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DOI: 10.1055/s-0037-1608114
STEROIDAL ALKALOIDS AS POTENT AGENTS AGAINST Trypanosoma brucei rhodesiense
Publication History
Publication Date:
24 October 2017 (online)
Against the backdrop of our previous preliminary report on steroid alkaloids with promising antitrypanosomal activity from the leaves of West African Holarrhena africana [1], we have extended our search for such alkaloids to the stem bark. Bioactivity-guided isolation by repeated column chromatographic separation and purification of various alkaloidal fractions yielded six (1 – 6) steroidal alkaloids from the leaves [1], and eleven (7 – 17) steroidal alkaloids as well as one (18) nitrogen-free steroid from the stem bark. The structures were resolved by comparison of HRMS, 1D and 2D NMR spectra with reported data [2, 3]. All compounds were tested in vitro against Trypanosoma brucei rhodesiense and for cytotoxicity to mammalian cells (L6 cell line) and some structure-activity relationships became evident. The presence of a basic amino group at position 3 was found to be necessary for high antitrypanosomal activity of the steroid alkaloids. Pairwise comparison of the IC 50 values (µM) of 1 (0.40 ± 0.28) and 3 (0.08 ± 0.01), 12 (0.42 ± 0.09) and 13 (0.17 ± 0.11), 15 (1.66 ± 0.39) and 14 (0.12 ± 0.08) showed that monomethylation at the 3-amino group represents an optimum for antitrypanosomal activity. Comparison of the IC 50 values of 4 (1.20 ± 0.75) and 5 (0.67 ± 0.03) furthermore indicates that the C-3β amino substitution enhances activity. Overall, antitrypanosomal potency increases in the order O<NH<nh2<N(CH<n(ch3)2<NHCH<nhch3 with respect to substitution at C-3. The antitrypanosomal activities of these steroid alkaloids have not been reported before. Further studies on structure-activity relationships in terms of QSAR are currently in progress and will represent the basis for eventual lead optimization.</nhch</n(ch</nh
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