Department of Chemistry, Faculty of Arts and Science, Sakarya University, Sakarya, 54187, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, 24002, Turkey.
Arch Biochem Biophys. 2024 Sep;759:110099. doi: 10.1016/j.abb.2024.110099. Epub 2024 Jul 14.
In contemporary medicinal chemistry, employing a singular small molecule to concurrently multi-target disparate molecular entities is emerging as a potent strategy in the ongoing battle against metabolic disease. In this study, we present the meticulous design, synthesis, and comprehensive biological evaluation of a novel series of 1,2,3-triazolylmethylthio-1,3,4-oxadiazolylbenzenesulfonamide derivatives (8a-m) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, hCA I/II), α-glycosidase (EC.3.2.1.20, α-GLY), and α-amylase (EC.3.2.1.1, α-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of hCA I/II, a-GLY, and a-AMY inhibition across the tested compounds. hCA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (K) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (K of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with K values spanning the nanomolar range 16.44 ± 1.53-70.82 ± 4.51 nM, while three specific compounds, namely 8a-b and 8d, showcased lower inhibitory potency than other derivatives that did not exceed that of the reference drug AAZ (with a K of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (K values spanning from 0.54 ± 0.06 μM to 5.48 ± 0.50 μM), while significant inhibition effects were noted against α-AMY, with IC values ranging between 0.16 ± 0.04 μM and 7.81 ± 0.51 μM) compared to reference standard ACR (K of 23.53 ± 2.72 μM and IC of 48.17 ± 2.34 μM, respectively). Subsequently, these inhibitors were evaluated for their DPPH· and ABTS· radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of hCA I/II, α-GLY, and α-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.
在当代药物化学中，采用单一小分子同时多靶点靶向不同的分子实体，作为对抗代谢疾病的有效策略正在出现。在这项研究中，我们设计、合成了一系列新的 1,2,3-三唑基甲基硫代-1,3,4-噁二唑基苯磺酰胺衍生物（8a-m），并对其进行了综合的生物学评价，这些衍生物可能作为针对人碳酸酐酶（EC.4.2.1.1，hCA I/II）、α-糖苷酶（EC.3.2.1.20，α-GLY）和α-淀粉酶（EC.3.2.1.1，α-AMY）的多靶点抑制剂。每个磺酰胺都经过了严格的评估，以测试其对四种不同酶的抑制作用，结果显示，在所测试的化合物中，hCA I/II、α-GLY 和 α-AMY 的抑制程度各不相同。hCA I 对所有化合物都表现出明显的抑制作用，其抑制常数（K）范围从 42.20±3.90 nM 到 217.90±11.81 nM，与参考标准 AAZ（K 值为 439.17±9.30 nM）相比，具有显著的低抑制常数。对 hCA II 的评估表明，大多数合成的化合物都表现出较强的抑制作用，K 值在纳摩尔范围内 16.44±1.53-70.82±4.51 nM，而三个特定的化合物，即 8a-b 和 8d，其抑制作用比其他衍生物弱，没有超过参考药物 AAZ（K 值为 98.28±1.69 nM）。此外，在所合成的化合物中，对糖尿病相关的α-GLY（K 值范围从 0.54±0.06 μM 到 5.48±0.50 μM）表现出很强的抑制作用，同时对α-AMY 也表现出显著的抑制作用，IC 值范围在 0.16±0.04 μM 到 7.81±0.51 μM）与参考标准 ACR（K 值为 23.53±2.72 μM 和 IC 值为 48.17±2.34 μM）相比。随后，对这些抑制剂进行了 DPPH·和 ABTS·自由基清除活性的评价。此外，还对 hCA I/II、α-GLY 和 α-AMY 的活性部位进行了细致的分子对接研究，为观察到的抑制结果提供了全面的阐明和依据。
