Trifluoromethyl-Benzimidazole-Hydrazone Derivatives as Promising Selective Anticancer Agents: Synthesis, Cytotoxicity, and Molecular Docking Insights
PHARMACEUTICALS, cilt.19, sa.8, ss.1-12, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 19 Sayı: 8
- Basım Tarihi: 2026
- Doi Numarası: 10.3390/ph19081270
- Dergi Adı: PHARMACEUTICALS
- Derginin Tarandığı İndeksler: Academic Search Ultimate (EBSCO), Biomedical Reference Collection: Corporate Edition (EBSCO), Scopus, Science Citation Index Expanded (SCI-EXPANDED), EMBASE, Directory of Open Access Journals
- Sayfa Sayıları: ss.1-12
- Recep Tayyip Erdoğan Üniversitesi Adresli: Evet
Özet
Background/Objectives: Benzimidazole and hydrazone scaffolds are widely investigated in anticancer drug discovery because of their structural versatility and capacity to interact with multiple cancer-related targets. This study aimed to synthesize a series of trifluoro-methyl-substituted benzimidazole-hydrazone derivatives, evaluate their antiproliferative activity and cancer-cell selectivity, and explore their potential interactions with breast can-cer-associated molecular targets. Methods: A series of benzimidazole-hydrazone deriva-tives were prepared through a four-step synthetic route using both conventional and mi-crowave-assisted procedures. The structures of the synthesized compounds were charac-terized using spectroscopic and analytical methods. Antiproliferative activity was evalu-ated in estrogen receptor-positive MCF-7 human breast cancer cells using the MTT assay after 48 h of exposure. Selected active compounds were additionally tested against non-tumorigenic hTERT cells to determine their selectivity indices. In silico analyses were per-formed against estrogen receptor alpha in antagonist and selective estrogen receptor de-grader conformations, bromodomain-containing protein 4, and the mTOR kinase domain. Results: Microwave irradiation substantially reduced reaction times from 12–24 h to 4–6 min and increased isolated yields by 7–24 percentage points compared with conventional conditions. Compounds 4, 7, 9, and 11 reduced MCF-7 cell viability below 50% at 20 μM. Compound 7 showed the highest antiproliferative activity, with an IC50 value of 7.5 ± 0.8 μM, and the greatest selectivity toward MCF-7 cells over hTERT cells, with a selectivity index of 12.66. Molecular docking, MD simulation, and MM/GBSA calculations predicted that compound 7 would effectively bind to the investigated targets, particularly estrogen receptor alpha, as well as the BRD4 and mTOR kinase domains. Conclusions: Compound 7 represents a selective, mid-micromolar benzimidazole-hydrazone lead against MCF-7 breast cancer cells. Its predicted molecular interactions warrant further target-based, mechanistic, pharmacokinetic, and in vivo evaluation