{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:07:00Z","timestamp":1789614420181,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo (ANID) of Chile","doi-asserted-by":"publisher","award":["SA77210078"],"award-info":[{"award-number":["SA77210078"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo (ANID) of Chile","doi-asserted-by":"publisher","award":["N\u00b01240289"],"award-info":[{"award-number":["N\u00b01240289"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Puente de Investigaci\u00f3n UCEN Convocatoria A\u00f1o 2025","award":["CIPPTE202505"],"award-info":[{"award-number":["CIPPTE202505"]}]},{"name":"Brazilian Funding Agencies from the S\u00e3o Paulo State Research Support Foundation","award":["#2012\/24105-3"],"award-info":[{"award-number":["#2012\/24105-3"]}]},{"name":"Brazilian Funding Agencies from the S\u00e3o Paulo State Research Support Foundation","award":["#2020\/13562-0"],"award-info":[{"award-number":["#2020\/13562-0"]}]},{"name":"Brazilian Funding Agencies from the S\u00e3o Paulo State Research Support Foundation","award":["#2024\/05757-7"],"award-info":[{"award-number":["#2024\/05757-7"]}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"crossref","award":["#443816\/2014-0"],"award-info":[{"award-number":["#443816\/2014-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel","doi-asserted-by":"crossref","award":["#001"],"award-info":[{"award-number":["#001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Leishmania amazonensis, one of the causative agents of cutaneous leishmaniasis, is responsible for a neglected tropical disease affecting nearly one million individuals worldwide. Although clinical treatments are available, their effectiveness is often compromised by high toxicity and limited selectivity. Methods: From a database, 64 chalcone derivatives were studied using Comparative Molecular Similarity Indices Analysis (CoMSIA) and Hansch analysis (2D-QSAR) to construct predictive computational models. Internal and external validation criteria were applied to identify structural determinants associated with antileishmanial activity. Based on these insights, twelve novel quinoline\u2013chalcone hybrids were designed, synthesized, and biologically evaluated against L. amazonensis. Results: The most robust CoMSIA model combined steric and hydrogen-bond acceptor fields (CoMSIA-SA), while Hansch analysis highlighted electronic descriptors\u2014specifically LUMO energy and the global electrophilicity index\u2014as critical for parasite growth inhibition. Guided by these computational findings, a new series of 12 hybrid quinoline\u2013chalcone derivatives (E001\u2013E012) was synthesized through a two-step procedure, achieving overall yields of 43\u201371%. Biological assays demonstrated that four compounds displayed inhibitory activity comparable to amphotericin B. Furthermore, physicochemical profiling and in silico pharmacokinetic predictions for the most active compounds (E003, E005, E006, and E011) indicated favorable biocompatibility and drug-like properties. Conclusions: These results underscore the value of an integrative computational\u2013experimental approach in the rational design of next-generation L. amazonensis inhibitors, reinforcing chalcone-based scaffolds as promising pharmacophoric frameworks for antileishmanial drug discovery.<\/jats:p>","DOI":"10.3390\/ph18101567","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T13:07:22Z","timestamp":1760706442000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design of Hybrid Quinoline\u2013Chalcone Compounds Against Leishmania amazonensis Based on Computational Techniques: 2D- and 3D-QSAR with Experimental Validation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3729-0980","authenticated-orcid":false,"given":"Marcos","family":"Lorca","sequence":"first","affiliation":[{"name":"Facultad de Ciencias de la Vida, Carrera de Qu\u00edmica y Farmacia, Universidad Vi\u00f1a del Mar, Vi\u00f1a del Mar 2572002, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2501-7119","authenticated-orcid":false,"given":"Gisela C.","family":"Muscia","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Qu\u00edmicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Jun\u00edn 956, Ciudad Aut\u00f3noma de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-8461","authenticated-orcid":false,"given":"Jaime","family":"Mella","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Av. Gran Breta\u00f1a 1111, Valpara\u00edso 2360102, Chile"},{"name":"Centro de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n de Productos Bioactivos (CInBIO), Universidad de Valparaiso, Av. Gran Breta\u00f1a 1111, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8944-9679","authenticated-orcid":false,"given":"Luciana","family":"Thomaz","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Department of Parasitology, University of S\u00e3o Paulo, Av. Prof. Lineu Prestes 1374, S\u00e3o Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8472-7500","authenticated-orcid":false,"given":"Jenicer K.","family":"Yokoyama-Yasunaka","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Department of Parasitology, University of S\u00e3o Paulo, Av. Prof. Lineu Prestes 1374, S\u00e3o Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7128-8174","authenticated-orcid":false,"given":"Daniel","family":"Moraga","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda, Departamento de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Tarapac\u00e1, Arica 1000000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4935-876X","authenticated-orcid":false,"given":"Yeray A.","family":"Rodriguez-Nu\u00f1ez","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis y Reactividad de Compuestos Org\u00e1nicos, Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andr\u00e9s Bello, Santiago 8370146, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3978-8638","authenticated-orcid":false,"given":"Silvia E.","family":"As\u00eds","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Qu\u00edmicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Jun\u00edn 956, Ciudad Aut\u00f3noma de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6536-4647","authenticated-orcid":false,"given":"Mauro","family":"Cortez","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Department of Parasitology, University of S\u00e3o Paulo, Av. 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