Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals

by Veerman J, van den Bergh T, Orrling K.M, Jansen C, Cos P, Maes L, Chatelain C, Ioset J-R, Edink E.E, Tenor H, Seebeck T, de Esch I, Leurs R, Jan Sterka G. Bioorganic & Medicinal Chemistry 2016. doi:10.1016/j.bmc.2016.02.032

Summary: Trypanosomal phosphodiesterases B1 and B2 play an important role in the life cycle of T. brucei, which causes human African trypanosomiasis; knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. The authors report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease.

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