Disruption of mitochondrial function in blood and sexual stages of Plasmodium falciparum by ferulenol

Abstract Background Malaria continues to be a significant global health challenge, necessitating the development of novel antimalarial compounds. This study explores the effects of ferulenol on multiple lifecycle stages of Plasmodium falciparum . Ferulenol has been identified as a promising antimalarial candidate, demonstrating high efficacy in inhibiting asexual blood-stage parasites at low micromolar concentrations. However, its effects on other parasite stages remain unexplored, despite its mitochondrial target being critical for sexual stage development. This study aims to investigate ferulenol’s potential as a dual-target antimalarial by assessing its effects on development of asexual blood-stage and transmission precursor-stage parasites. Methods Falciparum malaria parasites were cultured in vitro and incubated with or without ferulenol. Effects of the treatment on the development of the asexual blood-stage, early-stage gametocyte, late-stage gametocyte, and gamete formation were assessed using light microscopy. The impact of ferulenol on mitochondrial membrane potential was investigated using JC-1 staining and analyzed by fluorescence microscopy. Results The highest dose of ferulenol inhibited asexual blood-stage proliferation by 88%, early-stage gametocyte development by 82%, and stage V gametocyte maturation at about 90%. Moreover, the effect of ferulenol was more pronounced on male gamete formation than on female gamete formation, with the development inhibited at 81% and 27%, respectively. Conclusions These findings position ferulenol as a promising dual antimalarial activity on asexual blood-stage and gametocyte stages, which could lead the compound to disrupt both severity and transmission of disease. Graphical Abstract