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Bioorg Med Chem ; 24(7): 1573-81, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26935942

ABSTRACT

Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Protozoan Proteins/antagonists & inhibitors , Pyridazines/pharmacology , Tetrazoles/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Parasitic Sensitivity Tests , Phosphodiesterase Inhibitors/chemistry , Protozoan Proteins/metabolism , Pyridazines/chemical synthesis , Pyridazines/chemistry , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/enzymology , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitology
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