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.

No abstract

We aimed to synthesize novel macrocycles based upon structures type A and B (Scheme 1). Both of them have diaryl ether linkages that provide rigidity to the system. Inspired by polycyclic ethers as natural products, ether linkag-Abstract: The intramolecular Dçtz benzannulation with alkyne-tethered aryloxy Fischer carbenes has been applied to synthesize a nine membered diaryl ether linked macrocyclic library. In silico tools, that is, shape space analysis was used to assess the diversity of the library, and polar surface area (PSA) of the compounds were deduced to understand the range of their surface electrostatic potential.Scheme 2. "Build/couple/pair" synthetic strategy. Scheme 3. Build phase: synthesis of phenols 2-6. DIAD = diisopropyl azodicarboxylate Scheme 4. Coupling to generate alkyne-tethered aryloxy carbenes. 863 www.AsianJOC.org Subhabrata Sen et al. Scheme 5. Pairing towards the macrocycles. Scheme 6. Postpairing. DMSO = dimethyl sulfoxide.