Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites, such as the plasmodium of malaria. Here we report the results of a study aimed at evaluating antiparasitic effect of two classes of HDAC-Is bearing different zinc binding group (hydroxamic acid vs thiol). The study showed that only the hydroxamic acid based HDAC inhibitors were active, with Plasmodium falciparum being the most sensitive parasite, having from low double-digit to single-digit nanomolar range in vitro activities. Among three derivatives evaluated also in vivo, ST8086AA1 (8) effectively inhibited 88% of the development of Plasmodium falciparum.