Lead optimization of phthalazinone phosphodiesterase inhibitors as novel antitrypanosomal compounds

DOI: 10.1021/acs.jmedchem.9b00985

Authors: Irene G. Salado (University of Antwerp) , Abhimanyu Singh (University of Kent) , Carlos Moreno-Cinos (University of Antwerp) , Guna Sakaine (University of Antwerp) , Marco Siderius (Vrije Universiteit Amsterdam) , Pieter Van Der Veken (University of Antwerp) , An Matheeussen (University of Antwerp) , Tiffany Van Der Meer (Vrije Universiteit Amsterdam) , Payman Sadek (Vrije Universiteit Amsterdam) , Sheraz Gul (Fraunhofer-IME SP) , Louis Maes (University of Antwerp) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Rob Leurs (Vrije Universiteit Amsterdam) , David Brown (University of Kent) , Koen Augustyns (University of Antwerp)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 16207 , 15075

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.

Diamond Keywords: Sleeping Sickness; Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 24/03/2020 09:21

Discipline Tags:

Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)