<br>治疗高尿酸血症和痛风的潜在治疗剂：3,4-二羟基-5-硝基苯甲醛苯硫脲,European Journal of Pharmaceutical Sciences

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治疗高尿酸血症和痛风的潜在治疗剂：3,4-二羟基-5-硝基苯甲醛苯硫脲
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2024-04-21 , DOI: 10.1016/j.ejps.2024.106778
Xiongying Yu ₁ , Shuaiwei Ren ₂ , Jun Zhou ₁ , Yongcui Liao ₁ , Yousheng Huang ₂ , Huanhuan Dong ₂

Affiliation

尿酸是嘌呤的代谢产物，依赖黄嘌呤氧化酶（XOD）产生。 XOD是开发治疗高尿酸血症（HUA）和痛风药物的靶标。目前，痛风患者的治疗选择仍然有限。 3, 4-二羟基-5-硝基苯甲醛（DHNB）是天然产物原儿茶醛的衍生物，具有良好的生物活性。在这项工作中，我们鉴定了一种针对 XOD 的 DHNB 氨基硫脲类化合物。 3,4-Di羟基-5-硝基苯甲醛苯硫缩氨基脲可有效抑制XOD活性（IC50值：0.0437 μM），并表现出混合抑制作用。在急性高尿酸血症小鼠模型中，中等剂量（10 mg/kg.w）3,4-二羟基-5-硝基苯甲醛氨基硫脲可有效控制血清尿酸含量，并显着抑制血清XOD活性。此外，3,4-二羟基-5-硝基苯甲醛苯硫脲显示出良好的安全性，用目标化合物治疗的小鼠在单剂量 500 mg/kg 后没有表现出任何一般毒性症状。在别嘌呤醇组中，50% 的小鼠死亡。这些结果提供了 XOD 抑制的结构框架和机制，可能有助于高尿酸血症和痛风治疗的设计。

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A potential therapeutic agent for the treatment of hyperuricemia and gout: 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 μM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments.

更新日期：2024-04-21

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