Bukhari Asma, Nadeem Humaira, Zulfiqar Iqra, Anwar Maira, Masaud Syed Muzzammil, Murtaza Babar
Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Street 41, 7th Ave, G-7/4, Islamabad, Pakistan.
Department of Basic Medical Sciences, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Sci Rep. 2025 Aug 1;15(1):28100. doi: 10.1038/s41598-025-13538-7.
Diabetes mellitus remains a global health challenge, necessitating the development of novel therapeutic agents. In this study, a series of thiohydantoin derivatives (FP1-FP7) were synthesized and evaluated for their in silico, in vitro, and in vivo antidiabetic potential. Molecular docking studies revealed strong binding affinities of derivatives towards α-glucosidase (PDB: 3wy1) and α-amylase (PDB: 3dhp), with FP4 exhibiting the most favorable interactions (- 7.8 kcal/mol with α-amylase and - 7.0 kcal/mol with α-glucosidase), involving hydrogen bonding and π-π stacking. During in vitro enzyme inhibition assay, FP4 demonstrated potent inhibitory activity against α-glucosidase and α-amylase, with IC₅₀ values of 129.40 and 128.90 µg/mL, respectively. The DPPH scavenging assay also indicated that FP4 had relatively strong antioxidant activity, with an IC₅₀ value of 39.7 µg/mL. In vivo antidiabetic efficacy was evaluated in STZ-induced diabetic rats over a period of 6-week. FP4 treated diabetic rats exhibited significantly reduced fasting blood glucose by 28.9% than in diabetic controls. In addition, HbA1C levels and diabetes-associated weight loss were significantly curtailed in these animals than untreated diabetic group. Further FP4 treated animals exhibited significantly decreased LDL and triglyceride levels and elevated HDL levels, suggesting a broader metabolic benefit. Taken together, our results suggest that thiohydantoin derivatives, particularly FP4, exhibited interesting antidiabetic and antihyperlipidemic activities warranting further pharmacokinetic and mechanistic investigations also potential for clinical translation and long term safety assessment.
糖尿病仍然是一项全球性的健康挑战，因此需要开发新型治疗药物。在本研究中，合成了一系列硫代乙内酰脲衍生物（FP1-FP7），并对其进行了计算机模拟、体外和体内抗糖尿病潜力评估。分子对接研究表明，这些衍生物与α-葡萄糖苷酶（PDB：3wy1）和α-淀粉酶（PDB：3dhp）具有很强的结合亲和力，其中FP4表现出最有利的相互作用（与α-淀粉酶的结合亲和力为-7.8 kcal/mol，与α-葡萄糖苷酶的结合亲和力为-7.0 kcal/mol），涉及氢键和π-π堆积。在体外酶抑制试验中，FP4对α-葡萄糖苷酶和α-淀粉酶表现出强效抑制活性，IC₅₀值分别为129.40和128.90 μg/mL。DPPH清除试验还表明，FP4具有相对较强的抗氧化活性，IC₅₀值为39.7 μg/mL。在6周的时间里，对链脲佐菌素诱导的糖尿病大鼠进行了体内抗糖尿病疗效评估。与糖尿病对照组相比，接受FP4治疗的糖尿病大鼠空腹血糖显著降低了28.9%。此外，与未治疗的糖尿病组相比，这些动物的糖化血红蛋白水平和与糖尿病相关的体重减轻显著减少。此外，接受FP4治疗的动物的低密度脂蛋白和甘油三酯水平显著降低，高密度脂蛋白水平升高，表明具有更广泛的代谢益处。综上所述，我们的结果表明，硫代乙内酰脲衍生物，特别是FP4，表现出有趣的抗糖尿病和抗高血脂活性，值得进一步进行药代动力学和作用机制研究，也具有临床转化和长期安全性评估潜力。
