Discovery of Pyranochromone Derivatives as TLR4-MD2 Inhibitors for Alleviating Osteoarthritis

Abstract

Calomembranone G, isolated from Calophyllum membranaceum, displays in vivo anti-inflammatory activity in models of arthritis and acute lung injury. Using natural product calomembranone G as a hit compound and leveraging a strategy of structural simplification, a total of 66 pyranochromone derivatives were synthesized and their structure−activity relationships were analyzed. Among these analogues, compound PC-C7 displayed the most potent anti-inflammatory activity, inhibiting NO production with an IC50 value of 0.17 ± 0.07 μM. Surface plasmon resonance, molecular docking, and co-immunoprecipitation assays demonstrated that PC-C7 disrupts the formation of the TLR4−MD2 complex. In vivo, oral administration of PC-C7 (10 or 20 mg/kg) alleviated joint inflammation and chondrocyte catabolism, through suppressing TLR4-mediated inflammatory signaling. These findings demonstrated that PC-C7 might serve as a drug candidate for osteoarthritis therapy.