Caljon, Guy

de Esch, Iwan J.P.

Ellinger, Bernhard

Gul, Sheraz

Kuzikov, Maria

Leurs, Rob

Maes, Louis

Matheeussen, An

Siderius, Marco

Sterk, Geert Jan

Van den Kerkhof, Magali

van der Meer, Tiffany

Zheng, Yang

Abstract: Human African Trypanosomiasis (HAT), caused by Trypanosomabrucei, is one of the neglected tropical diseaseswith a continuing need for new medication. We here describe the discoveryof 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypicantitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC50 of 70 nM against T. b. brucei with no apparent toxicity against humanMRC-5 lung fibroblasts. Showing good physicochemical properties, lowtoxicity potential, acceptable metabolic stability, and other pharmacokineticfeatures, 30 was further evaluated in an acute mousemodel of T. b. brucei infection. Afteroral dosing at 50 mg/kg twice per day for five consecutive days, allinfected mice were cured. Given its good drug-like properties andhigh in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinoneanalog 30 represents a promising lead for future drugdevelopment to treat HAT

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Discovery of 5-phenylpyrazolopyrimidinone analogs as potent antitrypanosomal agents with in vivo efficacy

Discovery of 5-phenylpyrazolopyrimidinone analogs as potent antitrypanosomal agents with in vivo efficacy

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Institutional Repository Universiteit Antwerpen