Indolin-2-Ones: A New Approach to Inflammation, Targeting LPS via GSK3β/NLRP3

Chronic inflammation is a key pathogenic driver in cardiovascular, neurodegenerative and metabolic diseases. Previously we identified highly active GSK3β inhibitors with antidiabetic potential among 3,5-disubstituted indolin-2-one derivatives. We found that these derivatives also possess a direct antioxidant activity, which was shown in in luminol-H₂O₂ and ABTS in vitro systems with IC₅₀ level was up to 6.0 and 34.6 µM respectively. GSK3β is an essential part LPS-induced NF-κB and NLRP3 pathways activation. Hence, the most active compounds 3 and 5 were evaluated and found to exhibit high anti-inflammatory activity in LPS-induced activation of primary murine macrophages with IL-6 IC₅₀ from 8.7 to 63.5 µM without cytotoxicity and also prevent LPS + ATP-induced NLRP3 activation in macrophages and peripheral blood mononuclear cells. Alongside compounds 3 and 5 retain macrophages phagocytic activity unlike dexamethasone. Animal's studies showed effective prevention of LPS-induced rat paw edema volume, NO, TNFα, and IL-1β formation after 30 mg/kg per oral administration. Hence, we identified candidates combining antidiabetic, antioxidant and anti-inflammatory activities promising as agents against inflammation-linked chronic diseases.