Abstract

Malaria infection caused by Plasmodium falciparum 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 P. falciparum strains. Chemically synthesized, four dependensin analogs 85(A–D) 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 P. falciparum 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 85D 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

摘要

每年由恶性疟原虫引起的疟疾感染是造成数百万人死亡的主要原因。此外，对现有药物的抗药性的迅速增加已经迫切需要新的抗疟药。在这里，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疾活性，它是由天然存在的针对氯喹（CQ）敏感和耐药的恶性疟原虫菌株的依赖素所激发的。化学合成的四个依赖体类似物85（A–D）通过阻断在环和滋养体早期阶段的寄生虫发育，在63.96至725.8 nM的纳摩尔浓度下显示出生长抑制作用。通过计算分析，依赖素类似物的生长抑制活性与其抗疟原虫乳酸脱氢酶活性相关。分子对接，50 ns模拟和2D定量结构与活性关系（2D-QSAR）建模揭示了与它们的推定靶标恶性疟原虫乳酸脱氢酶（PfLDH）的相互作用。在这里，通过使用多元线性回归分析（MLRA）开发预测性2D描述符，例如热力学，空间，电子和拓扑，已经确定了有效和选择性PfLDH抑制活性的结构要求。化合物的牢固结合85D与PfLDH的催化烟酰胺腺嘌呤二核苷酸（NADH）结合口袋进一步支持了依赖素的类似物的PfLDH靶向潜力。总的来说，这项研究表明苯并吡喃并（4,3-b）苯并吡喃衍生物具有很高的抗疟疾活性，并具有推定的抗PfLDH活性。

由Ramaswamy H.Sarma沟通