Design, synthesis, biological evaluation, and in silico studies of novel 1,3-thiazole derivatives.

A series of novel 1,3-thiazole heterocyclic derivatives has been synthesized and structurally characterized using melting point, FT-IR, 1D and 2D NMR, and HR-MS. The compounds were screened for antibacterial activities, three human cancer cell lines (A549, HepG2, and MCF-7), and anti-inflammatory and α-glucosidase inhibitory activities, utilising MIC, MTT, α-glucosidase inhibitory, and NO assays, respectively. Entry 4e exhibited the most potent antibacterial activity (MIC = 83.5 µM). Entry 4g exhibited significant inhibitions against three cancer cell lines: MCF-7, HepG2, and A549 (IC50 = 2.6-6.6 µM). Entry 4f exhibited significant anti-inflammatory activity (IC50 = 15.4 ± 1.0 µM), comparable to the dexamethasone drug (IC50 = 13.7 ± 1.2 µM). Notably, 4a and 4l exhibited potent α-glucosidase inhibitory activity (IC50 = 46 ± 2 µM and 41 ± 2 µM, respectively), surpassing acarbose (IC50 = 117 ± 8 µM). Molecular docking studies revealed energetically favourable interactions between the ligands and the active sites of the target enzymes, in good agreement with the predicted biological activities obtained from in silico analyses. A 100 ns molecular dynamics simulation of the 4l-4J5T complex further confirmed its structural stability after 60 ns, with key residues Glu428 and Asn452 maintaining hydrogen bond interactions for approximately 80% of the simulation time. In addition, ADMET predictions indicated that compound 4l possesses favourable pharmacokinetic properties. Collectively, these findings highlight a novel thiazole-based scaffold exhibiting multi-target biological activity and underscore its promising potential for further drug development.