{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:52:52Z","timestamp":1779299572558,"version":"3.51.4"},"reference-count":20,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T00:00:00Z","timestamp":1525737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008895","name":"Tertiary Education Trust Fund","doi-asserted-by":"publisher","award":["will be added later"],"award-info":[{"award-number":["will be added later"]}],"id":[{"id":"10.13039\/501100008895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83 and P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure\u2013activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.<\/jats:p>","DOI":"10.3390\/molecules23051113","type":"journal-article","created":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T05:51:47Z","timestamp":1525758707000},"page":"1113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8749-3431","authenticated-orcid":false,"given":"Charles Okeke","family":"Nnadi","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of M\u00fcnster, PharmaCampus Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"},{"name":"Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State 410001, Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia Barbara","family":"Althaus","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of M\u00fcnster, PharmaCampus Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9914-6402","authenticated-orcid":false,"given":"Ngozi Justina","family":"Nwodo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State 410001, Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas J\u00fcrgen","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of M\u00fcnster, PharmaCampus Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nnadi, C.O., Nwodo, N.J., Kaiser, M., Brun, R., and Schmidt, T.J. (2017). Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense. Molecules, 22.","DOI":"10.3390\/molecules22071129"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.compbiolchem.2015.04.007","article-title":"Computational analysis of CRTh2 receptor antagonist: A ligand-based CoMFA and CoMSIA approach","volume":"56","author":"Babu","year":"2015","journal-title":"Comput. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.drudis.2007.08.004","article-title":"Multi-dimensional QSAR in drug discovery","volume":"12","author":"Lill","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/qsar.200290000","article-title":"3D QSAR of serotonin transporter ligands: CoMFA and CoMSIA studies","volume":"21","author":"Wellsow","year":"2002","journal-title":"Quant. Struct. Act. Relat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5959","DOI":"10.1021\/ja00226a005","article-title":"Comparative molecular field analysis (CoMFA). 1. Effects of shape on binding of steroids to carrier proteins","volume":"110","author":"Cramer","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0024-3205(93)90135-P","article-title":"Reversal of activity profile in analogs of the antiprogestin RU 486: Effect of a 16\u03b1-substituent on progestational (agonist) activity","volume":"52","author":"Cook","year":"1993","journal-title":"Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.2174\/1386207043328292","article-title":"Probability issues in molecular design: Predictive and modeling ability in 3D-QSAR schemes","volume":"7","author":"Polanski","year":"2004","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_8","first-page":"604","article-title":"3D-QSAR and Docking Study of the Binding Mode of Steroids to Progesterone Receptor in Active Site","volume":"22","author":"Chen","year":"2003","journal-title":"Mol. Inf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1021\/ci800240m","article-title":"3D QSAR\/CoMFA and CoMSIA studies on antileukemic steroidal esters coupled with conformationally flexible nitrogen mustards","volume":"48","author":"Kapou","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/BF00126215","article-title":"A comparison of progestin and androgen receptor binding using the CoMFA technique","volume":"6","author":"Loughney","year":"1992","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/BF00117403","article-title":"Experimental design based 3D QSAR analysis of steroid-protein interactions: Application to human CBG complexes","volume":"4","author":"Norinder","year":"1990","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/BF00125662","article-title":"3-D QSAR analysis of steroid\/protein interactions: The use of difference maps","volume":"5","author":"Norinder","year":"1991","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/(SICI)1099-128X(199609)10:5\/6<533::AID-CEM465>3.0.CO;2-J","article-title":"3D-QSAR investigation of the tripos benchmark steroids and some protein-tyrosine kinase inhibitors of styrene type using the TDQ approach","volume":"10","author":"Norinder","year":"1996","journal-title":"J. Chemom."},{"key":"ref_14","unstructured":"Chemical Computing Group (2014). Molecular Operating Environment (MOE) rel. 2011.10, Chemical Computing Group Inc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00894-010-0684-x","article-title":"Open3DQSAR: A new open-source software aimed at high throughput chemometric analysis of molecular interaction fields","volume":"17","author":"Tosco","year":"2011","journal-title":"J. Mol. Model."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.3390\/molecules19056184","article-title":"Antiprotozoal activity of Buxus sempervirens and activity-guided isolation of O-tigloylcyclovirobuxeine-B as the main constituent active against Plasmodium falciparum","volume":"19","author":"Althaus","year":"2014","journal-title":"Molecules"},{"key":"ref_17","unstructured":"Althaus, J.B. (2015). Natural Products with Antiprotozoal Activity: Alkamides Isolated from Asteraceae and Triterpene Alkaloids from Buxus sempervirens L.. [Doctoral Thesis (Dr. rer. nat.), IPBP, University of M\u00fcnster]."},{"key":"ref_18","unstructured":"Martin, Y.C., Willett, P., and Heller, S.R. (1998). Designing Bioactive Molecules: Three-Dimensional Techniques and Applications (Computer Applications in Chemistry Collection), American Chemical Society. [1st ed.]."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1021\/jo01340a516","article-title":"Buxus alkaloids. X. The Isolation and Constitution of Cyclovirobuxeine-B","volume":"31","author":"Kupchan","year":"1966","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4563","DOI":"10.1016\/S0040-4020(01)92557-8","article-title":"Buxus alkaloids-XII. Benzamide alkaloids from Buxus sempervirens L.","volume":"23","author":"Kupchan","year":"1967","journal-title":"Tetrahedron"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1113\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:03:45Z","timestamp":1760195025000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,8]]},"references-count":20,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["molecules23051113"],"URL":"https:\/\/doi.org\/10.3390\/molecules23051113","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201804.0282.v1","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,8]]}}}