在当代药物化学中,在正在进行的与代谢疾病的斗争中,采用单一的小分子同时多靶点不同的分子实体正在成为一种有效的策略。在这项研究中,我们提出了细致的设计,合成,并对一系列新的1,2,3-三唑基甲硫基-1,3,4-恶二唑烷苯磺酰胺衍生物(8a-m)作为抗人碳酸酐酶(EC.4.2.1.1,hCAI/II)的潜在多靶点抑制剂进行了全面的生物学评估,α-糖苷酶(EC.3.2.1.20,α-GLY),和α-淀粉酶(EC.3.2.1.1,α-AMY)。每种合成的磺胺都经过严格的评估,以评估对四种不同酶的抑制作用,揭示不同程度的HCAI/II,a-GLY,和对测试化合物的a-AMY抑制。hCAI特别容易受到所有化合物的抑制,与参考标准AAZ(KI为439.17±9.30nM)相比,显示出非常低的抑制常数(KI),范围为42.20±3.90nM至217.90±11.81nM。对hCAII的评估表明,大多数合成的化合物表现出有效的抑制作用,KI值跨越纳摩尔范围16.44±1.53-70.82±4.51nM,虽然有三种特定的化合物,即8a-b和8d,显示出比不超过参考药物AAZ(KI为98.28±1.69nM)的其他衍生物更低的抑制效力。此外,在合成化合物的光谱中,对糖尿病相关的α-GLY(KI值从0.54±0.06μM到5.48±0.50μM)进行了有效的抑制,虽然对α-AMY有明显的抑制作用,IC50值在0.16±0.04μM和7.81±0.51μM之间)与参考标准ACR(KI为23.53±2.72μM,IC50为48.17±2.34μM,分别)。随后,评估了这些抑制剂的DPPH·和ABTS·自由基清除活性。此外,在HCAI/II的活性位点内精心进行了分子对接研究,α-GLY,和α-AMY为观察到的抑制结果提供全面的阐明和理论基础。
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 (KI) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (KI of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with KI 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 KI of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (KI values spanning from 0.54 ± 0.06 μM to 5.48 ± 0.50 μM), while significant inhibition effects were noted against α-AMY, with IC50 values ranging between 0.16 ± 0.04 μM and 7.81 ± 0.51 μM) compared to reference standard ACR (KI of 23.53 ± 2.72 μM and IC50 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.