Anti-glycemic potential of benzophenone thio/semicarbazone derivatives: synthesis, enzyme inhibition and ligand docking studies

Inhibition of dipeptidyl peptidase-IV (DPP-IV) has been identified as a promising approach for the treatment of type 2 diabetes mellitus (T2DM). Therefore, development of DPP-IV inhibitors with new chemical scaffold is of utmost importance to medicinal chemistry. In the present study, we identified benzophenone thio- and semicarbazone scaffolds as novel DPP-IV inhibitors. For that purpose, benzophenone thio- and semicarbazone were synthesized through a 2-step reaction. These newly synthetic derivatives were characterized by different spectroscopic techniques, including HREI-MS and NMR. whereas stereochemistry of the iminic bond was predicted by NOESY experiments. Thio- and semicarbazones derivatives were evaluated for their DPP-IV inhibitory potential and found to exhibit a good to moderate enzyme inhibitory activity. Most active and non-cytotoxic derivatives were further evaluated for their DPP-IV inhibitory potential in <i>in cellulo</i> model. The binding sites as well as affinity of active compounds for DPP- IV enzyme were predicted by <i>in silico</i> studies, and compared to a standard drug, sitagliptin. Pharmacophore studies of thio- and semicarbazones derivatives 1–29 suggest that substitution of aryl group, particularly a lipophilic substituents at C-4″ of benzene ring, and a hydroxyl at C-4′ strongly influenced the DPP-IV inhibitory activity. Compound 9 showed the highest inhibitory activity (IC₅₀ = 15.0 ± 0.6 µM), whereas compounds 10, 17, 12, 14 and 23 showed a moderate activity with IC₅₀ values in the range of 28.9–39.2 µM. This study identifies thio- and semicarbazones as new classes of DPP-IV inhibitors which may translate into safe and effective therapeutics for a better management of type 2 diabetes. Communicated by Ramaswamy H. Sarma

二肽基肽酶-IV（dipeptidyl peptidase-IV, DPP-IV）抑制作用已被证实为治疗2型糖尿病（type 2 diabetes mellitus, T2DM）的极具前景的策略。因此，开发具有全新化学骨架的DPP-IV抑制剂对药物化学领域而言至关重要。本研究中，我们发现二苯甲酮缩氨基硫脲与缩氨基脲骨架可作为新型DPP-IV抑制剂。为此，我们通过两步反应合成了二苯甲酮缩氨基硫脲与缩氨基脲类化合物。这些新合成的衍生物借助多种光谱技术进行了结构表征，包括高分辨电子轰击质谱（HREI-MS）与核磁共振波谱（NMR），并通过NOESY实验预测了亚胺键的立体化学构型。我们评估了缩氨基硫脲与缩氨基脲类衍生物的DPP-IV抑制活性，结果显示其表现出良好至中等的酶抑制活性。对活性最强且无细胞毒性的衍生物，我们进一步在细胞内（in cellulo）模型中检测了其DPP-IV抑制潜力。通过计算机模拟（in silico）研究预测了活性化合物与DPP-IV酶的结合位点及亲和力，并与对照药物西格列汀（sitagliptin）进行了对比。对1–29号缩氨基硫脲与缩氨基脲衍生物的药效团研究表明，芳基取代基——尤其是苯环C-4″位的亲脂性取代基——以及C-4′位的羟基，可显著影响DPP-IV抑制活性。化合物9展现出最高的抑制活性（IC₅₀ = 15.0 ± 0.6 µM），而化合物10、17、12、14与23则表现出中等活性，其IC₅₀值范围为28.9–39.2 µM。本研究确认缩氨基硫脲与缩氨基脲类为新型DPP-IV抑制剂类别，有望开发为安全有效的治疗药物，用于2型糖尿病的更优管理。本文由Ramaswamy H. Sarma通讯。