Highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives and in silico interaction analysis with putative target Plasmodium falciparum lactate dehydrogenase

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

Keywords:

• Plasmodium falciparum
• lactate dehydrogenase
• benzopyrano(4,3-b)benzopyran
• docking
• QSAR
• molecular dynamics simulation
• malaria

Acknowledgements

Authors would like to thank Jawaharlal Nehru University (JNU), New Delhi and Shiv Nadar University (SNU), Delhi NCR for providing required lab facilities to conduct this research. NJ and RH acknowledge the Shiv Nadar Foundation for providing the PhD fellowship. JK acknowledges UGC-MANF for PhD fellowship. SG acknowledges SERB-NPDF (PDF/2019/001767) for postdoctoral research fellowship. The funders had no role in study design, analysis of results, preparation, or publishing of the manuscript.

Author contributions

SS, PKD and NK conceived and designed the experiments. NJ, RH, SG and JK performed laboratory experiments, analysed data and wrote the manuscript. JD synthesized the dependensin analogs. NJ performed the bioinformatics work. NJ, RH, SG, JK and SS drafted and critically revised the manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

SS is supported by National Bio-Scientist Award from Department of Biotechnology (DBT). Funding from Science and Engineering Research Board (SERB) (EMR/2016/005644) and Drug and Pharmaceuticals Research Programme (DPRP) (Project No. P/569/2016-1/TDT) for SS is acknowledged.