Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Uttar Pradesh, India.
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
J Biomol Struct Dyn. 2022 Jul;40(11):5159-5174. doi: 10.1080/07391102.2020.1868336. Epub 2021 Jan 8.
Malaria infection caused by is majorly responsible for millions of deaths in humans every year. Moreover, a rapid increase in resistance to existing drugs has posed an urgent need for new anti-malarials. Herein, we report the highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives, inspired from naturally occurring dependensin against chloroquine (CQ) sensitive and resistant strains. Chemically synthesized, four dependensin analogs exhibited growth inhibition at nanomolar concentrations ranging from 63.96 to 725.8 nM by blocking the parasite development at the ring and early trophozoite stages. The growth inhibitory activity of dependensin analogs was correlated with their anti-plasmodial lactate dehydrogenase activity by computational analysis. Molecular docking, 50 ns simulation and a 2D-Quantitative Structure-Activity Relationship (2D-QSAR) modelling revealed the interaction with their putative target lactate dehydrogenase (PfLDH). Here, developing the predictive 2D descriptors such as thermodynamic, spatial, electronic, and topological with multiple linear regression analysis (MLRA), the structural requirements for potent and selective PfLDH inhibitory activity has been identified. The strong binding of compound to the catalytic Nicotinamide adenine dinucleotide (NADH) binding pocket of the PfLDH further supported the PfLDH targeting potential of dependensin analogs. Overall, this study revealed a highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives with their putative anti-PfLDH activity.Communicated by Ramaswamy H. Sarma.
疟原虫感染主要导致每年数百万人死亡。此外，现有药物耐药性的迅速增加迫切需要新的抗疟药物。在此，我们报告了苯并吡喃并[4,3-b]苯并吡喃衍生物的高效抗疟活性，该衍生物受天然存在的依赖素启发，针对氯喹（CQ）敏感和耐药株。通过化学合成，四个依赖素类似物在纳摩尔浓度范围内表现出生长抑制作用，范围从 63.96 到 725.8 nM，通过阻断环和早期滋养体阶段的寄生虫发育来实现。依赖素类似物的生长抑制活性与其抗疟原乳酸脱氢酶活性通过计算分析相关。分子对接、50 ns 模拟和二维定量构效关系（2D-QSAR）建模揭示了与假定靶标乳酸脱氢酶（PfLDH）的相互作用。在这里，通过多元线性回归分析（MLRA）开发了热力学、空间、电子和拓扑等预测性 2D 描述符，确定了具有强大和选择性 PfLDH 抑制活性的结构要求。化合物与 PfLDH 的催化烟酰胺腺嘌呤二核苷酸（NADH）结合口袋的强结合进一步支持了依赖素类似物对 PfLDH 的靶向潜力。总体而言，这项研究揭示了苯并吡喃并[4,3-b]苯并吡喃衍生物具有很强的抗疟活性，其潜在的抗 PfLDH 活性。由 Ramaswamy H. Sarma 交流。
