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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:
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)