{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:09:42Z","timestamp":1792789782410,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Firat University","award":["ECZF.26.02"],"award-info":[{"award-number":["ECZF.26.02"]}],"id":[{"id":"https:\/\/ror.org\/05teb7b63","id-type":"ROR","asserted-by":"crossref"}]},{"award":["ECZF.26.02"],"award-info":[{"award-number":["ECZF.26.02"]}],"id":[{"id":"https:\/\/ror.org\/05teb7b63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Epidermal growth factor receptor (EGFR) has become one of the most important molecular targets for the development of anticancer agents because of its critical role in regulating cell proliferation, differentiation, and survival. In the present study, a novel series of benzimidazole\u2013triazole derivatives were designed by incorporating pharmacophoric features of clinically used EGFR inhibitors, synthesized, characterized, and evaluated for their anticancer potential. Cytotoxicity studies against the A549 lung cancer cell line identified 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(hydroxymethyl)acetamide, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methoxy-N-methylacetamide, and 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide as active derivatives, with compound 5a exhibiting the highest antiproliferative activity (IC50 = 6.014 \u00b1 0.758 \u00b5M), and relatively low cytotoxicity toward NIH\/3T3 cells. Based on these findings, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide was further evaluated against EGFR and its clinically relevant mutant forms, EGFR-L858R and EGFR-L858R\/T790M. Retrospective in silico ADME analysis indicated that the synthesized compounds generally possessed favorable drug-like properties, with 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide showing the most favorable overall drug-likeness profile among the series. Molecular docking and molecular dynamics studies revealed that compound 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide formed stable interactions with key residues in the ATP-binding site of unmutated EGFR, supporting the in vitro inhibition results. Overall, synthesized benzimidazole\u2013triazole derivatives may be promising precursor compounds for the development of novel EGFR inhibitors, particularly against unmutated EGFR cancer cells.<\/jats:p>","DOI":"10.3390\/molecules31193433","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"3433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, In Vitro and In Silico Evaluation of Triazole\u2013Benzimidazole Hybrid Derivatives as Potential Inhibitors of EGFR, EGFR-L858R, and EGFR-L858R\/T790M"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8827-8557","authenticated-orcid":false,"given":"Harun","family":"Uslu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, F\u0131rat University, 23119 Elaz\u0131\u011f, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arzu","family":"H\u0131d\u0131r","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"},{"name":"Department of Pharmaceutical Chemistry, The Institute of Graduate Education, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"Yumu\u015fak","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0499-436X","authenticated-orcid":false,"given":"Derya","family":"Osmaniye","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"},{"name":"Central Research Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-7313","authenticated-orcid":false,"given":"B\u00fcnyamin","family":"G\u00f6kta\u015f","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, F\u0131rat University, 23119 Elaz\u0131\u011f, T\u00fcrkiye"},{"name":"Department of Pharmaceutical Chemistry, The Institute of Graduate Education, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8815-153X","authenticated-orcid":false,"given":"Yusuf","family":"\u00d6zkay","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"},{"name":"Central Research Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2252-0923","authenticated-orcid":false,"given":"Zafer As\u0131m","family":"Kaplanc\u0131kl\u0131","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"},{"name":"Central Research Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"ref_1","first-page":"e70090","article-title":"Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J. 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