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Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds

Salado, Irene G., Singh, Abhimanyu K., Moreno-Cinos, Carlos, Sakaine, Guna, Siderius, Marco, Van der Veken, Pieter, Matheeussen, An, van der Meer, Tiffany, Sadek, Payman, Gul, Sheraz, and others. (2020) Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds. Journal of Medicinal Chemistry, . ISSN 0022-2623. (doi:10.1021/acs.jmedchem.9b00985) (KAR id:80697)


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.

Item Type: Article
DOI/Identification number: 10.1021/acs.jmedchem.9b00985
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: David Brown
Date Deposited: 02 Apr 2020 09:57 UTC
Last Modified: 04 Mar 2024 18:07 UTC
Resource URI: (The current URI for this page, for reference purposes)

University of Kent Author Information

Singh, Abhimanyu K..

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Brown, David.

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