Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

Abstract

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro as well as in vivo in murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator as well as antiplasmodial. Compound 5f also interacted with free heme (KD =1.17 ± 0.8 μM), an iron containing tetrapyrrole released after hemoglobin digestion by the parasite and inhibited heme polymerisation by parasite lysate. Structure activity relationship studies indicated that nitrogen and sulphur substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [3H]-hypoxanthine incorporation and hemozoin formation in parasite respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against chloroquine/pyrimethamine resistant strain of P. falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple drug resistant (MDR) strain Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite and the infected mice experienced longer life span upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.