10.1021/acs.jmedchem.9b00985.s002 Irene G. Salado Irene G. Salado Abhimanyu K. Singh Abhimanyu K. Singh Carlos Moreno-Cinos Carlos Moreno-Cinos Guna Sakaine Guna Sakaine Marco Siderius Marco Siderius Pieter Van der Veken Pieter Van der Veken An Matheeussen An Matheeussen Tiffany van der Meer Tiffany van der Meer Payman Sadek Payman Sadek Sheraz Gul Sheraz Gul Louis Maes Louis Maes Geert-Jan Sterk Geert-Jan Sterk Rob Leurs Rob Leurs David Brown David Brown Koen Augustyns Koen Augustyns Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds American Chemical Society 2020 Novel Antitrypanosomal Compounds Human phtalazinone derivatives stability TbrPDEB 1 Derivative 1 brucei phenotypic screen Compound 14 novel treatment Compound 1 future efforts vivo mouse disease model TbrPDEB 1 inhibitor Phthalazinone Phosphodiesterase Inhibitors Lead Optimization 2020-03-26 08:43:21 Dataset https://acs.figshare.com/articles/dataset/Lead_Optimization_of_Phthalazinone_Phosphodiesterase_Inhibitors_as_Novel_Antitrypanosomal_Compounds/12033690 Human 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 <b>1</b> resulted in being a potent TbrPDEB1 inhibitor with interesting activity against <i>T. brucei</i> in a phenotypic screen. Derivative <b>1</b> was studied in an acute <i>in vivo</i> mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and <i>T. brucei</i>. Compound <b>14</b> presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.