Novel pyrrolo[2,1-a]isoquinoline aryl ketones attenuate carbon nanotube-induced acute lung injury through NF-κB pathway inhibition

Abstract

Acute lung injury (ALI), a life-threatening inflammatory disorder characterized by disrupted gas exchange and high mortality, urgently requires novel therapeutic strategies. Herein, anti-inflammatory activity of a series of pyrrolo[2,1-a]isoquinoline aryl ketones against carbon nanotube-induced ALI was evaluated, along with their mechanism. Sixteen aryl ketone derivatives incorporating a pyrrolo[2,1-a]isoquinoline scaffold were evaluated for their anti-inflammatory potential in RAW264.7 macrophage cells. Among them, 3g bearing 4-F-phenyl and 3k with 2-Me-phenyl demonstrated notably potent inhibitory effects on the LPS-induced release of nitric oxide (NO) in RAW264.7 macrophages, outperforming betulinic acid (IC₅₀ values: 3g = 6.91 μM, 3k = 10.10 μM, betulinic acid = 11.89 μM). Both compounds exhibited a dose-dependent suppression of TNF-α secretion, with IC₅₀ values of 7.85 μM and 8.30 μM for 3g and 3k, Furthermore, they effectively mitigated histopathological lung damage in SWCNT-exposed mice. Mechanistic studies revealed that 3g and 3k effectively diminished the activation of NF-κB through the inhibition of IκB phosphorylation and the subsequent blockade of p65 nuclear translocation. These results identify pyrrolo[2,1-a]isoquinoline aryl ketones as potential therapeutic agents capable of attenuating SWCNT-induced pulmonary inflammation through modulation of the NF-κB signaling pathway modulation.