Molecular Docking, Synthesis, and Characterization of Furanyl‐Pyrazolyl Acetamide and 2,4‐Thiazolidinyl‐Furan‐3‐Carboxamide Derivatives as Neuroinflammatory Protective Agents

Microglia are key immune cells in the brain that maintain homeostasis and defend against immune threats. Targeting the dysfunctional microglia is one of the most promising approaches to inhibit neuroinflammation. In the current study, a diverse series of molecular hybrids were designed and screened through molecular docking against two neuroinflammatory targets, namely HMGB1 (2LY4) and HMGB1 Box A (4QR9) proteins. Based on the outcomes of docking scores fifteen compounds; ten furanyl‐pyrazolyl acetamides 11(a–j), and five 2,4‐thiazolidinyl‐furan‐3‐carboxamide 15(a–e) derivatives were selected for further synthesis, followed by biological evaluation. The selected compounds, 11(a–j) and 15(a–e) were successfully synthesized with moderate to good yields, and structures were confirmed by IR, NMR, and mass spectra. The in‐vitro cytotoxicity was evaluated on microglial cells namely BV‐2, N‐9, HMO6, leukemic HAP1, and human fibroblast cells. Further western‐blot analysis revealed that 11h, 11f, 11c, 11j, 15d, 15c, 15e, and 15b compounds significantly suppressed anti‐inflammatory markers such as TNF‐α, IL‐1, IL‐6, and Bcl‐2. All derivatives were moderate in potency compared to reference doxorubicin and could potentially act as novel anti‐neuroinflammatory agents. This study can act as a beacon for further research in the application of furan‐pyrazole and furan‐2,4‐thiazolidinediones as lead moieties for anti‐neuroinflammatory and related diseases.