Design, synthesis, biological evaluation, and <i>in silico</i> 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 <i>in silico</i> 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.