{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T19:14:37Z","timestamp":1775762077391,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,11,22]],"date-time":"2018-11-22T00:00:00Z","timestamp":1542844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Three complementary quantitative structure\u2013activity relationship (QSAR) methodologies, namely, regression modeling based on (i) \u201cclassical\u201d molecular descriptors, (ii) 3D pharmacophore features, and (iii) 2D molecular holograms (HQSAR) were employed on the antitrypanosomal activity of sesquiterpene lactones (STLs) toward Trypanosoma brucei rhodesiense (Tbr), the causative agent of the East African form of human African trypanosomiasis. In this study, an extension of a previous QSAR study on 69 STLs, models for a much larger and more diverse set of such natural products, now comprising 130 STLs of various structural subclasses, were established. The extended data set comprises a variety of STLs isolated and tested for antitrypanosomal activity within our group and is furthermore enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses yielded models with comparable and good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of reactive enone groups within the molecular structure but is influenced by their hydrophilic\/hydrophobic properties and molecular shape.<\/jats:p>","DOI":"10.3390\/ijms19123721","type":"journal-article","created":{"date-parts":[[2018,11,23]],"date-time":"2018-11-23T03:41:31Z","timestamp":1542944491000},"page":"3721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Complementary Quantitative Structure\u2013Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5171-1940","authenticated-orcid":false,"given":"Njogu M.","family":"Kimani","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josphat C.","family":"Matasyoh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Egerton University, P.O. Box 536, Egerton 20115, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4051 Basel, Switzerland"},{"name":"University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro S.","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo H. G.","family":"Trossini","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas, Universidade de S\u00e3o Paulo, Av. Lineu Prestes 580, 05508-000 S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1016\/S0140-6736(17)31510-6","article-title":"Human African trypanosomiasis","volume":"390","author":"Cecchi","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrmicro.2016.193","article-title":"Anti-trypanosomatid drug discovery: An ongoing challenge and a continuing need","volume":"15","author":"Field","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1039\/b311021b","article-title":"Natural products active against African trypanosomes: A step toward new drugs","volume":"21","author":"Hoet","year":"2004","journal-title":"Nat. Prod. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1021\/acs.jnatprod.7b00747","article-title":"Antiprotozoal sesquiterpene lactones and other constituents from Tarchonanthus camphoratus and Schkuhria pinnata","volume":"81","author":"Kimani","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kimani, N.M., Matasyoh, J.C., Kaiser, M., Brun, R., and Schmidt, T.J. (2018). Sesquiterpene lactones from Vernonia cinerascens Sch. Bip. and their in vitro antitrypanosomal activity. Molecules, 23.","DOI":"10.3390\/molecules23020248"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kimani, N.M., Matasyoh, J.C., Kaiser, M., Brun, R., and Schmidt, T.J. (2017). Anti-trypanosomatid elemanolide sesquiterpene lactones from Vernonia lasiopus O. Hoffm. Molecules, 22.","DOI":"10.3390\/molecules22040597"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.3390\/molecules14062062","article-title":"Quantitative structure\u2014antiprotozoal activity relationships of sesquiterpene lactones","volume":"14","author":"Schmidt","year":"2009","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1128\/AAC.01263-13","article-title":"In Silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense","volume":"58","author":"Schmidt","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1055\/s-0029-1185676","article-title":"The antiprotozoal activity of sixteen asteraceae species native to sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum","volume":"75","author":"Nour","year":"2009","journal-title":"Planta Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1055\/s-2002-33799","article-title":"Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones","volume":"68","author":"Schmidt","year":"2002","journal-title":"Planta Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10546","DOI":"10.3390\/molecules190710546","article-title":"Hologram QSAR studies of antiprotozoal activities of sesquiterpene lactones","volume":"19","author":"Trossini","year":"2014","journal-title":"Molecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ejmech.2013.02.018","article-title":"Natural sesquiterpene lactones as inhibitors of Myb-dependent gene expression: Structure\u2013activity relationships","volume":"63","author":"Schomburg","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1021\/ci500581q","article-title":"Study of chromatographic retention of natural terpenoids by chemoinformatic tools","volume":"55","author":"Oliveira","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/1521-3838(200208)21:3<276::AID-QSAR276>3.0.CO;2-S","article-title":"Quantitative structure-cytotoxicity relationships of sesquiterpene lactones derived from partial charge (Q)-based fractional Accessible Surface Area descriptors (Q_frASAs)","volume":"21","author":"Schmidt","year":"2002","journal-title":"Quant. Struct. Relatsh."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0166-1280(99)00360-7","article-title":"Molecular fields in quantitative structure-permeation relationships: The VolSurf approach","volume":"503","author":"Cruciani","year":"2000","journal-title":"J. Mol. Struct."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S0968-0896(97)00003-5","article-title":"Helenanolide-type sesquiterpene lactones\u2014III. Rates and stereochemistry in the reaction of helenalin and related helenanolides with sulfhydryl containing biomolecules","volume":"5","author":"Schmidt","year":"1997","journal-title":"Bioorganic Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"S\u00fclsen, V.P., and Martino, V.S. (2018). Structure\u2013activity relationships of sesquiterpene lactones. Sesquiterpene Lactones Advances in Their Chemistry and Biological Aspects, Springer International Publishing.","DOI":"10.1007\/978-3-319-78274-4"},{"key":"ref_19","unstructured":"ur Rahman, A. (2006). Structure\u2013activity relationships of sesquiterpene lactones. Studies in Natural Products Chemistry\u2014Bioactive Natural Products (Part M), Elsevier."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Salum, L.B., Andricopulo, A.D., Salum, L.B., and Andricopulo, A.D. (2009). Fragment-based QSAR: Perspectives in drug design. Mol. Divers. Mol. Divers, 13.","DOI":"10.1007\/s11030-009-9112-5"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S0045-6535(02)00839-1","article-title":"Molecular hologram derived quantitative structure\u2013property relationships to predict physico-chemical properties of polychlorinated biphenyls","volume":"51","author":"Wang","year":"2003","journal-title":"Chemosphere"},{"key":"ref_22","first-page":"1","article-title":"HQSAR: A new, highly predictive QSAR technique","volume":"1","author":"Lowis","year":"1997","journal-title":"Tripos Tech. Notes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3846","DOI":"10.3390\/ijms11103846","article-title":"Recent advances in fragment-based QSAR and multi-dimensional QSAR methods","volume":"11","author":"Myint","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"ref_24","unstructured":"Nogueria, M. (2016). The Use of Chemometrics and Chemoinformatic Tools for Identification and Targeted Isolation of Compunds from Asteraceae With Antiprotozoal Activity. [Ph.D. Thesis, University of M\u00fcnster]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1021\/acs.jnatprod.6b00980","article-title":"Antiprotozoal activity-based profiling of a dichloromethane extract from Anthemis nobilis Flowers","volume":"80","author":"Monteleone","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Widom, B. (2002). Statistical Mechanics: A Concise Introduction for Chemists, Cambrige University Press.","DOI":"10.1017\/CBO9780511815836"},{"key":"ref_27","unstructured":"(2018, May 29). Chemical Computing Group, Molecular Operating Environment (MOE). Available online: https:\/\/www.chemcomp.com\/MOE-Pharmacophore_Discovery.htm."},{"key":"ref_28","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven, N.J., Kudin, T.K., and Burant, J.C. (Gaussian 03, 2003). Gaussian 03, Revision C.02."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11623","DOI":"10.1021\/j100096a001","article-title":"Ab Initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields","volume":"98","author":"Stephens","year":"1994","journal-title":"J. Phys. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6081","DOI":"10.1063\/1.460447","article-title":"A complete basis set model chemistry. II. Open-shell systems and the total energies of the first-row atoms","volume":"94","author":"Petersson","year":"1991","journal-title":"J. Chem. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/minf.201000061","article-title":"Best practices for QSAR model development, validation, and exploitation","volume":"29","author":"Tropsha","year":"2010","journal-title":"Mol. Inform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1093-3263(01)00123-1","article-title":"Beware of q2!","volume":"20","author":"Golbraikh","year":"2002","journal-title":"J. Mol. Graph. Model."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.chemolab.2015.04.013","article-title":"On a simple approach for determining applicability domain of QSAR models","volume":"145","author":"Roy","year":"2015","journal-title":"Chemom. Intell. Lab. Syst."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3721\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:31:29Z","timestamp":1760196689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,22]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["ijms19123721"],"URL":"https:\/\/doi.org\/10.3390\/ijms19123721","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,22]]}}}