thiourea and Influenza--Human

Evidence suggests that rapidly evolving virus subvariants risk rendering current vaccines and anti-influenza drugs ineffective. Hence, exploring novel scaffolds or new targets of anti-influenza drugs is of great urgency. Herein, we report the discovery of a series of acylthiourea derivatives produced via a scaffold-hopping strategy as potent antiviral agents against influenza A and B subtypes. The most effective compound 10m displayed subnanomolar activity against H1N1 proliferation (EC

Topics: Animals; Antiviral Agents; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Mice; RNA-Dependent RNA Polymerase; Thiourea

A series of polysubstituted and fused heterocycle derivatives of acylthiourea was prepared and the biological activity against influenza virus was evaluated. Of the analogues that demonstrated IC(50)s<0.1 microM, acylthiourea derivatives 16 and 50 were further investigated as candidates with the most potential for future development. The SAR of these compounds are discussed and they represent a novel class of highly potent and selective inhibitors of influenza virus.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; Humans; Influenza, Human; Inhibitory Concentration 50; Models, Chemical; Orthomyxoviridae; Pyrimidine Nucleosides; Structure-Activity Relationship; Thiourea

A series of substituted acyl(thio)urea and 2H-1,2,4-thiadiazolo [2,3-a] pyrimidine derivatives were prepared and both of their cell culture and enzymatic activity toward influenza virus were tested. Their in vitro neuraminidase inhibitory activities were in good agreement with the corresponding activities in cultured cells and they were evaluated as potent neuraminidase inhibitors. Of the analogues that demonstrated IC(50)s<0.1microM, 16 and 60 were further investigated as candidates with the most potential for future development. The molecular docking work of the representative compound was described to provide more insight into their mechanism of action and further rationalize the observations of this new series herein, which represents a novel class of highly potent and selective inhibitors of influenza virus.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; Enzyme Inhibitors; Humans; Influenza, Human; Inhibitory Concentration 50; Kidney; Models, Chemical; Molecular Structure; Neuraminidase; Orthomyxoviridae; Pyrimidines; Structure-Activity Relationship; Thiourea

Chronic low-grade inflammation is associated with increased risk of vascular diseases. The source of inflammation is unknown but may well be chronic and/or repetitive infections with microorganisms. Direct infection of endothelial cells (ECs) may also be a starting point for atherogenesis by initiating endothelial procoagulant activity, increased monocyte adherence and increased cytokine production. We hypothesized that iron-mediated intracellular hydroxyl radical formation after infection is a key event in triggering the production of interleukin-6 (IL-6) by ECs in vitro.. Cultured ECs were incubated with Fe(II) and Fe(III) or infected with Chlamydia pneumoniae or influenza A/H1N1/Taiwan/1/81 for 48 and 24 h, respectively. To determine the role of iron and reactive oxygen species, cells were coincubated with the H2O2 scavenger N-acetyl-l-cysteine, with the iron chelator deferoxamine (DFO) or with the intracellular hydroxyl radical scavenger dimethylthiourea (DMTU). After the incubation periods, supernatants were harvested for IL-6 determination.. Incubating ECs with Fe(II) and Fe(III) resulted in increased IL-6 production. Similarly, infection with C. pneumoniae and influenza A also induced an IL-6 response. Coincubating ECs with DFO or DMTU blocked this response. Nuclear factor-kappaB activity was increased after infection and blocked by coincubation with DFO or DMTU.. Cultured ECs respond to infection and iron incubation with increased production of IL-6. Iron, the generation of intracellular hydroxyl radical and NF-kappaB activity are essential in cellular activation, suggesting that reactive oxygen species generated in the Haber-Weiss reaction are essential in invoking an immunological response to infection by ECs.

Topics: Antioxidants; Cells, Cultured; Chlamydophila Infections; Chlamydophila pneumoniae; Deferoxamine; Endothelium, Vascular; Free Radical Scavengers; Humans; Influenza A virus; Influenza, Human; Interleukin-6; Iron; Iron Chelating Agents; NF-kappa B; Thiourea; Umbilical Veins

Topics: Anti-Bacterial Agents; Humans; Influenza, Human; Orthomyxoviridae; Thiourea

Topics: Anti-Bacterial Agents; Humans; Influenza, Human; Orthomyxoviridae; Sulfur; Thiosemicarbazones; Thiourea