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Molecules 2017, 22(7), 1129; https://doi.org/10.3390/molecules22071129

Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense

1
Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany
2
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria Nsukka, Enugu State 410001, Nigeria
3
Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, CH-4051 Basel, Switzerland
4
University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Received: 28 June 2017 / Revised: 4 July 2017 / Accepted: 5 July 2017 / Published: 6 July 2017
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Abstract

In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, “sleeping sickness”), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of T. brucei rhodesiense (Tbr; East African HAT). Bioactivity-guided chromatographic fractionation of the alkaloid-rich fractions resulted in the isolation of 17 steroid alkaloids, one nitrogen-free steroid and one alkaloid-like non-steroid. Impressive activities (IC50 in µM) against Tbr were recorded for 3β-holaphyllamine (0.40 ± 0.28), 3α-holaphyllamine (0.37 ± 0.16), 3β-dihydroholaphyllamine (0.67 ± 0.03), N-methylholaphyllamine (0.08 ± 0.01), conessimine (0.17 ± 0.08), conessine (0.42 ± 0.09), isoconessimine (0.17 ± 0.11) and holarrhesine (0.12 ± 0.08) with selectivity indices ranging from 13 to 302. Based on comparison of the structures of this congeneric series of steroid alkaloids and their activities, structure-activity relationships (SARs) could be established. It was found that a basic amino group at position C-3 of the pregnane or pregn-5-ene steroid nucleus is required for a significant anti-trypanosomal activity. The mono-methylated amino group at C-3 represents an optimum for activity. ∆5,6 unsaturation slightly increased the activity while hydrolysis of C-12β ester derivatives led to a loss of activity. An additional amino group at C-20 engaged in a pyrrolidine ring closed towards C-18 significantly increased the selectivity index of the compounds. Our findings provide useful empirical data for further development of steroid alkaloids as a novel class of anti-trypanosomal compounds which represent a promising starting point towards new drugs to combat human African trypanosomiasis. View Full-Text
Keywords: Holarrhena africana; Holarrhena floribunda; steroid alkaloid; Trypanosoma brucei rhodesiense; structure-activity relationship; anti-trypanosomal Holarrhena africana; Holarrhena floribunda; steroid alkaloid; Trypanosoma brucei rhodesiense; structure-activity relationship; anti-trypanosomal
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Nnadi, C.O.; Nwodo, N.J.; Kaiser, M.; Brun, R.; Schmidt, T.J. Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense. Molecules 2017, 22, 1129.

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{"cc_re__cc_re__cc_by_3_0": ["eta name=\"dc.creator\" content=\"Ngozi Justina Nwodo\">\n<meta name=\"dc.creator\" content=\"Marcel Kaiser\">\n<meta name=\"dc.creator\" content=\"Reto Brun\">\n<meta name=\"dc.creator\" content=\"Thomas J. Schmidt\">\n<meta name=\"dc.type\" content=\"Article\">\n<meta name=\"dc.source\" content=\"Molecules 2017, Vol. 22, Page 1129\">\n<meta name=\"dc.date\" content=\"2017-07-06\">\n<meta name=\"dc.identifier\" content=\"10.3390/molecules22071129\">\n<meta name=\"dc.publisher\" content=\"Multidisciplinary Digital Publishing Institute\">\n<meta name=\"dc.rights\" content=\"http://creativecommons.org/licenses/by/3.0/\">\n<meta name=\"dc.format\" content=\"application/pdf\">\n<meta name=\"dc.language\" content=\"en\">\n<meta name=\"dc.description\" content=\"In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, \u201csleeping sickness\u201d), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promi"], "cc_re__cc_re__cc_by_4_0": ["molecules-22-01129/article_deploy/html/images/molecules-22-01129-g002.png\" title=\"\n                    <strong>Figure 2</strong><br/>\n                                            &lt;p&gt;Proposed basic structure-activity relationships for anti-trypanosomal activity. &amp;gt;sign indicates higher activity.&lt;/p&gt;\n                                                            \"></a></div>\n<div class=\"licenseText in-tab\" style=\"padding: 1em 0;\">\nThis is an open access article distributed under the <a href=\"https://creativecommons.org/licenses/by/4.0/\" target=\"_blank\" rel=\"noopener noreferrer\">Creative Commons Attribution License</a> which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).\n</div>\n</div>\n<div id=\"tabs-4\" class=\"ui-tabs-panel\">\n<a id=\"suppl_id\" name=\"supplementary\"></a>\n<h1>Supplementary material</h1>\n<div class=\"in-tab\">\n<ul style=\"margin:0; list-style: none;\">\n<li><a name=\"supplementary_file1\"></a><b>Supplementary File 1:</b>\n<p>\n<a href=\"/1420-3049/22/7/1129/s1\">\nSupplementary\n</a>\n(PDF, 1"], "copyright__copyright__copyright": [" from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense. Molecules 2017, 22, 1129.\n\nShow more citation formats Show less citations formats\n\nNote that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nMolecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top", " from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense. Molecules 2017, 22, 1129.\n\nShow more citation formats Show less citations formats\n\nNote that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nMolecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top", " from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense. Molecules 2017, 22, 1129.\n\nShow more citation formats Show less citations formats\n\nNote that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nMolecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top"]}