Inhibition of mycobacteria proliferation in macrophages by diaryl ether derivatives of Dehydrozingerone compound and repurposed drugs (Rebamipide, Sofalcone) via NF-κB pathway inhibition.

BACKGROUND: Chronic inflammation fuels tissue damage and morbidity in numerous diseases, including Tuberculosis, underscoring the vital need for Host-Directed Therapies to safely modulate the exaggerated host response. We investigated the immunomodulatory potential of Sofalcone and Rebamipide alongside a novel Diaryl Ether derivative of Dehydrozingerone DHZ (6), hypothesizing that they exert therapeutic effects by targeting the central inflammatory driver, the NF-κB pathway.

METHODS: We evaluated the safety and efficacy of the compounds in THP-1 macrophages infected with M. smegmatis. Mechanistic studies utilized Western blotting, immunofluorescence, and ELISA to track NF-κB activation. MMP activity was assessed by gelatin zymography, and ROS production was quantified using the DCFH-DA assay.

RESULTS: All compounds exhibited low cytotoxicity and significantly reduced intracellular bacterial survival. Agents potently and consistently inhibited the NF-κB cascade, evidenced by ≈ 83 % suppression of upstream P-IKKα/IKKβ and up to ≈89 % reduction in p65 phosphorylation. This molecular blockade prevented p65 nuclear translocation and resulted in a downstream functional benefit: near total abolition of MMP-2/9 activity and ≈71 % mitigation of ROS production.

CONCLUSION: Our results unequivocally validate NF-κB inhibition by DHZ (6), Sofalcone, and Rebamipide as a powerful strategy for HDT. These compounds are promising adjunct therapies to suppress host inflammation and limit tissue damage.