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

Abstract

Malaria is a devastating disease that kills millions of people each year, and the emergence of multidrug-resistant <em>Plasmodium</em> parasites poses a major challenge to global malaria control efforts. This dissertation 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 <em>Plasmodium</em> parasites. All CB compounds exhibited broad-spectrum antiplasmodial activity, inhibiting the growth of drug-resistant or sensitive strains of <em>Plasmodium falciparum</em> blood stages with high potency. Interestingly, CB-41 showed prophylactic activity against hypnozoites and liver schizonts in the <em>Plasmodium cynomolgi</em>, a primate model for <em>Plasmodium vivax</em>. Four CB compounds (CB-27, CB-41, CB-53, and CB-61) inhibited <em>P. falciparum</em> oocyst formation in mosquitoes, and five CB compounds (CB-27, CB-41, CB-53, CB-58, and CB-61) hindered the <em>in vitro</em> development of <em>Plasmodium berghei</em> ookinetes. The CB compounds did not inhibit the activation of <em>P. berghei</em> female and male gametocytes<em> in vitro</em>. Six CB compounds showed no inhibition of <em>Plasmodium</em> glutathione S-transferase as a putative target, and no cytotoxicity was exhibited in HepG2 cells. The development and application of the Machine Learning Synergy Predictor (MLSyPred&copy;) tool, an open-sourced and accessible tool for predicting synergistic antimalarial drug combinations, is a significant contribution to malaria research. Using predictions made by MLSyPred&copy;, <em>P. berghei</em> blood stage isobologram analyses showed synergy between CB-61 and FDA-approved antimalarial drugs clindamycin and halofantrine, suggesting that CB compounds could be used in combination therapy to enhance the efficacy of existing antimalarial drugs. These findings demonstrate that CB compounds (CB-27, CB-41, CB-53, and CB-61) are promising candidates for further development as broad-spectrum antimalarial drugs that could treat multidrug-resistant malaria and prevent transmission. CB compounds and the MLSyPred&copy; tool have the potential to make important contributions to malaria research.