Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2024-11-06 DOI:10.1007/s00044-024-03317-w

Aya Y. Rashad, Hoda G. Daabees, Mohamed Elagawany, Mohamed Shahin, Ahmed E. Abdel Moneim, Maram Y. Marei, Sherif A. F. Rostom

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Abstract

The mutual prodrug approach appears as a promising strategy for developing candidates with great therapeutic effectiveness and enhanced safety profile. The present study addresses the assessment of merging the xanthine oxidase (XO) inhibitor febuxostat (FEB) with the URAT1 inhibitor probenecid (PRO) for managing hyperuricemia and gout associated with oxidative stress. Accordingly, FEB-PRO (5) prodrug was synthesized and proved to be a significant hypouricemic and free radical scavenging agent, when compared to its parents and the physical mixture. Moreover, (5) was found to remarkably decrease serum and hepatic XO as compared with the parent drugs and physical mixture. Inclusion of PRO imparted synergism and enhancement of the pharmacological profile of FEB. Additionally, the tested prodrug showed protective effect against hepatotoxicity caused by carbon tetrachloride, beside being non cytotoxic to normal breast cells. Also, RT-PCR analysis showed that the expression of antioxidant biomarkers CAT and SOD2 significantly increased in the group treated with FEB-PRO (5). Being an ester, (5) displayed reduced aqueous solubility and increased lipophilicity relative to the parent medications.

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互为原药的方法似乎是一种很有前景的策略，可以开发出治疗效果显著、安全性更高的候选药物。本研究评估了将黄嘌呤氧化酶（XO）抑制剂非布索坦（FEB）与URAT1抑制剂丙磺舒（PRO）合并用于治疗与氧化应激相关的高尿酸血症和痛风的效果。因此，FEB-PRO (5) 原药被合成出来，并证明与其母药和物理混合物相比，FEB-PRO (5) 原药具有显著的降尿酸和清除自由基的作用。此外，与母药和物理混合物相比，(5) 还能显著降低血清和肝脏 XO。原药的加入产生了协同作用，增强了 FEB 的药理特征。此外，测试的原药对四氯化碳引起的肝毒性具有保护作用，而且对正常乳腺细胞无细胞毒性。此外，RT-PCR 分析表明，在使用 FEB-PRO 的组别中，抗氧化生物标志物 CAT 和 SOD2 的表达量明显增加（5）。作为一种酯，(5) 与母药相比，水溶性降低，亲脂性增加。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.