Kshirsagar Rajendra R, Gadekar Pradip K, Khedkar Vijay M, Vijayakumar Vijayaparthasarathi
Centre for Organic and Medicinal Chemistry, Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, Tamil Nadu 632014, India.
Discovery Analytical Sciences Department, Piramal Enterprises Limited, 1A - Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai, Maharashtra 400 063, India.
ACS Omega. 2021 Sep 9;6(37):24118-24127. doi: 10.1021/acsomega.1c03600. eCollection 2021 Sep 21.
()9-Oxooctadec-10-en-12-ynoic acid is found to mediate its antidiabetic activity by increasing insulin-stimulated glucose uptake in L6 myotubes by activating the phosphoinositide 3-kinase (PI3K) pathway. A simultaneous study of site-specific modification followed by structure-activity relationship provides a tremendous scope for exploiting the bioactivity of the parent molecule. Therefore, in the present study, we focused on site-specific modification of ()9-oxooctadec-10-en-12-ynoic acid () to generate multiple derivatives and extensive structure-activity relationship (SAR) studies. We have done structural base design and synthesized a series of amides from acid compound . Compound consists of an acid functionality, which is known for its metabolism-related liabilities. The SAR has been generated using scaffolds of different antidiabetic drugs such as biguanides, sulfonylureas, thiazolidinediones/glitazones, peroxisome proliferator-activated receptors, K + ATP, α-glucosidase inhibitors, and others. Furthermore, the study demonstrates and explains the promising derivatives and importance of SAR of the compound ()9-oxooctadec-10-en-12-ynoic acid. In order to gain mechanistic insights, a molecular docking study was performed against PI3K, which could identify the binding modes and thermodynamic interactions governing the binding affinity. According to our research, compounds , , , , , , and are the best compounds from the series having EC values of 15.47, 8.89, 7.00, 13.99, 8.70, 12.27, and 16.14 μM, respectively.
发现（）9-氧代十八碳-10-烯-12-炔酸通过激活磷酸肌醇3-激酶（PI3K）途径增加L6肌管中胰岛素刺激的葡萄糖摄取来介导其抗糖尿病活性。对位点特异性修饰随后进行构效关系的同步研究为开发母体分子的生物活性提供了巨大空间。因此，在本研究中，我们专注于对（）9-氧代十八碳-10-烯-12-炔酸（）进行位点特异性修饰以生成多种衍生物并进行广泛的构效关系（SAR）研究。我们进行了基于结构的设计并从酸化合物合成了一系列酰胺。化合物 包含一个酸官能团，其因与代谢相关的缺陷而闻名。使用不同抗糖尿病药物的支架如双胍类、磺酰脲类、噻唑烷二酮类/格列酮类、过氧化物酶体增殖物激活受体、K + ATP、α-葡萄糖苷酶抑制剂等生成了构效关系。此外，该研究证明并解释了有前景的衍生物以及化合物（）9-氧代十八碳-10-烯-12-炔酸构效关系的重要性。为了获得机制上的见解，针对PI3K进行了分子对接研究，这可以确定控制结合亲和力的结合模式和热力学相互作用。根据我们的研究，化合物 、 、 、 、 、 和 是该系列中最好的化合物，其EC值分别为15.47、8.89、7.00、13.99、8.70、12.27和16.14 μM。
