HDAC-IN-76 (compound 6i), a histone deacetylase (HDAC) inhibitor, demonstrates robust antimalarial activity, particularly against the asexual blood stages of Plasmodium. The compound exhibits potent efficacy with IC 50 values of 30 nM and 98 nM against Pf3D7 (chloroquine drug-susceptible strain) and PfDd2 (chloroquine drug-resistant strain), respectively. Moreover, HDAC-IN-76 shows selective inhibition towards parasites, displaying IC 50 values of 7 nM and 9 nM against human HDAC1 and HDAC6, respectively, and effectively inhibits PfHDAC1.

hHDAC1:7 nM, hHDAC6:9 nM

HDAC-IN-76 在抑制 PfHDAC1 方面表现出色，抑制率达 70.2%（浓度为 1 μM）。该化合物对 HEK293 细胞具有较低的毒性（IC 50 =136 μM，选择指数 SI=544），同时在肝期寄生虫活性方面表现不突出（IC 50 PbEEF (伯氏疟原虫红细胞外肝期寄生虫)=0.25 μM）。此外，HDAC-IN-76 在微粒体中具有良好的稳定性（t 1/2 > 60 min），且能有效进入 HepG2 细胞并抑制 HDAC 活性。