2-苯基-5-吡啶基-1,3,4-噁二唑类化合物的合成及黄嘌呤氧化酶抑制活性

目的 设计合成2-苯基-5-吡啶基-1,3,4-噁二唑类化合物，并对其黄嘌呤氧化酶抑制活性进行初步评价。方法 以对羟基苯甲酸甲酯为原料，经烃化、肼解、环合等反应合成目标化合物。以非布司他为阳性对照药，采用牛源的黄嘌呤氧化酶对目标化合物的抑制活性进行评价。结果 共合成了15 个未见文献报道的目标化合物，结构经核磁共振氢谱、飞行时间质谱和红外光谱确证。目标化合物均表现出一定的黄嘌呤氧化酶抑制活性，其中化合物 4m（IC₅₀=1.04 µmol·L^-1）活性最好，但低于阳性对照药非布司他（IC₅₀=0.024 µmol·L^-1）。结论 2-苯基-5-吡啶基-1,3,4-噁二唑类化合物作为新型黄嘌呤氧化酶抑制剂，其构效关系值得进一步研究。

Synthesis and xanthine oxidase inhibitory activites of 2-phenyl-5-pyridyl-1,3,4- oxadiazole derivatives

The xanthine oxidase(XO) is generally recognized as a key enzyme in purine catabolism.The xanthine oxidase inhibitors(XOIs) could lower the level of urate,so they are effective agents for gout in clinic.The aim of this study is to discover new XOIs with high activity.According to the structure and function of xanthine oxidase,and the fundamental structures of FYX-051 and febuxostat together with their action mechanisms on XOIs,2-(4-alkoxy-3-substituted phenyl)-5-pyridyl-1,3,4-oxadiazole derivatives were designed.Starting from methyl 4-hydroxybenzoate via alkylation,hydrazinolysis,cyclization,and so on,fifteen target compounds were obtained and all of them were not reported yet,and their structures were confirmed by 1H-NMR,IR and TOF-HRMS.The in vitro inhibitory activity of the synthesized compounds was evaluated on xanthine oxidase from bovine.All of the tested compounds showed diverse inhibitory activity,among which compound 4m exhibited the strongest inhibitory activity with an IC50 of 1.04 μmol·L-1.For R1,cyano group is preferred,which may have a better hydrogen bond interaction with the amino residue of Asn768,than nitro and bromine groups;Most of compounds with aliphatic groups for R2,which may be more suitable for the narrow hydrophobic cavity,showed better inhibitory activity than their aromatic counterparts.Thus,the structure-activity relationship of 2-phenyl-5-pyridyl-1,3,4-oxadiazole derivatives,as a novel of xanthine oxidase inhibitors,should be investigated further.