulfate formation during the electrochemical treatment. From a final solution toxicity point of view, the best results were obtained using a BDD anode in a divided reactor applying the lowest current intensity.The authors are very grateful to the Ministerio de Economia y Competitividad (Projects CTQ2015-65202-C2-1-R and RTI2018-101341-B-C21) for their economic support.Montañés, M.; García Gabaldón, M.; Roca-Pérez, L.; Giner-Sanz, JJ.; Mora-Gómez, J.; Pérez-Herranz, V. (2020). Analysis of norfloxacin ecotoxicity and the relation with its degradation by means of electrochemical oxidation using different anodes. Ecotoxicology and Environmental Safety. 188:1-10. https://doi.org/10.1016/j.ecoenv.2019.109923S110188Banks, M. K., & Schultz, K. E. (2005). Comparison of Plants for Germination Toxicity Tests in Petroleum-Contaminated Soils. Water, Air, and Soil Pollution, 167(1-4), 211-219. doi:10.1007/s11270-005-8553-4Barreto, J. P. d. P., Araujo, K. C. d. F., de Araujo, D. M., & Martinez-Huitle, C. A. (2015). Effect of sp3/sp2 Ratio on Boron Doped Diamond Films for Producing Persulfate. ECS Electrochemistry Letters, 4(12), E9-E11. doi:10.1149/2.0061512eelBueno, F., Borba, F. H., Pellenz, L., Schmitz, M., Godoi, B., Espinoza-Quiñones, F. R., … Módenes, A. N. (2018). Degradation of ciprofloxacin by the Electrochemical Peroxidation process using stainless steel electrodes. Journal of Environmental Chemical Engineering, 6(2), 2855-2864. doi:10.1016/j.jece.2018.04.033Carlesi Jara, C., Fino, D., Specchia, V., Saracco, G., & Spinelli, P. (2007). Electrochemical removal of antibiotics from wastewaters. Applied Catalysis B: Environmental, 70(1-4), 479-487. doi:10.1016/j.apcatb.2005.11.035Charles, J., Crini, G., Degiorgi, F., Sancey, B., Morin-Crini, N., & Badot, P.-M. (2013). Unexpected toxic interactions in the freshwater amphipod Gammarus pulex (L.) exposed to binary copper and nickel mixtures. Environmental Science and Pollution Research, 21(2), 1099-1111. doi:10.1007/s11356-013-1978-1Chen, M., & Chu, W. (2012). Degradation of antibiotic norfloxacin in aqueous solution by visible-light-mediated C-TiO2 photocatalysis. Journal of Hazardous Materials, 219-220, 183-189. doi:10.1016/j.jhazmat.2012.03.074Coledam, D. A. C., Aquino, J. M., Silva, B. F., Silva, A. J., & Rocha-Filho, R. C. (2016). Electrochemical mineralization of norfloxacin using distinct boron-doped diamond anodes in a filter-press reactor, with investigations of toxicity and oxidation by-products. Electrochimica Acta, 213, 856-864. doi:10.1016/j.electacta.2016.08.003Da Silva, S. W., Navarro, E. M. O., Rodrigues, M. A. S., Bernardes, A. M., & Pérez-Herranz, V. (2019). Using p-Si/BDD anode for the electrochemical oxidation of norfloxacin. Journal of Electroanalytical Chemistry, 832, 112-120. doi:10.1016/j.jelechem.2018.10.049Davis, J., Baygents, J. C., & Farrell, J. (2014). Understanding Persulfate Production at Boron Doped Diamond Film Anodes. Electrochimica Acta, 150, 68-74. doi:10.1016/j.electacta.2014.10.104Oliveira, G. A. R. de, Leme, D. M., de Lapuente, J., Brito, L. B., Porredón, C., Rodrigues, L. de B., … Oliveira, D. P. de. (2018). A test battery for assessing the ecotoxic effects of textile dyes. Chemico-Biological Interactions, 291, 171-179. doi:10.1016/j.cbi.2018.06.026Drèze, V., Monod, G., Cravedi, J.-P., Biagianti-Risbourg, S., & Le Gac, F. (2000). Ecotoxicology, 9(1/2), 93-103. doi:10.1023/a:1008976431227Flaherty, C. M., & Dodson, S. I. (2005). Effects of pharmaceuticals on Daphnia survival, growth, and reproduction. Chemosphere, 61(2), 200-207. doi:10.1016/j.chemosphere.2005.02.016González-Pleiter, M., Gonzalo, S., Rodea-Palomares, I., Leganés, F., Rosal, R., Boltes, K., … Fernández-Piñas, F. (2013). Toxicity of five antibiotics and their mixtures towards photosynthetic aquatic organisms: Implications for environmental risk assessment. Water Research, 47(6), 2050-2064. doi:10.1016/j.watres.2013.01.020Gustavson, K. E., Sonsthagen, S. A., Crunkilton, R. A., & Harkin, J. M. (2000). Groundwater toxicity assessment using bioassay, chemical, and toxicity identification evaluation analyses. Environmental Toxicology, 15(5), 421-430. doi:10.1002/1522-7278(2000)15:53.0.co;2-zHeberle, A. N. A., Alves, M. E. P., da Silva, S. W., Klauck, C. R., Rodrigues, M. A. S., & Bernardes, A. M. (2019). Phytotoxicity and genotoxicity evaluation of 2,4,6-tribromophenol solution treated by UV-based oxidation processes. Environmental Pollution, 249, 354-361. doi:10.1016/j.envpol.2019.03.057Iniesta, J. (2001). Electrochemical oxidation of phenol at boron-doped diamond electrode. Electrochimica Acta, 46(23), 3573-3578. doi:10.1016/s0013-4686(01)00630-2Larsson, D. G. J., de Pedro, C., & Paxeus, N. (2007). Effluent from drug manufactures contains extremely high levels of pharmaceuticals. Journal of Hazardous Materials, 148(3), 751-755. doi:10.1016/j.jhazmat.2007.07.008Leme, D. M., & Marin-Morales, M. A. (2009). Allium cepa test in environmental monitoring: A review on its application. Mutation Research/Reviews in Mutation Research, 682(1), 71-81. doi:10.1016/j.mrrev.2009.06.002Li, Y., Niu, J., & Wang, W. (2011). Photolysis of Enrofloxacin in aqueous systems under simulated sunlight irradiation: Kinetics, mechanism and toxicity of photolysis products. Chemosphere, 85(5), 892-897. doi:10.1016/j.chemosphere.2011.07.008Liu, P., Zhang, H., Feng, Y., Yang, F., & Zhang, J. (2014). Removal of trace antibiotics from wastewater: A systematic study of nanofiltration combined with ozone-based advanced oxidation processes. Chemical Engineering Journal, 240, 211-220. doi:10.1016/j.cej.2013.11.057Mao, F., He, Y., & Gin, K. (2018). Evaluating the Joint Toxicity of Two Benzophenone-Type UV Filters on the Green Alga Chlamydomonas reinhardtii with Response Surface Methodology. Toxics, 6(1), 8. doi:10.3390/toxics6010008Mora-Gómez, J., García-Gabaldón, M., Ortega, E., Sánchez-Rivera, M.-J., Mestre, S., & Pérez-Herranz, V. (2018). Evaluation of new ceramic electrodes based on Sb-doped SnO2 for the removal of emerging compounds present in wastewater. Ceramics International, 44(2), 2216-2222. doi:10.1016/j.ceramint.2017.10.178Mora-Gomez, J., Ortega, E., Mestre, S., Pérez-Herranz, V., & García-Gabaldón, M. (2019). Electrochemical degradation of norfloxacin using BDD and new Sb-doped SnO2 ceramic anodes in an electrochemical reactor in the presence and absence of a cation-exchange membrane. Separation and Purification Technology, 208, 68-75. doi:10.1016/j.seppur.2018.05.017Özcan, A., Atılır Özcan, A., & Demirci, Y. (2016). Evaluation of mineralization kinetics and pathway of norfloxacin removal from water by electro-Fenton treatment. Chemical Engineering Journal, 304, 518-526. doi:10.1016/j.cej.2016.06.105Priac, A., Badot, P.-M., & Crini, G. (2017). Treated wastewater phytotoxicity assessment using Lactuca sativa : Focus on germination and root elongation test parameters. Comptes Rendus Biologies, 340(3), 188-194. doi:10.1016/j.crvi.2017.01.002Radix, P., Léonard, M., Papantoniou, C., Roman, G., Saouter, E., Gallotti-Schmitt, S., … Vasseur, P. (2000). Comparison of Four Chronic Toxicity Tests Using Algae, Bacteria, and Invertebrates Assessed with Sixteen Chemicals. Ecotoxicology and Environmental Safety, 47(2), 186-194. doi:10.1006/eesa.2000.1966Rizzo, L. (2011). Bioassays as a tool for evaluating advanced oxidation processes in water and wastewater treatment. Water Research, 45(15), 4311-4340. doi:10.1016/j.watres.2011.05.035Seco, J. I., Fernández-Pereira, C., & Vale, J. (2003). A study of the leachate toxicity of metal-containing solid wastes using Daphnia magna. Ecotoxicology and Environmental Safety, 56(3), 339-350. doi:10.1016/s0147-6513(03)00102-7Uzu, G., Sobanska, S., Sarret, G., Muñoz, M., & Dumat, C. (2010). Foliar Lead Uptake by Lettuce Exposed to Atmospheric Fallouts. Environmental Science & Technology, 44(3), 1036-1042. doi:10.1021/es902190uVasconcelos, T. G., Henriques, D. M., König, A., Martins, A. F., & Kümmerer, K. (2009). Photo-degradation of the antimicrobial ciprofloxacin at high pH: Identification and biodegradability assessment of the primary by-products. Chemosphere, 76(4), 487-493. doi:10.1016/j.chemosphere.2009.03.022Wang, W. C., & Freemark, K. (1995). The Use of Plants for Environmental Monitoring and Assessment. Ecotoxicology and Environmental Safety, 30(3), 289-301. doi:10.1006/eesa.1995.1033Wang, X., Sun, C., Gao, S., Wang, L., & Shuokui, H. (2001). Validation of germination rate and root elongation as indicator to assess phytotoxicity with Cucumis sativus. Chemosphere, 44(8), 1711-1721. doi:10.1016/s0045-6535(00)00520-8Yang, L.-H., Ying, G.-G., Su, H.-C., Stauber, J. L., Adams, M. S., & Binet, M. T. (2008). GROWTH-INHIBITING EFFECTS OF 12 ANTIBACTERIAL AGENTS AND THEIR MIXTURES ON THE FRESHWATER MICROALGA PSEUDOKIRCHNERIELLA SUBCAPITATA. Environmental Toxicology and Chemistry, 27(5), 1201. doi:10.1897/07-471.1Yuan, F., Hu, C., Hu, X., Wei, D., Chen, Y., & Qu, J. (2011). Photodegradation and toxicity changes of antibiotics in UV and UV/H2O2 process. Journal of Hazardous Materials, 185(2-3), 1256-1263. doi:10.1016/j.jhazmat.2010.10.040Zhou, Y., Xu, Y.-B., Xu, J.-X., Zhang, X.-H., Xu, S.-H., & Du, Q.-P. (2015). Combined Toxic Effects of Heavy Metals and Antibiotics on a Pseudomonas fluorescens Strain ZY2 Isolated from Swine Wastewater. International Journal of Molecular Sciences, 16(2), 2839-2850. doi:10.3390/ijms16022839Zhu, L., Santiago-Schübel, B., Xiao, H., Hollert, H., & Kueppers, S. (2016). Electrochemical oxidation of fluoroquinolone antibiotics: Mechanism, residual antibacterial activity and toxicity change. Water Research, 102, 52-62. doi:10.1016/j.watres.2016.06.00

Active Brownian Particles. From Individual to Collective Stochastic Dynamics

We review theoretical models of individual motility as well as collective dynamics and pattern formation of active particles. We focus on simple models of active dynamics with a particular emphasis on nonlinear and stochastic dynamics of such self-propelled entities in the framework of statistical mechanics. Examples of such active units in complex physico-chemical and biological systems are chemically powered nano-rods, localized patterns in reaction-diffusion system, motile cells or macroscopic animals. Based on the description of individual motion of point-like active particles by stochastic differential equations, we discuss different velocity-dependent friction functions, the impact of various types of fluctuations and calculate characteristic observables such as stationary velocity distributions or diffusion coefficients. Finally, we consider not only the free and confined individual active dynamics but also different types of interaction between active particles. The resulting collective dynamical behavior of large assemblies and aggregates of active units is discussed and an overview over some recent results on spatiotemporal pattern formation in such systems is given.Comment: 161 pages, Review, Eur Phys J Special-Topics, accepte

Estratégias, organização e gestão de empresas em mercados globalizados: a experiência recente do Brasil Strategies, organization and management of industrial companies in globalized markets: the recent experience of Brazil

No novo contexto de economia globalizada, as perspectivas de cada país são função das competências adquiridas por seus elementos constitutivos: pessoas, empresas, instituições. Este estudo analisa as mudanças em curso na indústria brasileira, recentemente envolvida na globalização produtiva, e suas conseqüências em termos de formação de competências. Destaca as profundas mudanças em termos de estratégias, arquiteturas organizacionais e sistemas de gestão que estão ocorrendo, tanto nas empresas estrangeiras quanto nas brasileiras. Mesmo que no curto prazo essas mudanças possam ser consideradas positivas, no longo prazos os seus efeitos serão prejudiciais para o desenvolvimento de competências locais, o que afetará o desempenho competitivo da indústria brasileira.<br>This study analyses the changes that are taking place in the Brazilian industry, recently involved in the process of productive globalization. It shows that drastic changes in terms of strategies, organization and management are in course, both in terms of transnational and Brazilian enterprises. The main conclusion is that knowledge intensive functions such as R&D, Strategic Management and Management Systems are being transferred abroad by the TNCs and the Logistics function is becoming the most "strategic" function in the operation of their subsidiaries. The Brazilian enterprises which succeed in operating in globalized productive chains are adopting similar structures. In the long run, those changes will be detrimental for the formation of local capabilities and consequently, for the maintenance of the competitive position of Brazilian industry