Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

• Published in: Chemical biology & drug design 2018-02, Vol.91 (2), p.391-397
• Main Authors: Freitas, Rosana H. C. N., Cordeiro, Natália M., Carvalho, Patrícia R., Alves, Marina A., Guedes, Isabella A., Valerio, Tayna S., Dardenne, Laurent E., Lima, Lídia M., Barreiro, Eliezer J., Fernandes, Patrícia D., Fraga, Carlos A. M.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; anti‐inflammatory; Binding Sites; Cell Movement - drug effects; Drug Design; ensemble docking; Humans; Hydrazones - chemistry; Hydrazones - metabolism; Hydrazones - pharmacology; Hydrazones - therapeutic use; Hydrogen Bonding; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - veterinary; Inhibitory Concentration 50; kinase inhibitor; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - metabolism; Mice; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - metabolism; Molecular Docking Simulation; N‐acylhydrazone; p38α MAPK; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Structure, Tertiary; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13085

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. New naphthyl‐N‐acylhydrazone derivatives were reported as MAPK p38α inhibitors. Ensemble docking studies at p38α MAPK active site and LASSBio‐1824 presented an unusual binding mode at kinase active site. LASSBio‐1824 showed in vivo anti‐inflammatory and anti‐TNF‐α properties.