Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/106702
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dc.contributor.authorMorais, Thiago R.-
dc.contributor.authorConserva, Geanne A. Alves-
dc.contributor.authorVarela, Marina T.-
dc.contributor.authorCosta-Silva, Thais A.-
dc.contributor.authorThevenard, Fernanda-
dc.contributor.authorPonci, Vitor-
dc.contributor.authorFortuna, Ana-
dc.contributor.authorFalcão, Amílcar C.-
dc.contributor.authorTempone, Andre G.-
dc.contributor.authorFernandes, João Paulo S.-
dc.contributor.authorLago, João Henrique G.-
dc.date.accessioned2023-04-18T07:54:52Z-
dc.date.available2023-04-18T07:54:52Z-
dc.date.issued2020-03-25-
dc.identifier.issn2045-2322pt
dc.identifier.urihttps://hdl.handle.net/10316/106702-
dc.description.abstractNeolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 μM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 μM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 μM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 μM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 μM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.pt
dc.language.isoengpt
dc.publisherSpringer Naturept
dc.relationSão Paulo Research Foundation - FAPESP (grants 2018/07885-1, 2018/10279-6, 2016/20633-6, and 2016/25028-3), CAPES (financial code 001), and National Council for Scientific and Technological Development - CNPq (455411/2014-0)pt
dc.relationPDSE grant n. 88881.134147/2016-01.pt
dc.relationCNPq scientific award grantspt
dc.rightsopenAccesspt
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt
dc.subject.meshAnimalspt
dc.subject.meshAntiparasitic Agentspt
dc.subject.meshBiological Productspt
dc.subject.meshChagas Diseasept
dc.subject.meshDrug Discoverypt
dc.subject.meshLauraceaept
dc.subject.meshLignanspt
dc.subject.meshOxidative Stresspt
dc.subject.meshPhytotherapypt
dc.subject.meshPlant Leavespt
dc.subject.meshReactive Oxygen Speciespt
dc.subject.meshStructure-Activity Relationshippt
dc.subject.meshTrypanocidal Agentspt
dc.subject.meshTrypanosoma cruzipt
dc.titleImproving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin Apt
dc.typearticle-
degois.publication.firstPage5467pt
degois.publication.issue1pt
degois.publication.titleScientific Reportspt
dc.peerreviewedyespt
dc.identifier.doi10.1038/s41598-020-62352-wpt
degois.publication.volume10pt
dc.date.embargo2020-03-25*
uc.date.periodoEmbargo0pt
item.cerifentitytypePublications-
item.languageiso639-1en-
item.fulltextCom Texto completo-
item.grantfulltextopen-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypearticle-
crisitem.author.orcid0000-0002-3854-6549-
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CIBIT - Artigos em Revistas Internacionais
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