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

Abstract 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‐H 2 O 2 and ABTS in vitro systems with IC 50 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 IC 50 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.