{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:01:19Z","timestamp":1791601279332,"version":"4.3.4"},"reference-count":77,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Recep Tayyip Erdogan University Development Foundation","award":["02025011020815"],"award-info":[{"award-number":["02025011020815"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Cancer is among the leading causes of mortality worldwide. In 2022 alone, the global cancer death toll stood at 9.74 million. Projections indicate that this figure will rise to 10.4 million by 2025. Methods: A new series of benzimidazolone-bridged hybrid compounds containing thiophene, furan, oxadiazole, piperazine, and coumarin moieties was synthesized and structurally characterized by 1H-NMR, 13C-NMR (APT), and elemental analysis. Their cytotoxic effects were evaluated by MTT assay against human lung (A549), human breast (MCF-7), and human cervical (HeLa) cancer cell lines, and the non-cancerous HEK293 cell line after 48 h exposure over a concentration range of 0.5\u2013250 \u00b5M. IC50 values were determined, and Selectivity Indexes (SI) were calculated using HEK293 as the reference normal cell line. Molecular docking studies were carried out using the Glide XP protocol against VEGFR2 (PDB ID: 4ASD) and CDK4\u2013Cyclin D3 (PDB ID: 7SJ3), with sorafenib and abemaciclib as reference inhibitors. Results: The results of anticancer activity were compared with doxorubicin (IC50 \u00b1 SD (\u00b5M)\/SI: 4.3 \u00b1 0.2\/1.20 for A549, 6.4 \u00b1 0.37\/0.77 for MCF-7, 3.4 \u00b1 0.19\/1.54 for HeLa), a drug used for cancer chemotherapy. The structures of the newly synthesized hybrid compounds were identified by 1H-NMR, 13C-NMR (APT), and elemental analysis data. These hybrid compounds represent a promising class of anticancer agents. Several compounds demonstrated marked and concentration-dependent cytotoxicity across all cancer cell lines, with HeLa cells showing the highest overall sensitivity. The introduction of an oxadiazole ring (compound 7) and coumarin substituents (compounds 12b\u201312d) markedly improved anticancer activity and selectivity, yielding low-micromolar IC50 values in HeLa cells (10.6\u201313.6 \u00b5M) and high Selectivity Indexes (SI = 2.0\u20133.63). Compound 6 also exhibited balanced potency across A549, MCF-7, and HeLa cells (IC50 = 28.3\u201331.2 \u00b5M) with SI values \u2265 2.0. Compound 9 showed strong cytotoxicity across all cancer cell lines; its moderate SI values indicate lower discrimination between malignant and non-malignant cells. Taken together, these findings identified compounds 7, 12b\u201312d, 6, and 12c as the most promising benzimidazolone-based candidates, displaying both potent cytotoxicity and favorable selectivity over non-malignant HEK293 cells. Conclusions: Among the synthesized molecules, the oxadiazole derivative (7) and the coumarin-based hybrids (12b\u201312d) exhibited the strongest combination of cytotoxic activity and selectivity, reflected by their low IC50 values and high SI ratios. Notably, compound 12c combined strong biological activity with the highest predicted VEGFR2 affinity in the series, highlighting it as a particularly promising scaffold. While compound 9 exhibited excellent docking scores toward both VEGFR2 and CDK4, its lower selectivity suggests a need for further structural refinement. Overall, the biological and computational findings converge to identify these benzimidazolone hybrids as credible lead candidates for future anticancer optimization.<\/jats:p>","DOI":"10.3390\/ph18121899","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T12:13:03Z","timestamp":1765973583000},"page":"1899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evaluation of Antiproliferative Activity and Molecular Modeling Studies of Some Novel Benzimidazolone-Bridged Hybrid Compounds"],"prefix":"10.3390","volume":"18","author":[{"given":"Okan","family":"G\u00fcven","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University, 53100 Rize, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3408-8202","authenticated-orcid":false,"given":"Emre","family":"Mente\u015fe","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University, 53100 Rize, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-3566","authenticated-orcid":false,"given":"Fatih","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Vocational School of Technical Sciences, Department of Chemistry and Chemical Process Technology, Recep Tayyip Erdogan University, 53100 Rize, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3295-3538","authenticated-orcid":false,"given":"Adem","family":"G\u00fcner","sequence":"additional","affiliation":[{"name":"Department of Occupational Health and Safety, Faculty of Health Sciences, Sinop University, 57000 Sinop, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-9093","authenticated-orcid":false,"given":"Mustafa","family":"Emirik","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University, 53100 Rize, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nedime","family":"\u00c7al\u0131\u015fkan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University, 53100 Rize, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1002\/ijc.33417","article-title":"Comprehensive Trends in Incidence, Treatment, Survival and Mortality of First Primary Invasive Breast Cancer Stratified by Age, Stage and Receptor Subtype in the Netherlands between 1989 and 2017","volume":"148","author":"Kramer","year":"2021","journal-title":"Int. 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