Dual inhibition of neutrophil superoxide generation and elastase release via JNK, ERK and FAK pathways: blockade by methoxy-chalcone derivatives

Abstract

A series of chalcone-based derivatives were synthesized and assessed for their ability to target neutrophil-driven inflammation. Strategic modifications on the 1,3-diaryl-prop-2-en-1-one scaffold, all bearing a methoxylated ring B, revealed two distinct anti-inflammatory profiles: inhibitors of both superoxide (SO) generation and elastase release, and selective SO inhibitors. Compound 17, featuring 3-methoxy and 2,4-dichlorophenyl substitutions, demonstrated the most potent dual inhibition (IC₅₀ = 1.17 µM for SO and 2.60 µM for elastase), while compound 15 selectively suppressed SO production (IC₅₀ = 2.63 µM) with minimal elastase impact. Compound 17 hampered neutrophil migration without inducing cytotoxicity, and mechanistically inhibited the phosphorylation of JNK, ERK, and FAK/paxillin—key signaling pathways in neutrophil migration and activation, without altering calcium flux. These findings highlight compound 17 as a promising lead for targeting neutrophil-mediated inflammatory disorders and underscore the potential of chalcone scaffolds for precise immunomodulation.