Antimycobacterial Eudesmanolides from Inula helenium and Rudbeckia subtomentosa

Abstract:

In a bioassay guided search for antimycobacterial compounds from higher plants, the root extracts of Elecampane (Inula helenium L.; Asteraceae) and Sweet Coneflower (Rudbeckia subtomentosa Pursh.; Asteraceae) were chemically investigated for their active constituents. Chromatographic fractions of root extracts of I. helenium, which exhibited significant activity against Mycobacterium tuberculosis, provided the known eudesmanolides alantolactone, isoalantolactone, and 11αH,13-dihydroisoalantolactone. Peracid epoxidation of alantolactone and isoalantolactone provided 5α-epoxyalantolactone and 4(15)α-epoxyisoalantolactone, respectively and oxidation of alantolactone with OsO⁴ gave 11,13-dihydroxyalantolactone. Active fractions from R. subtomentosa contained the known allo-alantolactone and 3-oxoalloalantolactone. The structures of the above compounds were established by spectroscopic methods including 1D and 2D NMR techniques as well as spectral comparison with previously reported data. The molecular structure of 5α-epoxyalantolactone was determined by single crystal X-ray diffraction. Eleven natural and semisynthetic eudesmanolides were tested in a radiorespirometric bioassay for activity against M. tuberculosis. 5α-Epoxyalantolactone and encelin from Montanoa speciosa showed minimum inhibitory concentrations (MICs) of 8 and 16 μg ml^-1, respectively. Alantolactone, isoalantolactone and its 4α,15-epoxide, 1,2-dehydro-3-epi-isotelekin and alloalantolactone gave MICs of 32 μg ml^-1. All other compounds showed MIC values of 128 μg ml^-1 or higher.

Key words:

Inula helenium - Rudbeckia subtomentosa - R. mollis - Montanoa speciosa - Asteraceae - sesquiterpene lactones - eudesmanolides - Mycobacterium tuberculosis - antituberculosis activity