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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Lead optimization of phthalazinone phosphodiesterase inhibitors as novel antitrypanosomal compounds Irene G. Salado , Abhimanyu Singh , Carlos Moreno-Cinos , Guna Sakaine , Marco Siderius , Pieter Van Der Veken , An Matheeussen , Tiffany Van Der Meer , Payman Sadek , Sheraz Gul , Louis Maes , Geert Jan Sterk , Rob Leurs , David Brown , Koen Augustyns Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00985 Diamond Proposal Number(s): [16207, 15075] Show Abstract ▼ Abstract: 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 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 due to low metabolic stability. 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 provides a good starting point for future efforts.	Mar 2020

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