Abstract：
Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 μM), comparable with that of the positive control (acarbose; IC50 = 0.420 μM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.
摘要：
糖尿病是一种慢性代谢紊乱，其特征是许多关键酶的表达/功能不正确，这些酶可被视为抗糖尿病药物设计的靶标。在这里，我们报告设计，合成，和生物学评估两个系列的基于噻唑烷酮的磺酰胺4a-l和5a-c作为多靶标定向配体（MTDL），通过靶向酶：α-葡萄糖苷酶和人碳酸酐酶（hCA）II具有潜在的抗糖尿病活性。评估了合成的磺酰胺对α-葡萄糖苷酶的抑制活性，其中大多数化合物显示出良好至有效的活性。化合物4d和4e显示出有效的抑制活性(IC50=0.440和0.3456μM),与阳性对照相当(阿卡波糖;IC50=0.420μM)。还测试了所有合成的衍生物对hCAI的抑制活性，II,IX,和XII。它们对这些同种型表现出不同水平的抑制。化合物4d是对hCAII最有效的化合物，Ki等于7.0nM，比参考标准(乙酰唑胺;Ki=12.0nM)更有效。对α-葡萄糖苷酶和hCAII活性位点内最具活性的化合物的计算机模拟研究揭示了良好的结合模式，可以解释其生物活性。对最有效的化合物4d的顶级对接姿势进行MM-GBSA改进和分子动力学模拟，以确认与两个靶标的稳定复合物的形成。通过使用口服葡萄糖耐量试验筛选化合物4d的体内抗高血糖功效。化合物4d降低血糖水平至217mg/dl，优于标准阿卡波糖（234mg/dl）。因此，这揭示了其对餐后高血糖和肝糖异生的协同作用模式。因此，这些苯磺酰胺噻唑烷酮杂种可被认为是治疗II型糖尿病的有希望的多靶点候选药物.
