Abstract Diabetes mellitus is a chronic illness that needs persistent medical attention and continuous patient self-management to avoid acute complications. Dipeptidyl peptidase-IV (DPP-IV) inhibitors minimize glucagon and blood glucose levels by increasing the incretin levels, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic poly-peptide (GIP), leading to insulin secretion from pancreatic beta cells. In the present study, nine 1,4-bis(phenylsulfonyl) piperazine derivatives 1a-i were synthesized and identified using 1H NMR, 13C NMR, MS and IR spectroscopies. These compounds were tested in vitro and showed inhibitory activity ranging from 11.2 to 22.6 % at 100 µmol L–1 concentration. Piperazine sulfonamide derivatives were found to be promising DPP-IV inhibitors, where the presence of electron-withdrawing groups such as Cl (1a-c) improved the activity of the compounds more than electron-donating groups such as CH3 ( 1d-f) at the same position. Additionally, meta-substitution is disfavored (1b, 1e, 1g). Induced-fit docking studies suggested that the targeted compounds 1a-i occupy the binding domain of DPP-IV and form H-bonding with the backbones of R125, E205, E206, F357, K554, W629, Y631, Y662 and R669.

中文翻译：

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哌嗪磺胺作为 DPP-IV 抑制剂：合成、诱导拟合对接和体外生物学评价

摘要 糖尿病是一种慢性疾病，需要持续的医疗护理和持续的患者自我管理以避免急性并发症。二肽基肽酶-IV (DPP-IV) 抑制剂通过增加肠促胰岛素水平、胰高血糖素样肽 (GLP-1) 和葡萄糖依赖性促胰岛素多肽 (GIP) 来降低胰高血糖素和血糖水平，从而导致胰腺 β 分泌胰岛素细胞。在本研究中，合成了九种 1,4-双（苯磺酰基）哌嗪衍生物 1a-i，并使用 1H NMR、13C NMR、MS 和 IR 光谱对其进行了鉴定。这些化合物在体外进行了测试，在 100 µmol L-1 浓度下显示出 11.2 至 22.6% 的抑制活性。哌嗪磺酰胺衍生物被发现是有前途的 DPP-IV 抑制剂，其中吸电子基团如 Cl (1a-c) 的存在比相同位置的供电子基团如 CH3 (1d-f) 更能提高化合物的活性。此外，不赞成元替代 (1b、1e、1g)。诱导拟合对接研究表明，目标化合物 1a-i 占据了 DPP-IV 的结合域，并与 R125、E205、E206、F357、K554、W629、Y631、Y662 和 R669 的主链形成氢键。