Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC₅₀ with 20–40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, ¹³¹I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of ¹³¹I-substrate in the pancreas and rapid clearance from most of the body organs.

2型糖尿病（T2D）是一种严重疾病，是全球范围内最严重的问题之一。这项研究涉及作为抗糖尿病药和二肽基肽酶-IV（DPP-4）抑制剂的一组新的四氢萘磺酰胺衍生物的设计，合成和体内测定。考虑到西他列汀作为参考药物，大多数新化合物均具有显着的降血糖作用以及DPP-4抑制能力。最有前途的化合物4，15显示2.80 nM的DPP-4 IC ₅₀与DPP-8和DPP-9相比具有20至40倍的选择性。分别使用Schrödinger的自动QSAR，MOE的QuaSAR和Schrödinger的基于3D场的QSAR进行了2D和3D QSAR模型。实验结果表明，与排列无关的描述符，静电场和空间场描述符与新衍生物的抗糖尿病活性显着相关。另外，相对于西他列汀，新化合物被停靠在DPP-4的活性位点，以合理化化合物与酶的氨基酸残基的结合方式。此外，选择了¹³¹ I-化合物4复合物以评估化合物4的药代动力学行为其身体器官的吸收以及消除途径是其余类似物的代表。示踪剂的生物分布模式证明了¹³¹ I底物在胰腺中的选择性积聚，并能从大多数人体器官中快速清除。