Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs

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 (IC 50 ) cutoff of 2 M for 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 IC 50 (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.T he phylum Apicomplexa comprises a group of unicellular eukaryotes, including obligate intracellular parasites that cause diseases ranging from benign to serious (1). In humans, the most devastating of these infections is malaria, caused by Plasmodium parasites, with Plasmodium falciparum being the deadliest. Malaria affects about 225 million humans and results in 650,000 deaths every year (2). Toxoplasma gondii is another Apicomplexa organism that causes toxoplasmosis, affecting one-third of the world population (3). Other parasites, such as Babesia spp., Neospora spp., and Eimeria spp., cause diseases of veterinary importance (4). Apicomplexa require large amounts of glycerolipids to build up membrane compartments throughout their life cycle. Plasmodium asexual proliferation illustrates this demand. Once invading a hepatocyte, a single sporozoite divides, producing 40,000 merozoites (5). Each merozoite then begins a cycle of schizogonic development inside erythrocytes. As a consequence, a 500 to 700% increase in membrane lipids is observed in infected erythrocytes compared to uninfected ones (6).The structure of glycerolipids is obtained by the assembly of (i) a 3-carbon glycerol backbone originating from glycerol-3-phosphate (G3P), (ii) fatty acids (FA) esterified at positions sn Ϫ1 and sn Ϫ2 in glycerol, and (iii) a polar head at position sn Ϫ3. It has long been considered that Apicomplexa scavenge their fatty acids and glycerolipids from the host (5-8). However, the existence of bi...

Targeting phospholipase D in cancer, infection and neurodegenerative disorders

“…Recently, it was found that certain parasites might also utilize pathways downstream of PLDs. This was illustrated by in vitro experiments showing that PLD inhibitors such as VU0285655 can block the proliferation of Plasmodium falciparum (one of the causal agents of malaria) and that of Toxoplasma gondii (which causes toxoplasmosis) 64 .…”

Identification par deux criblages simultanés indépendants d’une famille d’inhibiteurs du métabolisme des glycérolipides

“…En modélisant la structure tridimensionnelle de la galvestine-1 et du DAG, il a en effet été possible de superposer la partie pipéridinyl-benzimidazolone avec la zone proche du squelette glycérol du DAG [9]. En considérant, d'une part, l'importance vitale du métabolisme des glycérolipides pour les eucaryotes, et, parmi eux, des eucaryotes pathogènes de l'homme et, d'autre part, la possibilité de faire varier la spécificité de cible des pipéridinyl-benzimidazolone, une chimiothèque d'analogues, contenant des motifs structuraux communs à la galvestine-1, à l'halopémide et à VU0285655, a été criblée pour rechercher des agent anti-infectieux inhibant la prolifération de Plasmodium falciparum et de Toxoplasma gondii [22]. Ces parasites appartiennent au groupe des Apicomplexes, proches dans l'évolution des algues [23], responsables respectivement du paludisme et de la toxoplasmose.…”

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

“…The vestigial origin of the apicoplast has paved the way for innovative antimalarial drugs that can be described as herbicidal therapies. Among the biocides targeting the apicoplast, triclosan showed antiparasitic activity against Plasmodium through the fatty acid biosynthesis pathway inhibition located in the apicoplast [ 19 ], although it was off-target and not active in vivo [ 20 ].…”