García Salado, IreneSingh, Abhimanyu K.Moreno-Cinos, CarlosSakaine. GunaSiderius, MarcoVan der Veken, PieterMatheeussen, AnVan der Meerd, TiffanySadek, PaymanGul, SherazMaes, LouisSterk, Geert-JanLeurs, RobBrown, DavidAugustyns, Koen2025-10-202025-10-202020Salado IG, Singh AK, Moreno-Cinos C, Sakaine G, Siderius M, Van der Veken P, Matheeussen A, van der Meer T, Sadek P, Gul S, Maes L, Sterk GJ, Leurs R, Brown D, Augustyns K. Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds. J Med Chem. 2020 Apr 9;63(7):3485-3507. doi: 10.1021/acs.jmedchem.9b009850022-2623https://hdl.handle.net/10641/6214Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound 1 resulted to be a potent TbrPDEB1 inhibitor with interesting activity against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease model but unfortunately showed no efficacy. Its low metabolic stability is certainly one of the reasons. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and T. brucei. Compound 14, presented a good microsomal stability in mouse and human microsomes and will be studied in the future in an acute in vivo T. brucei mouse model.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articleopen access10.1021/acs.jmedchem.9b00985