Probing intermolecular interactions in a diethylcarbamazine citrate salt by fast MAS 1 H solid-state NMR spectroscopy and GIPAW calculations

Fast magic-angle spinning (MAS) NMR is used to probe intermolecular interactions in a diethylcarbamazine salt, that is widely used as a treatment against adult worms of Wuchereria bancrofti which cause a common disease in tropical countries named filariasis. Specifically, a dihydrogen citrate salt that has improved thermal stability and solubility as compared to the free form is studied. One-dimensional 1H, 13C and 15N and two-dimensional 1H-13C and 14N-1H heteronuclear correlation NMR experiments under moderate and fast MAS together with GIPAW (CASTEP) calculations enable the assignment of the 1H, 13C and 14N/15N resonances. A two-dimensional 1H-1H double-quantum (DQ) –single-quantum (SQ) MAS spectrum recorded with BaBa recoupling at 60 kHz MAS identifies specific proton-proton proximities associated with citrate-citrate and citrate-diethylcarbamazine intermolecular interactions

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

Twenty new 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition in vitro was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1β release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-amine derivatives 9b, 9c, and 9f, and 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole (11c) showed inhibitory effects with IC50 values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1β release. In addition, the in vitro ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/9f and murine P2X7R/9f indicated the putative intermolecular interactions. Compound 9f showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential

<i>In vitro</i> antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19

BackgroundCurrent approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity.MethodsSARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19.ResultsDaclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans.ConclusionsDaclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy

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Pharmaceutical market and opportunity in the 21st century for generic drugs : a brazilian case study of olanzapine

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La propriété industrielle dans le cancer et le droit à la vie : cas de l'intelligence économique au Brésil associé à la tuberculose

International audienceCet article a pour objectif de faire conna\ⁱtre aux professionnels de l'intelligence économique les grandes lignes d'une étude sur l'industrie pharmaceutique. D'après IMS Health, ce domaine scientifique est reconnu comme dynamique et rentable pour les ventes de médicaments. Celles-ci ont dépassé 900 \ US milliards et tendent vers le 1,2 trillion \ US en 2016, alors que 80 % des personnes dans le monde n'ont pas accès à ces médicaments et traitement. L'approche est faite par l'étude des tendances technologique dans les brevets d'oncologie et également la recherche en association avec la tuberculose. Dans ce sens, une étude de cas sur L'Imatinib Mésylate, médicament contre le cancer, est présentée. Au Brésil son prix a atteint 90 \ US la dose. Après la stratégie du gouvernement pour l'intelligence économique, le prix des médicaments a sensiblement baissé. Les chiffres ont été obtenus à partir de bases de données telles que l'OMPI, brevets de l'OEB et les références indexées comme PubMed, Scielo et Web of Science. What intelligence can be found in big data ? The case of the French public procure Industrial Property in cancer and the right to life : a case of economic intelligence in Brazil associated with tuberculosis. This article aims to demonstrate to the professionals of economic intelligence, a study on industrial property related to the pharmaceutical industry. According to IMS Health, this science area has been shown as dynamic and profitable for sales of drugs. Those sales exceed US\ 900 billion and tend to reach US\ 1.2 trillion in 2016. On the other hand, 80 % of people in the world do not have access to those drugs and treatment. The approach is through technology forecasting in patents oncology research and in association with tuberculosis. In this sense a case study of Imatinib Mesylate for the cancer is shown, where each dose in Brazil reached US\ 90. After the government's strategy in economic intelligence, there were significant reductions in drug prices. The information's were obtained from databases such as WIPO, EPO patents and indexed references as PubMed, Web of Science and Scielo

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Neglected disease in social network ? A blueprint of Dengue in twitter as a contribution of information science for public health

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