Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds

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.