Abstract

Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite’s death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite.

Highlights

  • Literature suggests that natural products have played an important role in the discovery of lead compounds for the development of drugs against human diseases including malaria[5]

  • We envisioned a library inspired from antimalarial indole natural products Usambarine and Aspidocarpine by using chiral bicyclic lactams 1–3 as building blocks (Scheme 1)

  • Two routes www.nature.com/scientificreports were followed, wherein route 1 involved functionalization of 1b and transformation of the bicyclic lactam obtained into Usambarine and Aspidocarpine scaffolds, and in route 2 it is conversion of the appropriate bicyclic lactams 1a–c to the Usambarine scaffold and its five membered homologue followed by their functionalization (Fig. 1)

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Summary

Introduction

Literature suggests that natural products have played an important role in the discovery of lead compounds for the development of drugs against human diseases including malaria[5]. KAE609 is more effective than the current gold standard treatment, Artemisinin against asexual blood-stage P. falciparum and is capable of blocking transmission to mosquitoes[10] In another example the Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) discovered a scaffold from a collection of indole based natural products that proved to be an ideal motif for malaria-growth inhibition[11]. Several analogs of this scaffold exhibited low micro molar activity against five malaria strains. PfATP4 contains the highly conserved acidic motif which is required for transport of Na+-ions in Na+-efflux ATPases (ENAs) present in lower eukaryotes including some protozoan which strongly supports the role of PfATP4 as ENA in the malaria parasite

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