Çapan İrfan, Hawash Mohammed, Qaoud Mohammed T, Jaradat Nidal
Department of Pharmaceutical Basic Sciences, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.
Sente Kimya Research and Development Inc., 06200 Ankara, Turkey.
ACS Omega. 2024 Dec 25;10(1):848-861. doi: 10.1021/acsomega.4c07896. eCollection 2025 Jan 14.
Currently, available therapies for diabetes cannot achieve normal sugar values in a high percentage of treated patients. This work synthesized a series of carbazole-triazole-thione derivatives, and their potential antidiabetic activity was investigated against the key diabetic enzymes α-amylase and glycosidase. Normal human hepatic stellate cells (LX-2) were employed to assess their cytotoxicity and safety, followed by in vivo testing to investigate the hypoglycemic effect of the most promising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione derivatives were synthesized. Seven structures demonstrated potential inhibitory activity against α-amylase enzyme, with IC lower than 6.4 μM. Among them, compounds , , and exhibited the highest potency, with IC values of 0.56, 0.53, and 0.97 μM, respectively, compared to the well-known α-amylase inhibitor acarbose, which has an IC value of 5.31 μM. Exploring the inhibition potency of these series against α-glucosidase enzyme revealed that and compounds act as moderate inhibitors, with IC values of 11.03 and 13.76 μM, respectively. Moreover, at 100 μM concentration, most of the evaluated compounds showed negligible cytotoxic effect against LX-2 cell lines, particularly compounds and , that demonstrated lower cytotoxic activity by 3-fold compared to the positive control 5-Flururicle (cell viability 13.45%). Thus, the compound was selected for in vivo evaluation, and after administering five doses of this compound (10 mg/kg) to group III of mice, a significant reduction in glucose concentration was observed, bringing it down from 290.54 to 216.15 mg/dL, in comparison with the control group which did not show a reduction in blood glucose level. These observed in vitro and in vivo results were upheld by performing a set of chemoinformatic studies that elucidated the binding interactions of the most active derivatives within the enzyme's active site and highlighted the critical roles of both the 1,2,4-triazole-3-thione and carbazole scaffolds in these interactions. Finally, the drug-likeness profiles of our carbazole-triazole-thione derivatives suggest their potential as candidates for further in vivo studies and clinical trials.
目前，现有的糖尿病治疗方法无法使大部分接受治疗的患者血糖值恢复正常。本研究合成了一系列咔唑 - 三唑 - 硫酮衍生物，并针对关键的糖尿病酶α - 淀粉酶和糖苷酶研究了它们潜在的抗糖尿病活性。使用正常人肝星状细胞（LX - 2）评估其细胞毒性和安全性，随后进行体内试验以研究最有前景的药物的降血糖作用。结果，合成了一组18种咔唑 - 1,2,4 - 三唑 - 硫酮衍生物。七种结构对α - 淀粉酶表现出潜在的抑制活性，IC值低于6.4μM。其中，化合物 、 和 表现出最高的活性，IC值分别为0.56、0.53和0.97μM，而著名的α - 淀粉酶抑制剂阿卡波糖的IC值为5.31μM。研究这些系列对α - 葡萄糖苷酶的抑制活性发现， 化合物和 化合物为中度抑制剂，IC值分别为11.03和13.76μM。此外，在100μM浓度下，大多数评估化合物对LX - 2细胞系的细胞毒性作用可忽略不计，特别是化合物 和 ，与阳性对照5 - 氟尿嘧啶相比，其细胞毒性活性降低了3倍（细胞活力为13.45%）。因此，选择 化合物进行体内评估，在给III组小鼠施用五剂该化合物（10mg / kg）后，观察到葡萄糖浓度显著降低，从290.54降至216.15mg / dL，而对照组的血糖水平未降低。通过进行一系列化学信息学研究证实了这些体外和体内结果，这些研究阐明了最具活性的衍生物在酶活性位点内的结合相互作用，并突出了1,2,4 - 三唑 - 3 - 硫酮和咔唑支架在这些相互作用中的关键作用。最后，我们的咔唑 - 三唑 - 硫酮衍生物的类药性质表明它们有潜力作为进一步体内研究和临床试验的候选药物。
