George Ginson, Auti Prashant S, Paul Atish T
Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani Campus, India.
Chem Biol Drug Des. 2021 Jul;98(1):49-59. doi: 10.1111/cbdd.13846. Epub 2021 May 2.
Pancreatic Lipase (PL) is a key enzyme responsible for the digestion of 50%-70% of dietary triglycerides, hence its inhibition is considered as a viable approach for the management of obesity. A series of indole-TZD hybrid analogues were synthesized, characterized and evaluated for their PL inhibitory activity. Knoevenagel condensation of various substituted indole-3-carboxaldehyde with substituted thiazolidinediones resulted in the formation of titled analogues. Analogues 6d and 6e exerted potent PL inhibitory activity (IC -6.19 and 8.96 µM, respectively). Further, these analogues exerted a competitive mode of PL inhibition. Moreover, molecular modelling studies were in agreement with the in vitro results (Pearson's r = .8682, p < .05). The fluorescence spectroscopic analysis further supported the strong binding affinity of these analogues with PL. A molecular dynamics study (20 ns) indicated that these analogues were stable in a dynamic environment. Thus, the present study highlighted the potential role of indole-thiazolidinedione hybrid analogues as potential PL inhibitors and further optimization might result in the development of new PL inhibitory lead candidates.
胰脂肪酶（PL）是一种关键酶，负责消化50%-70%的膳食甘油三酯，因此抑制该酶被认为是管理肥胖症的一种可行方法。合成了一系列吲哚-噻唑烷二酮杂化类似物，对其进行了表征，并评估了它们的PL抑制活性。各种取代的吲哚-3-甲醛与取代的噻唑烷二酮进行Knoevenagel缩合反应，生成了标题类似物。类似物6d和6e表现出强大的PL抑制活性（IC分别为6.19和8.96 μM）。此外，这些类似物表现出竞争性的PL抑制模式。而且，分子建模研究结果与体外实验结果一致（皮尔逊相关系数r = 0.8682，p < 0.05）。荧光光谱分析进一步证实了这些类似物与PL具有很强的结合亲和力。一项分子动力学研究（20纳秒）表明，这些类似物在动态环境中是稳定的。因此，本研究突出了吲哚-噻唑烷二酮杂化类似物作为潜在PL抑制剂的潜在作用，进一步优化可能会开发出新的PL抑制先导候选物。
