Date of Award

1998

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Nikolaus Fischer

Abstract

Two-hundred and thirty crude organic extracts from 118 plant species distributed among ten families of higher plants have been evaluated for antimycobacterial activity against Mycobacterium tuberculosis (H$\sb{37}$Rv) and M. avium using the BACTEC 460 radiorespirometric assay. At 100 $\mu$g/ml, twenty-four and ten of the extracts caused more than 95% inhibition of growth of M. tuberculosis and M. avium, respectively. Bioactive chromatographic fractions of Borrichia frutescens (Asteraceae) provided two new triterpenes and one known cycloartenol. In radiorespirometric bioassays against M. tuberculosis, the new (24R)-24,25-epoxycycloartan-3-one and the known (24R)-24,25-epoxycycloartan-3$\beta$-ol exhibited minimum inhibitory concentrations (MICs) of 8 $\mu$g/ml. In contrast, the new (23R)-3-oxolanosta-8,24-dien-23-ol showed no significant inhibition at 128 $\mu$g/ml. In an attempt to study the structural dependence of antimycobacterial activity of the highly active guaianolide dehydrocostus lactone (MICs of 2 and 16 $\mu$g/ml against Mycobacterium tuberculosis and M. avium, respectively) and its derivatives, and to determine configurational and possible conformational effects upon activity, m-chloroperoxybenzoic acid oxidations of dehydrocostus lactone were performed. Three new monoepoxides, one previously synthesized diepoxide, and two new diepoxides were obtained, all of which showed strongly reduced antimycobacterial activity. Antimycobacterial root extracts of Inula helenium and Rudbeckia subtomentosa were chemically investigated. Chromatographic fractions of active root extracts of I. helenium provided the known eudesmanolides alantolactone, isoalantolactone, and 11$\alpha$H, 13-dihydroisoalantolactone. Active fractions from root extracts of R. subtomentosa gave the known alloalantolactone and 3-oxoalloalantolactone. All natural and semisynthetic eudesmanolides were tested for biological activity against M. tuberculosis and demonstrated MICs ranging from 8 $\mu$g/ml for 5,6$\alpha$-epoxyalantolactone to $>$128 $\mu$g/ml for 11,13-dihydroisoalantolactone and 11,13-dihydroxyalantolactone. Methanol extracts of fruits of Melia volkensii were chemically investigated and shown to contain two new triterpenes and the known triterpenoid kulonate. The structures of the new 12$\beta$-hydroxykulactone and 6$\beta$-hydroxykulactone were elucidated by 1D and 2D NMR experiments and FABMS studies. All three triterpenes exhibited significant activity against M. tuberculosis with MICs ranging from 4 $\mu$g/ml to 16 $\mu$g/ml.

ISBN

9780591905182

Pages

173

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