Department of Chemistry , University of Calcutta , 92, A. P. C. Road , Kolkata - 700 009 , India.
Department of Physiology, Oxidative Stress, and Free Radical Biology Laboratory , University of Calcutta , 92, A. P. C. Road , Kolkata - 700 009 , India.
J Med Chem. 2019 Jul 11;62(13):6315-6329. doi: 10.1021/acs.jmedchem.9b00717. Epub 2019 Jun 27.
Reduction of mitochondrial oxidative stress-mediated diseases is an important pharmaceutical objective in recent biomedical research. In this context, a series of novel pyrrolobenzoxazines (PyBs) framework with enormous diversity (compounds -) was synthesized by employing a low-temperature greener pathway, and antioxidant property of the synthesized compounds was successfully demonstrated on preclinical model goat heart mitochondria, . Copper-ascorbate (Cu-As) was utilized as an oxidative stress generator. Out of screened PyBs, the compound possessing -OH and -OMe groups on benzene nucleus along with pyrrolobenzoxazine core moiety (compound ) displayed magnificent antioxidant property with a minimum effective dose of 66 μM during the biochemical assessment. The ameliorative effect of synthesized pyrrolobenzoxazine moiety on levels of biomarkers of oxidative stress, antioxidant enzyme, activities of Krebs cycle and respiratory chain enzymes, mitochondrial morphology, and Ca permeability of mitochondrial membrane was investigated in the presence of Cu-As. Furthermore, the binding mode of Cu-As by compound was explored successfully using isothermal titration calorimetry (ITC) analysis.
降低线粒体氧化应激介导的疾病是近年来生物医学研究的一个重要药物目标。在这方面，通过采用低温绿色途径，合成了一系列具有巨大多样性的新型吡咯苯并恶嗪（PyB）骨架（化合物 -），并成功地在临床前山羊心脏线粒体模型上证明了合成化合物的抗氧化特性， 。铜抗坏血酸（Cu-As）被用作氧化应激发生器。在所筛选的 PyB 中，苯核上具有 -OH 和 -OMe 基团以及吡咯苯并恶嗪核心部分的化合物（化合物 ）表现出极好的抗氧化特性，在生化评估中，最小有效剂量为 66 μM。在存在 Cu-As 的情况下，研究了合成的吡咯苯并恶嗪部分对氧化应激生物标志物、抗氧化酶、克雷布斯循环和呼吸链酶活性、线粒体形态以及线粒体膜钙通透性水平的改善作用。此外，还成功地使用等温滴定量热法（ITC）分析探索了化合物 与 Cu-As 的结合模式。
