Abstract:
A piperidinyl-benzimidazolone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism,
acting on enzymes manipulating diacylglycerol and phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolone
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 to be unaffected,
whereas cell division was inhibited at compound 1 concentrations in the micromolar range. In P. falciparum, the 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 a 50% inhibitory concentration (IC50) cutoff of 2 Mfor 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 the IC50 (in the 100 nM range) and SI (up to 1,000 to 2,000) values. Isobole analyses of two of the most active compounds
against P. falciparum indicated that their interactions with artemisinin were additive. Here, we propose the use of structureactivity
relationship (SAR) models, which will be useful for designing probes to identify the target compound(s) and optimizations
for monotherapy or combined-therapy strategies.
