Structure-activity relationship-guided design of carbazole-thiazole hybrids as α-glucosidase inhibitors: DFT analysis, molecular modelling, ADMET prediction and in vivo validation.

A series of novel carbazole-thiazole hybrids (5a-5q) was synthesised to explore structure-activity relationships (SAR) toward α-glucosidase inhibition. Enzymatic evaluation identified compound 5k as the most potent inhibitor (IC₅₀ = 5.23 µM), exhibiting approximately 20-fold greater activity than acarbose (IC₅₀ = 117.12 µM). Kinetic analysis indicated that 5k decreased both Vmax and Km, with near-parallel Lineweaver-Burk plots, suggesting a mixed-type inhibition with a predominant uncompetitive component. SAR analysis showed that electronic effects of substituents significantly influence inhibitory potency. Molecular docking revealed that 5k favourably binds within the α-glucosidase active site, forming interactions with Gly383, Phe385, and Lys439. Molecular dynamics simulations supported complex stability (RMSD < 2 Å). In silico ADMET analysis (ADMETlab 2.0) suggested low BBB permeability and limited oral bioavailability, indicating potential for intestinal-targeted activity. DFT calculations (ΔEgap = 3.770 eV; dipole moment = 2.225 D) provided theoretical insight into electronic properties, although their biological relevance remains tentative. In vivo evaluation using a zebrafish model of postprandial hyperglycaemia demonstrated that 5k significantly reduced glucose levels (Cmax ↓36.4%, AUC0-180 ↓27.7%) at 75 mg.kg-1, outperforming acarbose. These results support 5k as a promising lead for further optimisation.