Development of flavonoid compounds as antileishmanial agents

Abstract

A library of 49 novel flavonoid compounds were designed, synthesized and characterized. Some of them were demonstrated to be potent in vitro against Leishmania parasites that cause leishmaniasis, an endemic tropical disease prevalent in 80 countries worldwide. Among them, FM05b and FM09h were selected for further study. FM05b was found to be active against promastigotes (IC₅₀ = 0.6 - 0.9 μM) and amastigotes (IC₅₀ = 0.3 - 0.7 μM), metabolically-stable (89% and 83.1% remained after 30-minute incubation with human liver microsomes (HLM) and rat liver microsomes (RLM)), safe (no toxicity in mice), orally available (F = 32%) and accumulated in the spleen and liver (target organs of visceral Leishmania) at a level (4.5 and 3.2 μM respectively) above its in vitro IC₅₀ of 0.7 μM at 24 hours after oral administration at 50 mg/kg. In vivo efficacy study demonstrated that intralesional administration of FM05b (10 mg/kg, once every 4 days for 8 times) reduce the footpad lesion thickness in a cutaneous model of Leishmaniasis (L. amazonensis LV78) by 49 ± 22% compared with solvent control group. In addition, oral administration of FM05b (50 mg/kg; once daily for 14 days) reduce the parasite burden of a visceral model of leishmaniasis (L. donovani HU3) in the liver by 32 ± 18% with no toxicity observed. Another potent drug candidate, FM09h (IC₅₀ = 0.5 - 1.1 μM against promastigotes, IC₅₀ = 0.3 μM against amastigotes, metabolic stability in HLM and RLM = 39.4% and 65.7 % respectively and F = 5%) was found effective in reducing the lesion thickness of the footpad in cutaneous leishmaniasis by 72 ± 15% via intralesional injection (10 mg/kg, once every 4 days for 8 times). To conclude, the antileishmanial activities and pharmacokinetics of synthetic flavonoid monomers had been improved through structural modification. FM05b and FM09h were generated. Additionally, FM05b was found to accumulate in liver and spleen, the target organs of visceral leishmaniasis. It was also demonstrated that both FM05b and FM09h were effective in treat cutaneous leishmaniasis via intralesional administration. Oral administration of FM05b reduce the parasite burden in liver in the visceral leishmaniasis model. This suggests the use of synthetic flavonoids to treat leishmaniasis.