Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents

Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity

Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies

Skin vaccination using microneedles coated with a plasmid DNA cocktail encoding nucleosomal histones of Leishmania spp.

Vaccine delivery using microneedles (MNs) represents a safe, easily disposable and painless alternative to traditional needle immunizations. The MN delivery of DNA vaccines to the dermis may result in a superior immune response and/or an equivalent immune response at a lower vaccine dose (dose-sparing). This could be of special interest for immunization programs against neglected tropical diseases such as leishmaniasis. In this work, we loaded a MN device with 60 μg of a plasmid DNA cocktail encoding the Leishmania infantum nucleosomal histones H2A, H2B, H3 and H4 and compared its immunogenicity and protective capacity against conventional s.c. or i.d. injection of the plasmid. Mice immunized with MNs showed increased ratios of IFN-γ/IL-10, IFN-γ/IL-13, IFN-γ/IL-4, and IFN-γ/TGF-β in the spleens and lymph nodes compared with mice immunized by s.c. and i.d. routes. Furthermore, CCXCL9, CXCL10 and CCL2 levels were also higher. These data suggest that the nucleic acid immunization using MNs produced a better bias towards a Th1 response. However, none of the immunizations strategies were able to control Leishmania major infection in BALB/c mice, as illustrated by an increase in lesion size and parasite burden

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Selenoester-containing compounds for use in the treatment of microbial infections or colorectal cancer

The invention relates to a compound of formula (I) for use in the treatment of microbial infections or colorectal cancer, wherein R1 to R4, X, n, p, q, r and s are defined in the description.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad de Navarra, Universidad de Szeged, Universität des SaarlandesA1 Solicitud de patente con informe sobre el estado de la técnic

Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents

Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity

Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies

Anales de Edafología y Agrobiología Tomo 41 Número 11-12

Suelos. Aplicación del método de evaluación de tierras de la F.A.O. a Galicia, por F. Díaz Fierros Viqueira, F. Gil Sotres y M. Puga Pereira.-- II. Lepidocrocita, goethita y vermiculita en el solum de un Ultisol, por E. Barragán y J. lñiguez. Modelo experimental de alteración de limonita, por Hoyos de Castro A., Hernando Costa, J, Hernando Massanel, l. y Millán Pérez, R.-- La fracción arcilla de suelos de alta montaña. III. Rendolls, por L. J. Alias Pérez y J. Hernández Bastida.-- Suelos empardecidos. IV. Mineralogía de arcillas y génesis de suelos, por Hoyos de Castro, A., Paloma G.Villamil, M. L., Hernando Costa, J. y Egido Rodríguez.-- The manganese transformation in soils, por B. L. Baser and L. L. Somani.-- Effect of soil application of manganese. por B. L. Baser and L. L. Somani.-- Fraccionamiento de sustancias húmicas. por A. Hoyos, M. A. Candas y J. González.—Fertilidad de Suelos. Adsorción de fosfato por minerales de la arcilla. por Sama Cruz, F., Bolarín, M. C .. Romero, M. y Fernández, F. G.--Actividad ureásica del suelo. por Pérez Mateos, M. y González Carcedo, S.-- Adición de resíduos vegetales. l. Evolución del carbono y nitrógeno. por M. T. Hernández, J. Cegarra, A. Lax y F. Costa.-- Efecto de la aplicación molíbdica sobre el rendimiento de maíz. por P. Díaz Luis. C. E. Alvarez, V. García y B. Eleizalde.—Fisiología Vegetaly Nutrición. Almidón en estatuillas juveniles de castaño y enraizamiento. por M. T. García, A. Ballesler y E. Veitez.--Fitotoxicidad de suelo bajo brezal de Erica Australis L. por A. Carballeira.--Benzylamino purine effect on seeds in culture, por Roberto Rodríguez y Belén Fernández.-- Inducción y crecimiento de cultivos de tejidos, por J. F. Pérez Francés, E. Iglesias, N. Samarín y A. C. Blesa.-- Inhibición de la reacción de Hill por herbicidas, por J. M. Durán y M. L. Manín.-- Actividad nitrato reductasa en hojas de olivo por V. Valpuesta, L Catalina, R. Romero, C. Mazuelos y R. Sarmiemo.-- Estudios cinélicos de la actividad ureásica en suelos calizos por González Carcedo, S. Pérez Maleas. M.-- Actividad ureásica y poblaciones microbianas: efecto del tolueno, por González Carcedo, S., Pérez Maleas, M. y Fueme Marcos, M. A.-- Comportamiento de Chlorella pyrenoidosa frente a boro, por Sánchez, E., Maleo, P., Fernández, E., Bonilla, l. y Onega, P. --Influencia de la nutrición nítrica o amoniacal sobre planta de lechuga, por M. P. Sánchez Conde.-- Influencia del embrión en la actividad proteolítica, por Amonio García Díez, Mercedes Villa Robledo y M. del Carmen Rodríguez Buján.—Fisiología Vegetal y Nutrición en estaquillas juveniles de castaño y enraizamiento, por Ma. T. Garda, A. Ballester y E. Veitiez.-- Fitotoxicidad de suelo bajo brezal de Erica Australis L., por A. Carballeira.-- Benzylarnino purine effect on seeds in culture, por Roberto Rodríguez y Belén Fernández.-- Inducción y crecimiento de cultivos de tejidos, por J.F. Pérez Francés, E. Iglesias, N. Samarín y A.C. Blesa.--Inhibición de la reacción de Hill por herbicidas, por J.M.Durán y M. L. Martín.-- Actividad nitrato reductasa en hojas de olivo, por V. Va/puesta, L. Catalina, R. Romero, C. Mazuelos y R. Sarmiento.-- Estudios cinéticos de la actividad ureásica en suelos calizos, por González Carcedo, S. y Pérez Mateos, M.-- Actividad ureásica y poblaciones ¡nicrobianas: efecto del tolueno, por González Carcedo, S., Pérez Mateos, M. y Fuente Marcos, M.A.-- Comportamiento de Chlorella pyrenoidosa frente a boro, por Sánchez, E., Mateo, P., Fernández, E., Bonilla, l. y Ortega P.-- Influencia de la nutrición nítrica o amoniacal sobre planta de lechuga, por Ma. P. Sánchez Conde.-- Influencia del embrión en la actividad proteolítica, por Antonio García Díez, Mercedes Villa Robledo y Ma. del Carmen Rodríguez BujánPeer reviewe