Novel Furan‐Pyrazole Molecular Hybrids as Prospective Anti‐Neuroinflammatory Agents: Design, Synthesis, and In‐Vitro Screening Thereof

Abstract Neuro‐inflammatory responses lead to various neurodegenerative disorders. A small library of 1H‐pyrazole‐1‐carbothioamidoacetamido)‐furan‐3‐carboxamide molecular hybrids were designed and subjected to molecular docking against two neuroinflammatory targets, HMGB1 (2LY4) and Box A (4QR9) proteins. The in‐silico investigations indicated notable binding of 9 c and 9 d against HMGB1(2LY4), while compounds 9 c , 9 h , and 9 g demonstrated high affinity towards HMGB1 Box A (4QR9) proteins. A total of ten compounds, which showed good binding interactions with the target proteins were selected for further synthesis and evaluated for anti‐neuroinflammatory activity. The compounds, 9 a – j were synthesized by reacting pyrazole‐carbothioamides (iii & iv) with furanyl acetamides (7a–e). FTIR, NMR, and mass spectrometric data confirmed all structures. The in‐vitro cytotoxicity was evaluated on microglial cells BV‐2, N‐9, HMO6, leukemic HAP1 and human fibroblast cells. Notable suppression of anti‐inflammatory markers TNF‐α, IL‐1β, IL‐6, and Bcl‐2 was observed by 9 a – d and 9 f . All derivatives were moderate in potency compared to reference doxorubicin and could act as novel anti‐neuroinflammatory agents. The current discoveries could provide insights for developing novel lead compounds that could target neuroinflammation and related diseases.