Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents

Chalcones have a distinctive 1,3-diarylpropenone skeleton and exert numerous biological effects. Using a one-step Claisen–Schmidt condensation, we synthesized eleven bis-chalcones (3–13) and three acetyl chalcones (14–16) from substituted aldehydes and diacetylresorcinol. The compounds were tested for in vitro cytotoxic activity against four human cancer cell lines (A549, DU145, KB, and KB-VIN) and inhibition of NO production in lipopolysaccharide (LPS)-activated microglial cells. Among them, four compounds (3, 5, 6, and 13) showed significant cytotoxic activity with EC50 values ranging from 1.57 to 5.14 μM, and seven compounds (3, 5–8, 10, and 13) displayed potent anti-inflammatory activity by inhibiting NO production with IC50 values ranging from 0.95 to 8.65 μM. A mechanism of action study of active compounds 6 and 7 discovered that these compounds down-regulated iNOS expression by inhibiting p65 NF-κB activation/nuclear translocation due to prevention of IκBα degradation. Structure-activity relationship (SAR) findings are also discussed.

Several synthetic bis-chalcones showed significant cytotoxic activity and potent inhibition of NO production. The compounds down-regulated iNOS expression by inhibiting p65 NF-κB activation/nuclear translocation due to prevention of IκBα degradation.Figure optionsDownload as PowerPoint slideHighlights
► Bis-chalcones were prepared via a one step Claisen–Schmidt condensation.
► Seven bis-chalcones were more potent NO inhibitors than the control drug L-NAME.
► Bis-chalcones 6 and 7 inhibited p65NFκB-dependent iNOS expression.
► Bis-chalcones 3 and 5 showed the highest cytotoxicity (EC50 1.57–2.88 μM).