Malaria remains one of the most severe and life-threatening infectious diseases. Among the various Plasmodium spp., Plasmodium falciparum is the most virulent and life-threatening form, prevailing in Southeast Asia and Africa. At present, artemisinin derivatives or quinine-based compounds are for treating malaria-infected patients. Acute treatment of non-falciparum malaria still requires the use of chloroquine, which is seldom used as a preventive treatment due to resistance developed against it. There is an emergent need for developing prompt treatment methods against multidrug-resistant strains of P. falciparum. Epigenetic mechanisms have been promising therapeutic targets for a variety of diseases ranging from cancer, cardiovascular diseases, inflammation, and infection. The interaction between the histone acetyltransferases (HATs) and the histone deacetylases (HDACs) facilitates the structure of the intact DNA. In addition, HDAC is a promising target for malaria. FNDR-20123 is an anti-malarial HDAC inhibitor. It has activities against Plasmodium and human HDAC, respectively.
FNDR-20123 is a histone deacetylase inhibitor for the research of Plasmodium falciparum malaria.
FNDR-20123 is a safe, first-in-class, and orally active anti-malarial HDAC inhibitor with IC50s of 31 nM and 3 nM for Plasmodium and human HDAC, respectively. Moreover, it exerts antimalarial activity against Plasmodium falciparum asexual stage (IC50=41 nM) and sexual blood stage (IC50=190 nM for male gametocytes). FNDR-20123 also inhibits HDAC1, HDAC2, HDAC3, HDAC6, and HDAC8 (IC50= 25, 29, 2, 11, and 282 nM, respectively). It also inhibits Class III HDAC isoforms at nanometer concentrations. In addition, FNDR-20123 is active against some resistant strains, which will be highly valuable in eliminating the rapidly evolving drug-resistant parasite. Furthermore, it is also able to reduce parasitemia significantly in a mouse model for P. falciparum infection.
FNDR-20123 has relatively better potency and bioavailabilities, and it may provide a more cost-effective option, benefiting a large population of malaria-infected patients. Therefore, FNDR-20123 may be a suitable candidate for the treatment of malaria.