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(CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","award":["88887.369957\/2019-00"],"award-info":[{"award-number":["88887.369957\/2019-00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC50s = 5\u201316 \u03bcM). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FICindex~1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria.<\/jats:p>","DOI":"10.3390\/ph15070814","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T01:40:36Z","timestamp":1656639636000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis, Structure\u2013Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium\u00a0falciparum Inhibitors"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9631-3172","authenticated-orcid":false,"given":"Camila S.","family":"Barbosa","sequence":"first","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anees","family":"Ahmad","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Chemistry, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah El Chamy","family":"Maluf","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3279-6894","authenticated-orcid":false,"given":"Igor M. R.","family":"Moura","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3278-6688","authenticated-orcid":false,"given":"Guilherme E.","family":"Souza","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna A. H.","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04023-062, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto R. Moraes","family":"Barros","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04023-062, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-6831","authenticated-orcid":false,"given":"Marcos L.","family":"Gazarini","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Federal University of S\u00e3o Paulo, Rua Silva Jardim, 136, Santos 11015-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C. C.","family":"Aguiar","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"},{"name":"Department of Biosciences, Federal University of S\u00e3o Paulo, Rua Silva Jardim, 136, Santos 11015-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2203-1556","authenticated-orcid":false,"given":"Antonio C. B.","family":"Burtoloso","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Chemistry, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael V. C.","family":"Guido","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, Av. Jo\u00e3o Dagnone, 1100, Santa Angelina, S\u00e3o Carlos 13563-120, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","unstructured":"(2021). World Health Organization World Malaria Report 2021, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/INF.0000000000001887","article-title":"Malaria-Update on Antimalarial Resistance and Treatment Approaches","volume":"37","author":"Yeung","year":"2018","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1039\/b908984e","article-title":"Structure, Biosynthetic Relationships and Chemical Synthesis of the Icetexane Diterpenoids","volume":"26","author":"Simmons","year":"2009","journal-title":"Nat. Prod. 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