Structure-based design and molecular modelling of n-propylcarbazole-1,3-thiazole hybrids as potent α-glucosidase inhibitors: Kinetic, in vitro, and in vivo evaluation.

A series of seventeen novel N-propylcarbazole-1,3-thiazole derivatives (5a-5q) were synthesised via a five-step route and fully characterised by FT-IR, 1H/13C NMR, and HR-MS. The compounds were evaluated for antibacterial, antifungal, α-glucosidase inhibitory, and anti-inflammatory (NO inhibition) activities. The compounds were primarily evaluated for their α-glucosidase inhibitory activity as potential antidiabetic agents. Among them, compound (5k) exhibited outstanding inhibitory potency (IC50 = 6.25 ± 0.17 μM), significantly surpassing the reference drug acarbose (IC50 = 118.09 ± 8.39 μM). Additionally, selected compounds exhibited moderate antimicrobial and anti-inflammatory activities, highlighting their potential as multifunctional scaffolds. Compound (5k) decreased both Vmax and Km, with parallel Lineweaver-Burk plots, indicating a typical uncompetitive inhibition mechanism toward α-glucosidase. Molecular docking studies revealed favourable binding modes of the most active compounds with their respective targets. Density functional theory (DFT) calculations further supported these findings, with compound (5k) exhibiting the smallest HOMO-LUMO energy gap (ΔEgap ≈ 3.70 eV), indicating enhanced electronic polarizability. A 100 ns molecular dynamics simulation of the (5k)-4J5T complex confirmed its structural stability, with RMSD values below 2 Å and persistent interactions involving key residues Phe444, Gln442, and Pro441. ADMET predictions suggested favourable pharmacokinetic properties and acceptable drug-likeness for compound (5k). Moreover, in vivo evaluation in a Zebrafish model demonstrated that compound (5k) significantly reduced postprandial blood glucose levels, with efficacy comparable to that of acarbose. Overall, these results identify compound (5k) as a promising lead for further antidiabetic drug development.