Abstract
Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.
Highlights
Human African trypanosomiasis, known as African sleeping sickness, is one of the neglected tropical diseases (NTDs) listed by the WHO and is caused by the protozoan Trypanosoma brucei (T.b.) rhodesiense and T.b. gambiense (Büscher et al, 2017)
The compound dataset for the virtual screening was based on commercially available heteroaryl chlorides which were combined with the core phenyltetrahydrophthalazinone scaffold using the MOE Combinatorial Library module (Figure 2)
In a second virtual screening approach, all computation library compounds were compared to the binding pose of NPD-039 in TbrPDEB1 using ROCS
Summary
Human African trypanosomiasis, known as African sleeping sickness, is one of the neglected tropical diseases (NTDs) listed by the WHO and is caused by the protozoan Trypanosoma brucei (T.b.) rhodesiense and T.b. gambiense (Büscher et al, 2017). The first oral drug fexinidazole has recently been approved for HAT and will significantly improve the status of the disease (Deeks, 2019). This new therapy benefits greatly from the ease of administration, but still has some drawbacks including potential relapse and a lower efficacy for late-stage patients compared to the commonly used NECT treatment (De MoraisTeixeira et al, 2019; Pelfrene et al, 2019). The reported increasing drug resistance could have a detrimental effect on the already limited arsenal of antiprotozoal drugs (Munday et al, 2015; De Koning, 2017). The number of reported cases is slowly decreasing as a result of active screening in endemic regions, still an estimated 65 million people are at risk of infection
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