Design, synthesis, and biological evaluation of 4,6-dimethoxybenzofuran derivatives: BRD4 inhibition and selective α-glucosidase activity
JOURNAL OF MOLECULAR STRUCTURE, cilt.1373, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1373
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.146776
- 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
Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator implicated in cancer progression and metabolic disorders such as diabetes mellitus, making it an attractive therapeutic target. In this study, a range of novel 4,6-dimethoxybenzofuran-based thiosemicarbazones 4a-f and their corresponding thiazole analogs 5a-h were designed, synthesized, and evaluated for their BRD4 inhibitory activity along with antidiabetic potential. The synthesized compounds were fully characterized using spectroscopic techniques and the molecular structures of the compounds 4e, 4h, and 5d were further confirmed by single-crystal X-ray diffraction analysis. Biological evaluation revealed that while the thiosemicarbazone intermediates exhibited limited cytotoxicity and weak enzyme inhibition, benzofuran-thiazole hybrid compounds showed improved biological profiles. Certain thiazole derivatives demonstrated moderate BRD4 inhibition and selective cytotoxicity toward cancer cell lines. Additionally, in vitro antidiabetic screening indicated that several benzofuran-thiazole derivatives 5a, 5b, and 5g displayed potent alpha-glucosidase inhibition with IC50 values of 35.78, 15.49, and 46.76 & micro;M, respectively. These compounds exhibited stronger alpha-glucosidase activity than the reference drug acarbose. Structure-activity relationship (SAR) analysis highlighted the critical influence of phenyl ring substitution patterns on alpha-glucosidase inhibitory potency. Molecular docking studies further supported the experimental findings, revealing that most of benzofuran-thiazoles exhibited high binding affinity to the BRD4 B1 binding site. Among the synthesized compounds, 5a, 5b, 5d, 5f, 5g, and 5h exhibited high binding affinity to the active site of the BRD4 B1 protein, with binding free energies of -9.0 kcal/mol and lower. Similarly, compounds 5a, 5b, 5d, 5f, and 5h were found to exhibit high affinity to the S. cerevisiae alpha-glucosidase catalytic core with binding free energies of -11.3 kcal/ mol and lower. In conclusion, the current findings suggest that newly synthesized benzofuran-based thiazoles, given their potential as dual BRD4 B1 and alpha-glucosidase inhibitors, could be novel drug candidate molecules for the treatment of diabetes mellitus.