Commercial drugs containing flavonoids are active in mice withmalaria and in vitro against chloroquine-resistantPlasmodium falciparum

摘要

BACKGROUND The main strategy to control human malaria still relies on specific drug treatment, limited now by Plasmodium falciparum-resistant parasites, including that against artemisinin derivatives. Despite the large number of active compounds described in the literature, few of them reached full development against human malaria. Drug repositioning is a fast and less expensive strategy for antimalarial drug discovery, because these compounds are already approved for human use. OBJECTIVES To identify new antimalarial drugs from compounds commercially available and used for other indications. METHODS Accuvit^®, Ginkgo^® and Soyfit^®, rich in flavonoids, and also the standard flavonoids, hesperidin, quercetin, and genistein were tested against blood cultures of chloroquine-resistant P. falciparum, as well as chloroquine, a reference antimalarial. Inhibition of parasite growth was measured in immunoenzymatic assay with monoclonal anti-P. falciparum antibodies, specific to the histidine-rich protein II. Tests in mice with P. berghei malaria were based on percent of parasitaemia reduction. These compounds were also evaluated for in vitro cytotoxicity. FINDINGS Theinhibition of parasite growth in vitro showed thatAccuvit^® was the most active drug (IC50 5 ± 3.9μg/mL). Soyfit^® was partially active (IC50 13.6 ± 7.7μg/mL), and Ginkgo^® (IC50 38.4 ± 14 μg/mL) was inactive.All such compounds were active in vivo at a dose of 50 mg/kgbody weight. Accuvit^® and quercetin induced the highest reduction ofP. berghei parasitaemia (63% and 53%, respectively) on day5 after parasite inoculation. As expected, the compounds tested were not toxic.MAIN CONCLUSIONS The antimalarial activity of Accuvit^® was notrelated to flavonoids only, and it possibly results from synergisms with othercompounds present in this drug product, such as multivitamins. Multivitamins inAccuvit^® may explain its effect against the malaria parasites.This work demonstrated for the first time the activity of these drugs, which arealready marketed.