Hydroxamic Acids as HDAC Inhibitor Drug Leads for Malaria

Malaria is a global health threat, with an estimated 282 million cases and 610,000 malaria-associated deaths reported in 2024. Most mortality is due to infection by Plasmodium falciparum parasites, with the highest burden occurring in Sub-Saharan Africa. Malaria eradication is a global priority; however, progress has been hampered by the lack of broadly applicable and highly effective vaccines and by parasite drug resistance. To address drug resistance, the discovery of drugs with novel modes of action is crucial. Histone/lysine deacetylases (HDACs) are enzymes that control the posttranslational modification of lysine acetylation on histone and non-histone proteins. Due to their essential roles in regulating key processes in Plasmodium parasites, including transcriptional and developmental control, HDACs are prospective drug targets for malaria. Here, the potential of HDAC inhibitors as antimalarial drug leads is reviewed, including an assessment of antiplasmodial structure-activity relationships for more than 750 hydroxamic acids with published in vitro activity against P. falciparum. These comparative data provide unprecedented insights into potency, selectivity and physicochemical properties that can help to guide investigations of this chemotype as drug leads for malaria and other parasitic diseases.