Journal
BIOORGANIC CHEMISTRY
Volume 125, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105912
Keywords
Trichomonas vaginalis; Anti-T. vaginalis activity; 8-Hydroxyquinoline; Sulfonamides; Ion chelator; Peptidases
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [428538/2018-5]
- Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS) [19/2551-0001972-6, 16/2551-0000244-4]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) Finance [001]
- CNPq [166092/2018-5, 312292/2017-1, 304014/2019-2]
- CAPES [88882.345922/2019-01]
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In this study, a derivative with selective anti-Trichomonas vaginalis activity was reported. Cytotoxicity assays showed selectivity for the parasite, and low toxicity was confirmed in animal models. The mode of action was related to the disruption of Fe-S clusters-dependent enzyme activities in the parasite. Proteomic analysis indicated inhibition of metallopeptidases related to T. vaginalis virulence mechanisms and metabolic pathways.
Trichomoniasis is a neglected parasitic infection, with no oral therapeutic alternatives to overcome the pitfalls of currently approved drugs. In this context, the search for new anti-Trichomonas vaginalis drugs is imperative. Here we report the selective anti-T. vaginalis activity of a substituted 8-hydroxyquinoline-5-sulfonamide derivative. Six different derivatives were evaluated for anti-T. vaginalis. In vitro and in vivo toxicity methods, association with metal ions, and investigation on the mechanism of action were performed with the most active derivative, PH 152. Cytotoxicity assays showed selectivity for the parasite and the low toxicity was confirmed in G. mellonella larvae model. The mode of action is related to iron chelation by disrupting Fe-S clusters-dependent enzyme activities in the parasite. Proteomic analysis indicated inhibition of metallopeptidases related to T. vaginalis virulence mechanisms and metabolic pathways. PH 152 presented selective trichomonacidal activity through multitarget action.
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