Novel hydrazone compounds with broad-spectrum antiplasmodial activity and synergistic interactions with antimalarial drugs

The development of novel antiplasmodial compounds with broad-spectrum activity against different stages of parasites is crucial to prevent malaria disease and parasite transmission. This study evaluated the antiplasmodial activity of seven novel hydrazone compounds (referred to as CB compounds: CB-27, CB-41, CB-50, CB-53, CB-58, CB-59, and CB-61) against multiple stages of parasites. All CB compounds inhibited blood stage proliferation of drug-resistant or sensitive strains of in the low micromolar to nanomolar range. Interestingly, CB-41 exhibited prophylactic activity against hypnozoites and liver schizonts in , a primate model for . Four CB compounds (CB-27, CB-41, CB-53, and CB-61) inhibited oocyst formation in mosquitoes and five CB compounds (CB-27, CB-41, CB-53, CB-58, and CB-61) hindered the development of ookinetes. The CB compounds did not inhibit the activation of female and male gametocytes . Isobologram assays demonstrated synergistic interactions between CB-61 and the FDA-approved antimalarial drugs, clindamycin and halofantrine. Testing of six CB compounds showed no inhibition of glutathione S-transferase as a putative target and no cytotoxicity in HepG2 liver cells. CB compounds are promising candidates for further development as antimalarial drugs against multidrug-resistant parasites, which could also prevent malaria transmission.