Design, synthesis, DFT characterization, biological evaluation, and molecular modeling studies of carbazole-based 1,2,4-triazol-3-one derivatives as potential EGFR-targeted anticancer agents
JOURNAL OF MOLECULAR STRUCTURE, cilt.1379, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1379
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.molstruc.2026.147378
- Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Karadeniz Teknik Üniversitesi Adresli: Evet
Özet
In this study, a series of novel carbazole-based 2,4-dihydro-3H-1,2,4-triazol-3-one derivatives (3a-d) were synthesized and structurally characterized. The molecular structures were confirmed by IR, H-1 NMR, C-13 NMR, and Q-TOF LC/MS analyses. The newly synthesized compounds (3a-3d) were theoretically investigated using the DFT/B3LYP/6-311++G(d,p) method. Optimized molecular structures, spectral parameters, and molecular electrostatic potential (MEP) maps of compounds 3a-3d were obtained, and a detailed evaluation of the molecular structures was performed. The compounds were evaluated for anticancer and antimicrobial activities. Compound 3d, bearing a 4-chlorobenzyl substituent, showed the most favorable overall biological profile within the tested series, with the lowest IC50 value against HCT-116 cells (0.971 mM), selectivity indices of 3.31 and 3.17 in the colorectal and breast cancer paired models, respectively, and MIC values of 156 & micro;g/mL against several bacterial and fungal strains. However, the biological activities were moderate to weak compared with reference agents and previously reported potent analogues, indicating that further structural optimization is required. Molecular docking, 100 ns molecular dynamics simulation, and MM/GBSA analyses suggested that compound 3d forms a stable and energetically favorable complex within the EGFR ATP-binding pocket, mainly stabilized by hydrophobic and van der Waals interactions. Overall, the findings provide preliminary information on substituent-dependent activity trends in this structurally distinct carbazole-1,2,4-triazolone series, while the predicted EGFR interactions remain hypothesis-generating and require experimental validation.