Abstract
Aim:The recurring resistance of the malaria parasite to many drugs compels the design of innovative chemical entities in antimalarial research. Pan-histone deacetylase inhibitors (pan-HDACis) have recently been presented in the literature as powerful novel antimalarials, although their application is hampered due to toxic side effects. This drawback might be neutralized by the deployment of isoform-selective HDACis.Results:In this study, 42 thiaheterocyclic benzohydroxamic acids, 17 of them being potent and selective hHDAC6 inhibitors, were tested to investigate a possible correlation between hHDAC6 inhibition and antiplasmodial activity.Conclusion:Four hHDAC6 inhibitors showed submicromolar potency against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with high selectivity indices, pointing to the relevance of exploring hHDAC6 inhibitors as potential new antiplasmodial agents.
Highlights
Four potent and selective hHDAC6 inhibitors were shown to be highly active as antiplasmodial agents, displaying a good therapeutic window and resistance index as well
HHDAC6 inhibitory activity and antiplasmodial activity are somehow interconnected, and these HDAC6i new chemical entities can certainly be considered a valuable starting point for further medicinal chemistry investigation en route to novel types of antiplasmodial drugs
Summary
The recurring resistance of the malaria parasite to many drugs compels the design of innovative chemical entities in antimalarial research
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