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We report the development of two 3D-QSAR models based on comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and a 2D-QSAR model, using a database of 349 compounds with activity against the P. falciparum 3D7 strain. The models were validated internally and externally, complying with all metrics (q2 &gt; 0.5, r2test &gt; 0.6, r2m &gt; 0.5, etc.). The final models have shown the following statistical values: r2test CoMFA = 0.878, r2test CoMSIA = 0.876, and r2test 2D-QSAR = 0.845. The models were experimentally tested through the synthesis and biological evaluation of ten quinoline derivatives against P. falciparum 3D7. The CoMSIA and 2D-QSAR models outperformed CoMFA in terms of better predictive capacity (MAE = 0.7006, 0.4849, and 1.2803, respectively). The physicochemical and pharmacokinetic properties of three selected quinoline derivatives were similar to chloroquine. Finally, the compounds showed low cytotoxicity (IC50 &gt; 100 \u00b5M) on human HepG2 cells. These results suggest that the QSAR models accurately predict the toxicological profile, correlating well with experimental in vivo data.<\/jats:p>","DOI":"10.3390\/ph17070889","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T14:40:50Z","timestamp":1720449650000},"page":"889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["2D\/3D-QSAR Model Development Based on a Quinoline Pharmacophoric Core for the Inhibition of Plasmodium falciparum: An In Silico Approach with Experimental Validation"],"prefix":"10.3390","volume":"17","author":[{"given":"Marcos","family":"Lorca","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica y Bioqu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Av. Gran Breta\u00f1a 1111, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, C1113AAB Ciudad Aut\u00f3noma de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"P\u00e9rez-Benavente","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-881X","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Bautista","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Acosta","sequence":"additional","affiliation":[{"name":"Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Qu\u00edmicas, Vi\u00f1a del Mar 2531015, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0830-8507","authenticated-orcid":false,"given":"Cesar","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad T\u00e9cnica Federico Santa Mar\u00eda, Av. Espa\u00f1a 1680, Valpara\u00edso 2390123, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1925-3167","authenticated-orcid":false,"given":"Gianfranco","family":"Sabadini","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica y Bioqu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Av. Gran Breta\u00f1a 1111, Valpara\u00edso 2360102, Chile"}],"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 y Bioqu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Av. Gran Breta\u00f1a 1111, Valpara\u00edso 2360102, Chile"},{"name":"Centro de Investigacion, Desarrollo e Innovacion 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\/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, C1113AAB Ciudad Aut\u00f3noma de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-5180","authenticated-orcid":false,"given":"Marco","family":"Mellado","sequence":"additional","affiliation":[{"name":"Facultad de Medicina y Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"key":"ref_1","unstructured":"(2023, October 27). 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