Design, synthesis, biological evaluation, and in silico studies of quinoxaline derivatives as potent p38α MAPK inhibitors

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in‐vitro anti‐inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2′‐diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen‐activated protein (MAP) kinase inhibition. The in‐vivo anti‐inflammatory activity was assessed by the carrageenan‐induced rat paw edema inhibition method. All the compounds (4a–n) exhibited moderate to high in‐vitro anti‐inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a–4d and 4f) with good in‐vitro profiles were selected for in‐vivo anti‐inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity. Quinoxaline derivatives possessing the hydrazone moiety were designed and synthesized by a multistep reaction protocol. Compound 4a was found to be highly selective toward p38α mitogen‐activated protein (MAP) kinase, with IC50 = 0.042. Molecular docking and molecular dynamics simulation studies also confirmed the p38α MAP kinase inhibition as a possible mechanism of action.