Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent
a potential source of new antitrypanosomatidic
leads. Starting from a library of natural products, we combined target-based
screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols
were identified as hits, and a library of 16 derivatives was synthesized.
Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures
and docking studies explained the observed structure–activity
relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies.
Encapsulation of compound 2 in PLGA nanoparticles or
cyclodextrins resulted in lower in vitro toxicity when compared to
the free compound. Combination studies with methotrexate revealed
that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration
of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward
host cells. Our results provide the basis for further chemical modifications
aimed at identifying novel antitrypanosomatidic agents showing higher
potency toward PTR1 and increased metabolic stability.