HDAC1-IN-12 is an inhibitor of the malignant malaria parasite (Plasmodium falciparum) HDAC1 (PfHDAC1), with an IC50 of 4.1 nM. This inhibitor functions by inhibiting PfHDAC1, increasing histone H3 acetylation in the P. falciparum parasite, and reducing the expression of genes associated with malaria invasion. It exhibits favorable safety profiles, improved physicochemical properties, and effective in vivo antimalarial activity, making HDAC1-IN-12 a valuable tool for malaria research.

HDAC1-IN-12 (compound 5ac) significantly inhibits the growth of the malignant malaria parasite P. falciparum 3D7 with an IC50 of 4.1 nM, while demonstrating high selectivity towards human HepG2 (IC50 of 1.5 μM) and HEK293T (IC50 of 15 μM) cells. It remains active against multidrug-resistant P. falciparum strains, inhibiting artemisinin-resistant ring-stage parasites with IC50 values of 3.9 nM for GB4, 6 nM for CP286, and 5.3 nM for 6267. Additionally, HDAC1-IN-12 enhances acetylation levels of histone H3 in P. falciparum at concentrations of 5-50 nM over 3 hours. Furthermore, it downregulates invasion-related genes and obstructs the parasite's egress and erythrocyte invasion.

HDAC1-IN-12 (compound 5ac) (30 mg/kg; intraperitoneal injection; daily; for 4 consecutive days) demonstrated significant in vivo antimalarial activity in a model using BALB/c mice infected with Plasmodium berghei ANKA strain.