Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals. Issue 7 (1st April 2016)

• Record Type: Journal Article
• Authors: Veerman, Johan; van den Bergh, Toine; Orrling, Kristina M.; Jansen, Chimed; Cos, Paul; Maes, Louis; Chatelain, Eric; Ioset, Jean-Robert; Edink, Ewald E.; Tenor, Hermann; Seebeck, Thomas; de Esch, Iwan; Leurs, Rob; Sterk, Geert Jan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 7(2016)
• Page Start: 1573
• Page End: 1581
• Publication Date: 2016-04-01
• Subjects: MOE Molecular Operating Environment -- MW microwave -- TbrPDEB1 Trypanosoma brucei phosphodiesterase B1 -- TbrPDEB2 Trypanosoma brucei phosphodiesterase B2; Pyridazinone -- Phosphodiesterase -- Trypanosome brucei -- African trypanosomiasis -- TbrPDEB1 -- Human PDEs; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.02.032
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 : 4 nM) and TbrPDEB2 (IC50 : 3 nM) ( 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.