Design And Synthesis Of XOD-NLRP3 Dual Inhibitors With Hypouricemic Activity As Drugs For Acute Gouty Arthritis

Gout is a crystal associated arthropathy caused by deposition of monosodium urate(MSU),Acute gouty arthritis is the most common first symptom of gout.In the pathogenesis of acute gout arthritis,the intra-articular uric acid concentration is supersaturated to form crystallization of MSU,which acts as a foreign body and triggers the body's innate immune response,causing the immune system to overreact,leading to an acute inflammatory reaction of the joint and its surrounding tissues.Studies shows that,as a pattern recognition receptor,NOD-like receptor protein 3(NLRP3)inflammasome can be activated by urate crystallization triggering an immune inflammatory response and causing acute gout arthritis symptoms.Currently,reducing uric acid and relieving inflammation are the two main methods of treating gout.Uric acid-reducing drugs such as allopurinol and anti-inflammatory drugs colchicine have serious side effects.At present,there is no bifunctional drug with both uric acid-reducing effect and anti-inflammatory activity for the treatment of acute gout arthritis.Therefore,this paper designs and synthesizes of XOD-NLRP3 dual inhibitors and is used in the study of anti-acute gouty arthritis drugs,which has good innovation and application value.In the early stage,the research group selected the deoxybenzoin compound I1-7 which has a good Inhibition on NLRP3 and XOD.Based on this,30 novel benzoxazole derivatives were designed and synthesized.We screened the synthesized compounds for XOD and NLRP3 inhibition activity and evaluated the anti-gout activity in vivo.The results show that compound 13-2 has the best anti-NLRP3 and anti-XOD activity.