ABSTRACT
Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC50 = 4.45 µm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration.
Subject(s)
Anti-Inflammatory Agents/chemistry , Hydrazones/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Binding Sites , Cell Movement/drug effects , Drug Design , Humans , Hydrazones/metabolism , Hydrazones/pharmacology , Hydrazones/therapeutic use , Hydrogen Bonding , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/veterinary , Inhibitory Concentration 50 , Leukocytes/cytology , Leukocytes/drug effects , Leukocytes/metabolism , Mice , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Abstract Choisya ternata Kunth, C. ternata var. sundance Kunth and the hybrid Choisya 'Aztec-Pearl' are three related species belonging to the Rutaceae family. Ethanol extracts were prepared from the leaves of these three species and evaluated in relation to their antioxidant activity using in vitro and ex vivo models. The ethanol extracts belonging to the three species produced a very high antioxidant profile as evidenced by the DPPH radical scavenging activity, the determination of total phenolics and flavonoid equivalent. The generation of reactive species of oxygen in leukocytes stimulated with LPS was dramatically reduced when the three ethanol extracts were used. The alkaloids anhydroevoxine and choisyine were isolated from the ethanol extract of C. ternata using HEMWat (4:6:5:5) as the solvent system by means of high-speed countercurrent chromatography. This was the first time quinoline alkaloids were isolated from this species using HSCCC. These compounds were also assayed for their capacity to inhibit the generation of ROS in leukocytes stimulated by LPS and the results also suggested that they are reactive oxygenase inhibitors.
