Development of 3D-QSAR and pharmacophoric models to design new anti-<i>Trypanosoma cruzi</i> agents based on 2-aryloxynaphthoquinone scaffold

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dc.contributor.authorPaulino, M.
dc.contributor.authorEspinosa-Bustos, C.
dc.contributor.authorBertrand, J.
dc.contributor.authorCabezas, D.
dc.contributor.authorMella, J.
dc.contributor.authorDavila, B.
dc.contributor.authorCerecetto, H.
dc.contributor.authorBallesteros-Casallas, A.
dc.contributor.authorSalas, C. O.
dc.date.accessioned2025-01-20T21:02:38Z
dc.date.available2025-01-20T21:02:38Z
dc.date.issued2022
dc.description.abstractIn this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on T. cruzi epimastigotes of five new compounds (33a-e). According to CoMFA model, three out of five compounds showed pIC(50) values within one logarithmic unit of deviation. The two compounds that did not fit the predictions were those with high lipophilicity, which agreed with the SAR and pharmacophore models. Docking and molecular dynamic studies were performed on T. cruzi trypanothione reductase, in a proposed binding site for this type of naphthoquinone. Interestingly, 33a-e showed the same interaction pattern as a naphthoquinone inhibitor (2). Finally, predicted drug-likeness properties indicated that 33a-e have optimal oral bioavailability. Thus, this study provides new in silico models for obtaining novel trypanosomicidal compounds.
dc.fuente.origenWOS
dc.identifier.doi10.1080/1062936X.2022.2120069
dc.identifier.eissn1029-046X
dc.identifier.issn1062-936X
dc.identifier.urihttps://doi.org/10.1080/1062936X.2022.2120069
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93064
dc.identifier.wosidWOS:000854031700003
dc.issue.numero9
dc.language.isoen
dc.pagina.final728
dc.pagina.inicio701
dc.revistaSar and qsar in environmental research
dc.rightsacceso restringido
dc.subjectTrypanosoma cruzi
dc.subjectaryloxy-quinones
dc.subjecttrypanosomicidal activity
dc.subjectstructure-activity relationship
dc.subject3D-QSAR
dc.subjectpharmacophore analysis
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleDevelopment of 3D-QSAR and pharmacophoric models to design new anti-<i>Trypanosoma cruzi</i> agents based on 2-aryloxynaphthoquinone scaffold
dc.typeartículo
dc.volumen33
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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