Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic  Plasmodium species.

Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic Plasmodium species. ChemMedChem. 2020 Dec 18;: Authors: Walloch P, Hansen C, Priegann T, Schade D, Beitz E Abstract The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate-nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydroxy-pent-2-en-1-ones, we discovered PfFNT inhibitors that potently kill P. falciparum parasites in vitro. Four additional human-pathogenic Plasmodium species require attention, i.e. P. vivax, most prevalent outside of Africa, and the regional P. malariae, P. ovale, and P. knowlesi. Here, we show that the plasmodial FNT variants are highly similar in terms of protein sequence and functionality. The FNTs from all human-pathogenic plasmodia and the rodent malaria parasite were efficiently inhibited by pentafluoro-3-hydroxy-pent-2-en-1-ones. We further established a phenotypic yeast-based FNT inhibitor screening, and found very low compound cytotoxicity and monocarboxylate transporter 1 off-target activity on human cells, particularly of the most potent FNT inhibitor BH267.meta, allowing to proceed towards animal model malaria studies. PMID: 33336890 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research