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Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds. 2020
Irene G Salado, and
Abhimanyu K Singh, and
Carlos Moreno-Cinos, and
Guna Sakaine, and
Marco Siderius, and
Pieter Van der Veken, and
An Matheeussen, and
Tiffany van der Meer, and
Payman Sadek, and
Sheraz Gul, and
Louis Maes, and
Geert-Jan Sterk, and
Rob Leurs, and
David Brown, and
Koen Augustyns
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
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 in being 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.
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