Trypanosomiasis and
leishmaniasis are important
parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several
flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of
flavonoid aglycones and
glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their
antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by
7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by
3-hydroxyflavone,
rhamnetin, and 7,8,3',4'-tetrahydroxyflavone (IC50s, 0.5 microg/ml) and
catechol (IC50, 0.8 microg/ml). The activity against T. cruzi was moderate, and only
chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 microg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential.
Fisetin,
3-hydroxyflavone,
luteolin, and
quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 microg/ml, respectively.
7,8-Dihydroxyflavone and
quercetin appeared to ameliorate
parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of
flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of
7,8-dihydroxyflavone and
quercetin derivatives as potent and effective
antiprotozoal agents.