{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:18:41Z","timestamp":1788470321927,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003069","name":"Instituto Polit\u00e9cnico Nacional","doi-asserted-by":"crossref","award":["20241803"],"award-info":[{"award-number":["20241803"]}],"id":[{"id":"10.13039\/501100003069","id-type":"DOI","asserted-by":"crossref"}]},{"award":["20241803"],"award-info":[{"award-number":["20241803"]}],"id":[{"id":"https:\/\/ror.org\/059sp8j34","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Secretar\u00eda de Investigaci\u00f3n y Posgrado","award":["20254069"],"award-info":[{"award-number":["20254069"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Humanidades, Ciencias y Tecnolog\u00edas","doi-asserted-by":"crossref","award":["832980"],"award-info":[{"award-number":["832980"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"crossref"}]},{"award":["832980"],"award-info":[{"award-number":["832980"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and imidazole scaffolds, leading to the rational design of novel hybrid molecules. Molecular docking against thioredoxin reductase (PDB ID: 4CBQ), a key enzyme in the redox metabolism of Leishmania mexicana, showed improved binding affinity compared to miltefosine, with compound 3f showing the most favourable interaction profile. Among the synthesized series 3a\u2013f, compound 3f (4-NO2Ph) exhibited the most favourable predicted binding parameters within the series (\u2206G = \u221216.08, Ki = 0.0019 nM). Biological evaluation was performed against L. mexicana promastigotes as an early-stage phenotypic screening model to identify active compounds with potential relevance during the initial infective phase, and a markedly improved in vitro inhibitory effect (IC50 = 22.41 \u00b5M) compared to miltefosine (IC50 = 132.42 \u00b5M), representing a six-fold increase in molar potency. Furthermore, hybrid thiazolyl\u2013imidazole systems (series 3) consistently outperformed single-core analogues, likely due to enhanced molecular planarity and lipophilicity provided by the imine linkage. Cytotoxicity assays in Vero cells revealed a high safety margin for the lead compounds, with compound 3f achieving a Selectivity Index (SI) of around 89, significantly outperforming the reference drug. Acute toxicity studies (LD50) in murine models further confirmed the safety profile, with values exceeding 2000 mg\/kg for the most active derivatives. These findings identify thiazolyl\u2013imidazole hybrids as promising early-stage scaffolds for antileishmanial drug discovery, particularly for early infection\/prophylactic screening.<\/jats:p>","DOI":"10.3390\/pathogens15050544","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:07:26Z","timestamp":1779206846000},"page":"544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Thiazolylimidazole Hybrids as Promising Antileishmanial Agents: Rational Design and Biological Evaluation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4811-2668","authenticated-orcid":false,"given":"Cristoper","family":"Ram\u00edrez-Sandoval","sequence":"first","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n 7 y 10, Departamento de Qu\u00edmica Org\u00e1nica, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Colonia Santo Tom\u00e1s, Mexico City C.P. 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5237-6171","authenticated-orcid":false,"given":"Mar\u00eda Elena","family":"Campos-Aldrete","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n 7 y 10, Departamento de Qu\u00edmica Org\u00e1nica, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Colonia Santo Tom\u00e1s, Mexico City C.P. 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Estela","family":"Mel\u00e9ndez-Camargo","sequence":"additional","affiliation":[{"name":"Laboratorio de Toxicolog\u00eda de Productos Naturales, Departamento de Farmacia, Escuela Nacional de Ciencias Biol\u00f3gicas, Campus Zacatenco, Instituto Polit\u00e9cnico Nacional, Av. Wilfrido Massieu s\/n Col. Zacatenco, Mexico City C.P. 07738, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025). Global Report on Neglected Tropical Diseases 2025, WHO."},{"key":"ref_2","unstructured":"World Health Organization (2020). Ending the Neglect to Attain the SDGs: A Road Map for Neglected Tropical Diseases 2021\u20132030, WHO."},{"key":"ref_3","unstructured":"World Health Organization (2024). Leishmaniasis: Key Facts, WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00281-020-00788-y","article-title":"Leishmaniasis immunopathology: Impact on design and use of vaccines, diagnostics and drugs","volume":"42","author":"Kaye","year":"2020","journal-title":"Semin. 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