Novel hydrazone compounds with broad-spectrum antiplasmodial activity and synergistic interactions with antimalarial drugs
Author
Rosado Quiñones, Angélica M
Advisor
Serrano, Adelfa EType
DissertationDegree Level
Ph.D.Date
2023-12-12Metadata
Show full item recordAbstract
Malaria is a devastating disease that kills millions of people each year, and the emergence of multidrug-resistant Plasmodium 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 Plasmodium parasites. All CB compounds exhibited broad-spectrum antiplasmodial activity, inhibiting the growth of drug-resistant or sensitive strains of Plasmodium falciparum blood stages with high potency. Interestingly, CB-41 showed prophylactic activity against hypnozoites and liver schizonts in the Plasmodium cynomolgi, a primate model for Plasmodium vivax. Four CB compounds (CB-27, CB-41, CB-53, and CB-61) inhibited P. falciparum oocyst formation in mosquitoes, and five CB compounds (CB-27, CB-41, CB-53, CB-58, and CB-61) hindered the in vitro development of Plasmodium berghei ookinetes. The CB compounds did not inhibit the activation of P. berghei female and male gametocytes in vitro. Six CB compounds showed no inhibition of Plasmodium 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©) 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©, P. berghei 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© tool have the potential to make important contributions to malaria research.