{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:39:36Z","timestamp":1765805976747,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T00:00:00Z","timestamp":1576800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005672","name":"Funda\u00e7\u00e3o de Apoio ao Desenvolvimento do Ensino, Ci\u00eancia e Tecnologia do Estado de Mato Grosso do Sul","doi-asserted-by":"publisher","award":["23\/200.137\/2010"],"award-info":[{"award-number":["23\/200.137\/2010"]}],"id":[{"id":"10.13039\/501100005672","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In the search for new compounds with antileishmanial activity, we synthesized a triazole hybrid analogue of the neolignans grandisin and machilin G (LASQUIM 25), which was previously found highly active against both promastigotes and intracellular amastigote forms of Leishmania amazonensis. In this work, we investigated the leishmanicidal effects of LASQUIM 25 to identify the mechanisms involved in the cell death of L. amazonensis promastigotes. Transmission electron microscopy (TEM) analysis showed marked effects of LASQUIM 25 (IC50 = 7.2 \u00b5M) on the morphology of promastigote forms, notably on mitochondria. The direct action of the triazole derivative on the parasite was noticed over time from 2 h to 48 h, and cells displayed several ultrastructural alterations characteristic of apoptotic cells. Also, flow cytometric analysis (FACS) after TMRE staining detected changes in mitochondrial membrane potential after LASQUIM 25 treatment (64.83% labeling versus 83.38% labeling in nontreated cells). On the other hand, FACS after PI staining in 24 h-treatment showed a slight alteration in the integrity of the cell membrane, a necrotic event (16.76% necrotic cells versus 3.19% staining in live parasites). An abnormal secretion of lipids was observed, suggesting an exocytic activity. Another striking finding was the presence of autophagy-related lysosome-like vacuoles, suggesting an autophagic cell death that may arise as consequence of mitochondrial stress. Taken together, these results suggest that LASQUIM 25 leishmanicidal mechanisms involve some degree of mitochondrial dysregulation, already evidenced by the treatment with the IC50 of this compound. This effect may be due to the presence of a methylenedioxy group originated from machilin G, whose toxicity has been associated with the capacity to generate electrophilic intermediates.<\/jats:p>","DOI":"10.3390\/molecules25010037","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T03:23:12Z","timestamp":1577071392000},"page":"37","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Triazole Hybrid of Neolignans as a Potential Antileishmanial Agent by Triggering Mitochondrial Dysfunction"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-781X","authenticated-orcid":false,"given":"Carla","family":"Cardozo Pinto de Arruda","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Parasitologia Humana, Instituto de Bioci\u00eancias, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, Mato Grosso do Sul, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daiana","family":"de Jesus Hardoim","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunomodula\u00e7\u00e3o e Protozoologia (LIMP), Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), 21040-360 Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmin","family":"Silva Rizk","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunomodula\u00e7\u00e3o e Protozoologia (LIMP), Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), 21040-360 Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celeste","family":"da Silva Freitas de Souza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunomodula\u00e7\u00e3o e Protozoologia (LIMP), Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), 21040-360 Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00e2nia","family":"Zaverucha do Valle","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunomodula\u00e7\u00e3o e Protozoologia (LIMP), Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), 21040-360 Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Bento Carvalho","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese e Qu\u00edmica Medicinal (LASQUIM), Faculdade de Ci\u00eancias Farmac\u00eauticas, Alimentos e Nutri\u00e7\u00e3o, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, Mato Grosso do Sul, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi","family":"Nosomi Taniwaki","sequence":"additional","affiliation":[{"name":"N\u00facleo de Microscopia Eletr\u00f4nica, Instituto Adolfo Lutz, 01246-000 S\u00e3o Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano Cesar","family":"de Morais Baroni","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese e Qu\u00edmica Medicinal (LASQUIM), Faculdade de Ci\u00eancias Farmac\u00eauticas, Alimentos e Nutri\u00e7\u00e3o, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, Mato Grosso do Sul, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-3765","authenticated-orcid":false,"given":"K\u00e1tia","family":"da Silva Calabrese","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunomodula\u00e7\u00e3o e Protozoologia (LIMP), Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), 21040-360 Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2019, February 22). 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