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In search of safer and more effective alternatives, bithiophene derivatives have emerged as promising scaffolds. In this study, we evaluated the antileishmanial potential of BT-Ac, a bithiophene previously shown to exert antitrypanosomal activity. BT-Ac displayed selective antiproliferative activity with IC50 for 28.9 and 50 \u03bcM against promastigotes and amastigotes of Leishmania amazonensis at nontoxic concentrations for host cells, achieving a selectivity index of 4.69 against intracellular amastigotes. Electron microscopy revealed early morphological damage in promastigotes, including unprecedented changes at the plasma membrane and cytoskeletal interface, mitochondrial swelling, lipid body accumulation, and autophagic vacuole formation. Three-dimensional reconstructions further validated these findings, confirming that the ultrastructural alterations were intrinsic to BT-Ac treatment rather than technical artifacts. Biochemical analyses demonstrated reactive oxygen and nitrogen species overproduction, lipid peroxidation, and ATP fluctuations, indicating oxidative stress as a central mechanism. These events culminated in apoptosis-like and autophagic death in promastigotes, while amastigote death was primarily mediated by macrophage activation, evidenced by nitric oxide release. Together, our findings identify BT-Ac as a selective leishmanicidal agent that disrupts parasite homeostasis through oxidative damage, highlighting its potential as a lead compound for therapeutic strategies against leishmaniasis.<\/jats:p>","DOI":"10.1021\/cbmi.6c00109","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T21:21:31Z","timestamp":1782422491000},"page":"2102-2118","source":"Crossref","is-referenced-by-count":0,"title":["Cell Death and Unprecedent\nCytoskeletal Changes in\n                    <i>Leishmania amazonensis<\/i>\n                    Parasites Evidenced by 3D\nReconstruction"],"prefix":"10.1021","volume":"4","author":[{"given":"Rayanne Regina Beltrame","family":"Machado","sequence":"first","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4156-3662","authenticated-orcid":true,"given":"Amanda Beatriz Kawano","family":"Bakoshi","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta\u0302nia","family":"Ueda-Nakamura","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9303-0804","authenticated-orcid":true,"given":"Sueli de Oliveira Silva","family":"Lautenschlager","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Helena","family":"Sarragiotto","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-0048","authenticated-orcid":true,"given":"Danielle","family":"Lazarin-Bido\u0301ia","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9911-7369","authenticated-orcid":true,"given":"Celso Vataru","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Universidade Estadual de Maringa\u0301 (UEM) , , , ,","place":["Maringa\u0301, Parana\u0301, Brazil, 87020-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"issue":"2","key":"2026092808070468400_cit1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s40475-021-00232-7","article-title":"A Review of Leishmaniasis:\nCurrent Knowledge and Future Directions","volume":"8","author":"Mann","year":"2021","journal-title":"Curr.\nTrop. 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