Discovery of compounds blocking the proliferation of Toxoplasma gondii and Plasmodium falciparum in a chemical space based on piperidinyl-benzimidazolidinone analogs.
Résumé
: A piperidinyl-benzimidazolidinone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism, acting on enzymes manipulating diacylglycerol or phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolidinone analogs might therefore identify compounds acting against infectious parasites. We first evaluated the in vitro effects of (S)-2-(dibenzylamino)-3-phenylpropyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate (compound 1) on Toxoplasma gondii and Plasmodium falciparum. In T. gondii, motility and apical complex integrity appeared unaffected, whereas cell division was inhibited at concentrations of compound 1 in the micromolar range. In P. falciparum, proliferation of erythrocytic stages was inhibited, without any delayed death phenotype. We then explored a library of 250 analogs in two steps. We selected 114 compounds with an IC50 cutoff of 2 μM on at least one species and determined in vitro selectivity indexes (SI), based on toxicity against K-562 human cells. We identified compounds with high gains in IC50 (in the 100 nM range) and SI (up to 1,000-2,000). Isobole analyses of two of the most active compounds against P. falciparum indicated that their interaction with artemisin was additive. We propose structure activity relationship (SAR) models, which will be useful for the design of probes to identify the compounds' target(s), and optimizations for mono- or combined-therapeutic strategies.