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Leishmaniasis treatment remains a challenge because it relies on drugsknown for their high toxicity and limited efficacy, making itimperative to identify new molecules that offer greater effectiveness and safety. This study sought to explore the impact of seven synthetic guanidine derivatives (LQOF-G1, LQOF-G2, LQOF-G6, LQOF-G7, LQOF-G32, LQOF-G35 and LQOF-G36) onthe parasite Leishmania (Viannia) braziliensis and in vitro macrophage infection by this parasite, as well as cytotoxic approaches in vitro models of mammalian host cells and tissues. The synthesized compounds showed purity \u2265 99.65% and effectively inhibited parasite growth. LQOF-G1 proved the most potent, yielding the best half-maximal inhibitory concentration (IC50) values against promastigotes (4.62 \u03bcmol\/L), axenic amastigotes (4.27 \u03bcmol\/L), and intracellular amastigotes (3.65 \u03bcmol\/L). Notably, the antileishmanial activity of LQOF-G1, LQOF-G2, and LQOF-G6 was related to immunomodulatory effects, evidenced by alterations in TNF-\u03b1, IL-12, IL-10, nitric oxide (NO), and reactive oxygen species (ROS) levels in the supernatant of culture macrophages infected with L. (V.) braziliensis and coincubated with these compounds. LQOF-G2 and LQOF-G36 compounds exhibited vasodilator and spasmolytic effects at higher concentrations (\u2265100 \u03bcmol\/L). Generally, LQOF-G1, LQOF-G2, and LQOF-G32 compounds were found to be nontoxic to assessed organs and cells. No toxic effects were observed in human cell lines, such as HEK-293, CaCo-2 and A549, at concentrations \u2265 500 \u03bcmol\/L. Collectively, data have shown unequivocal evidence of the effectiveness of these compounds against L. (V.) braziliensis parasite, one of the causative agents of Tegumentary Leishmaniasis and Mucocutaneous Leishmaniasis in America.<\/jats:p>","DOI":"10.3390\/biom14010026","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T20:44:15Z","timestamp":1703450655000},"page":"26","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Evidence of Guanidines Potential against Leishmania (Viannia) braziliensis: Exploring In Vitro Effectiveness, Toxicities and of Innate Immunity Response Effects"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-6176","authenticated-orcid":false,"given":"Luana Ribeiro","family":"dos Anjos","sequence":"first","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Maria Rodrigues","family":"de Souza","sequence":"additional","affiliation":[{"name":"Infectious Disease Laboratory\u2014LADIC, Federal University of Parna\u00edba Delta\u2014UFDPar, Campus Ministro Reis Velloso, S\u00e3o Benedito, Parna\u00edba 64202-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmim Alves Aires","family":"Machado","sequence":"additional","affiliation":[{"name":"Infectious Disease Laboratory\u2014LADIC, Federal University of Parna\u00edba Delta\u2014UFDPar, Campus Ministro Reis Velloso, S\u00e3o Benedito, Parna\u00edba 64202-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor Moreira","family":"Partite","sequence":"additional","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6693-4530","authenticated-orcid":false,"given":"Mohammed","family":"Aufy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Josef Holaubek Platz 2, UZAII (2D 259), 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4448-1398","authenticated-orcid":false,"given":"Geovane","family":"Dias Lopes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Molecular e Doen\u00e7as End\u00eamicas, Funda\u00e7\u00e3o Oswaldo Cruz, Instituto Oswaldo Cruz, 4365, Manguinhos, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0910-4573","authenticated-orcid":false,"given":"Christian","family":"Studenik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Josef Holaubek Platz 2, UZAII (2D 259), 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Roberto","family":"Alves","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Molecular e Doen\u00e7as End\u00eamicas, Funda\u00e7\u00e3o Oswaldo Cruz, Instituto Oswaldo Cruz, 4365, Manguinhos, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6333-9461","authenticated-orcid":false,"given":"Gert","family":"Lubec","sequence":"additional","affiliation":[{"name":"Department of Neuroproteomics, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-8554","authenticated-orcid":false,"given":"Eduardo Rene Perez","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-3529","authenticated-orcid":false,"given":"Klinger Antonio da Franca","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Infectious Disease Laboratory\u2014LADIC, Federal University of Parna\u00edba Delta\u2014UFDPar, Campus Ministro Reis Velloso, S\u00e3o Benedito, Parna\u00edba 64202-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rocha, R., Pereira, A., and Maia, C. 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