Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti‐inflammatory Ascidian Metabolites and Celecoxib

Abstract

The serious adverse effects caused by non‐selective and selective cyclooxygenase‐2 (COX‐2) inhibitors remain significant concerns for current anti‐inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti‐inflammatory drugs (NSAIDs) against COX‐1 and COX‐2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti‐inflammatory assays. Treatment with 6 m effectively suppressed the NF‐κB signaling pathway in lipopolysaccharide (LPS)‐stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro‐inflammatory factors such as inducible nitric oxide synthase (iNOS), COX‐2, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐1β, as well as decreased production of prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti‐inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.

Synthesis and anti‐inflammatory activity of novel firocoxib analogues with balanced COX inhibition

“…Encouraged by our previously published findings (Fang et al, 2023;Ju et al, 2019Ju et al, , 2023 and as part of ongoing research toward the discovery of novel COX-2 inhibitors with well-balanced inhibitory activity, we have designed a new series of firocoxib analogs utilizing a molecular hybridization strategy. Amide bonds serve as pharmacophores or linking groups, playing an increasingly prominent role in the design and development of pharmaceuticals.…”