Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, G-7/4, Islamabad, Pakistan.
Bioorg Chem. 2021 Nov;116:105385. doi: 10.1016/j.bioorg.2021.105385. Epub 2021 Sep 24.
Managing diabetes that is a global life-threatening problem, remains a challenge for the scientific community. The inhibition of α-amylase and α-glucosidase enzymes which are responsible for the digestion of dietary carbohydrates is an effective strategy to control postprandial hyperglycemia. Herein, we report the novel and highly potent inhibitors of α-amylase and α-glucosidase, namely isatin-hydrazide conjugates 1a - 1j that are easily accessed in two steps from simple and inexpensive commercially available isatin. The in vitro bio-evaluations of these compounds revealed that conjugates 1a, 1h and 1f are highly potent inhibitors of α-amylase with IC values of 19.6, 12.1 and 18.3 µg/ml, respectively as compared to the standard, acarbose (IC = 36.2 µg/ml). Similarly, the conjugates 1a, 1b, 1d, 1f and 1i showed significant activity against α-glucosidase with IC values of 14.8, 25.6, 13.2, 14.5 and 16.5 µg/ml, respectively as compared to the acarbose (IC = 34.5 µg/ml). Notably, the compounds 1a and 1f were found to be highly potent against both α-amylase and α-glucosidase enzymes, demonstrating about two-fold better inhibitory activity than the reference inhibitor. Molecular docking studies were performed to recognize the possible binding modes of the compounds with the active pocket of the enzymes. The results of this study divulge the potential of these compounds as powerful and inexpensive lead molecules for future investigations.
管理糖尿病是一个全球性的威胁生命的问题，仍然是科学界面临的挑战。抑制负责消化膳食碳水化合物的α-淀粉酶和α-葡萄糖苷酶是控制餐后高血糖的有效策略。在此，我们报告了新型且高效的α-淀粉酶和α-葡萄糖苷酶抑制剂，即色氨酸酰肼缀合物 1a-1j，它们可以通过两步反应从简单且廉价的市售色氨酸轻松获得。这些化合物的体外生物评估表明，与标准药物阿卡波糖（IC=36.2μg/ml）相比，缀合物 1a、1h 和 1f 是高效的α-淀粉酶抑制剂，IC 值分别为 19.6、12.1 和 18.3μg/ml。类似地，缀合物 1a、1b、1d、1f 和 1i 对α-葡萄糖苷酶表现出显著的活性，IC 值分别为 14.8、25.6、13.2、14.5 和 16.5μg/ml。值得注意的是，化合物 1a 和 1f 对α-淀粉酶和α-葡萄糖苷酶均表现出高活性，抑制活性比参考抑制剂高约两倍。进行了分子对接研究以识别化合物与酶的活性口袋的可能结合模式。这项研究的结果揭示了这些化合物作为未来研究的强大且廉价的先导分子的潜力。
