Schiff Base-Containing Citral Derivatives as Potential Amoebicidal Agents against Acanthamoeba spp

Background Current therapies for Acanthamoeba keratitis rely on a limited number of drugs that often exhibit high toxicity and suboptimal efficacy. These limitations highlight the urgent need for safer and more effective amoebicidal agents. In this context, natural products and their derivatives offer a promising source of new therapeutic candidates. Objective This study aimed at evaluating the amoebicidal activity of citral ( 1 ) and a series of derivatives ( 2 – 9 ), and to elucidate the mechanisms underlying their antiparasitic effects Results All compounds ( 1 – 9 ) exhibited a strong inhibitory effect on the trophozoite stage of Acanthamoeba L10, A. griffini , and A. culbertsoni , with IC₅₀ values in the micromolar range (15–132 μM). In addition, compounds 7 – 9 demonstrated potent activity against trophozoites of A. castellanii and A. polyphaga , with IC₅₀ values in the micromolar range (21–92 μM and 29–114 μM, respectively). These compounds exhibited a favorable selectivity index in a eukaryotic cell line, showing an improved safety profile relative to the reference drugs. Notably, tosyl-hydrazone 8 emerged as the most promising compound, showing a good activity against dormant cysts of A. L10. Additionally, compound 8 could induce late-stage apoptotic/necrotic features Acanthamoeba L10 through various cellular signaling routes. According to the structure–activity relationship analysis, the type of the aldehyde derivatives plays a pivotal role in the amoebicidal effect. Conclusion These results highlight the therapeutic potential of monoterpenoids, providing support for the continued design of citral derivatives as potential antiamoebic agents.