Leishmanicidal constituents from the leaves of Piper rusbyi

The kavapyrone (+)-(7R,8S)-epoxy-5,6-didehydrokavain (1) and the chalcone flavokavain B (2) were isolated from Piper rusbyi as the bioactive components by bioassay-guided fractionation, using an in vitro assay against promastigote forms of three Leishmania strains. In addition, the new kavapyrone, (7R,8R/7S,8S)-dihydroxy-5,6-didehydrokavain (3), which is very likely an artifact, and four known compounds (4-7) were isolated. Their structures were elucidated on the basis of spectral analysis, and the absolute configurations of compounds 1 and 3 were established by CD studies and the modified Mosher ester procedure, respectively. All compounds were evaluated for in vitro leishmanicidal activity. The most active compounds 1 (IC₅₀ = 81.9 μM) and 2 (IC₅₀ = 11.2 μM) were also evaluated in vivo against a New World strain of cutaneous leishmaniasis, and the results showed the efficacy of 2 at a dose of 5 mg/kg/day. Compounds 1 and 3 were also assayed as reversal agents against a multidrug-resistant Leishmania tropica line, but were found to be inactive.