Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, India.
Biochem Pharmacol. 2017 Apr 1;129:26-42. doi: 10.1016/j.bcp.2016.12.012. Epub 2016 Dec 22.
Visceral Leishmaniasis is a deadly parasitic disease caused by Leishmania donovani. Paucity exists in the discovery of novel chemotherapeutics against Leishmaniasis. In this study, we synthesized a natural product inspired Diversity Oriented Synthesis library of L. donovani Trypanothione reductase (LdTR) inhibitor β-carboline-quinazolinone hybrids, which are different in stereochemical architecture and diverse in the bioactive chemical space. It is noteworthy that chirality affects drug-to-protein binding affinity since proteins in any living system are present only in one of the chiral forms. Upon evaluation of the hybrids, one of the chiral forms i.e. Compound 1 showed profound cytotoxic effect in micromolar range as compared to its other chiral form i.e. Compound 2. In-silico docking studies confirmed high binding efficiency of Compound 1 with the catalytic pocket of LdTR. Treatment of L. donovani parasites with Compound 1 inhibits LdTR activity, induces imbalance in redox homeostasis by enhancing ROS, disrupts the mitochondrial membrane potential, modifies actin polymerization and alters the surface topology and architecture. All these cellular modifications eventually led to apoptosis-like death of promastigotes. Furthermore, we synthesized the analogues of Compound 1 and found that these compounds show profound antileishmanial activity in the nanomolar range both in promastigotes and intracellular amastigotes. The enhanced inhibitory potential of these compounds was further supported by in-silico analysis of protein-ligand interactions which revealed high binding efficiency towards the catalytic pocket of LdTR. Taken together, this study reports the serendipitous discovery of β-carboline-quinazolinone hybrids with enhanced antileishmanial activity along with the in-depth structure-activity relationships and mechanism of action of these analogues.
内脏利什曼病是一种由利什曼原虫引起的致命寄生虫病。目前缺乏针对利什曼病的新型化学疗法。在这项研究中，我们合成了一个基于天然产物的多样性导向合成库，其中包含利什曼原虫硫醇还原酶（LdTR）抑制剂β-咔啉-喹唑啉酮杂合体，这些杂合体在立体化学结构上有所不同，在生物活性化学空间上也具有多样性。值得注意的是，手性会影响药物与蛋白质的结合亲和力，因为任何生命系统中的蛋白质都只存在于一种手性形式中。在对这些杂合体进行评估后，其中一种手性形式（即化合物 1）在毫摩尔范围内表现出明显的细胞毒性作用，而其另一种手性形式（即化合物 2）则没有。计算机对接研究证实，化合物 1 与 LdTR 的催化口袋具有很高的结合效率。用化合物 1 处理利什曼原虫寄生虫可抑制 LdTR 活性，通过增强 ROS 导致氧化还原平衡失衡，破坏线粒体膜电位，改变肌动蛋白聚合并改变表面拓扑结构和形态。所有这些细胞修饰最终导致前鞭毛体凋亡样死亡。此外，我们合成了化合物 1 的类似物，并发现这些化合物在毫摩尔范围内对前鞭毛体和细胞内无鞭毛体均具有显著的抗利什曼原虫活性。这些化合物的增强抑制潜力进一步得到了蛋白质-配体相互作用的计算机分析的支持，该分析表明它们对 LdTR 催化口袋具有很高的结合效率。综上所述，本研究报告了β-咔啉-喹唑啉酮杂合体的偶然发现，这些杂合体具有增强的抗利什曼原虫活性，以及这些类似物的深入结构-活性关系和作用机制。
