Ali Syed Parween, Mansoor Farheen, Albaayit Shaymaa Fadhel Abbas, Ali Farman, Dera Ayed A, Shahbaz Muhammad, Ullah Jawad, Almohaimeed Hailah M, Gahtani Reem M, Abdulfattah Ahmed M, Alshabrmi Fahad M, Alam Sarfaraz, Ullah Saeed
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, 62529, Saudi Arabia.
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Sci Rep. 2024 Dec 30;14(1):31761. doi: 10.1038/s41598-024-82765-1.
Diabetes is a prevalent and serious metabolic disorder affecting millions globally, and it poses extensive health risks due to elevated blood glucose levels. One promising approach for managing diabetes is the inhibition of α-glucosidase, an enzyme that plays a crucial role in carbohydrate metabolism. Targeting α-glucosidase can help delay glucose absorption, thus controlling postprandial blood sugar spikes. Dihydropyrimidones, a core structural class present in various biologically active natural compounds, have been recognized for their diverse therapeutic potential, including anti-diabetic properties. In this study, we evaluated a library of previously synthesized 37 Dihydropyrimidone derivatives to assess their potential as α-glucosidase inhibitors. We identified 34 derivatives with significant inhibitory activity, exhibiting IC values in the range of 5.30-56.72 µM. Among these, compounds 2, 4-7, 9-11, 13-16, 31, 32, and 33 demonstrated high potency, with IC values below 20 µM; the most active compound, 5, achieved an IC of 5.30 µM. A detailed kinetic study on compound 5 revealed a competitive inhibition mode with a Ki value of 16.10 ± 0.0075 µM. Additionally, cytotoxicity assays confirmed that compound 5 is non-toxic to BJ cell lines, underscoring its safety for therapeutic use. The computational studies further supported the inhibitory potential by illustrating key interactions and binding affinities between the Dihydropyrimidone derivatives and the α-glucosidase, highlighting these compounds as promising candidates for diabetes management.
糖尿病是一种普遍且严重的代谢紊乱疾病，全球数以百万计的人受其影响，由于血糖水平升高，它会带来广泛的健康风险。一种有前景的糖尿病管理方法是抑制α-葡萄糖苷酶，该酶在碳水化合物代谢中起关键作用。靶向α-葡萄糖苷酶有助于延迟葡萄糖吸收，从而控制餐后血糖峰值。二氢嘧啶酮是各种生物活性天然化合物中的一类核心结构，因其具有多种治疗潜力，包括抗糖尿病特性而受到认可。在本研究中，我们评估了一个由先前合成的37种二氢嘧啶酮衍生物组成的文库，以评估它们作为α-葡萄糖苷酶抑制剂的潜力。我们鉴定出34种具有显著抑制活性的衍生物，其IC值在5.30 - 56.72 µM范围内。其中，化合物2、4 - 7、9 - 11、13 - 16、31、32和33表现出高效力，IC值低于20 µM；活性最高的化合物5，其IC值为5.30 µM。对化合物5的详细动力学研究揭示了一种竞争性抑制模式，Ki值为16.10 ± 0.0075 µM。此外，细胞毒性试验证实化合物5对BJ细胞系无毒，强调了其治疗用途的安全性。计算研究通过阐明二氢嘧啶酮衍生物与α-葡萄糖苷酶之间的关键相互作用和结合亲和力，进一步支持了其抑制潜力，突出了这些化合物作为糖尿病管理有前景候选物的地位。
