Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators

Abstract

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 μM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE₂, IL-6, TNF-α and IL-1β. Compound 5z inhibited the induced production of NO, PGE₂, IL-6, TNF-α and IL-1β at the low 1 μM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC₅₀ values as low as 2.11 and 0.98 μM against NO and PGE₂ production respectively. Compounds 5q and 5g showed potent submicromolar IC₅₀ values of 0.31 and 0.59 μM respectively against PGE₂ production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.

Keywords: Anti-inflammatory; Flavones; Hybrid molecules; IL-1β; IL-6; Macrophages; Natural products-based drug discovery; Nitric oxide; PGE(2); Repurposing; Resveratrol; TNF-α; p38-α inhibitors.