Design, synthesis and in Silico evaluation of novel thiazol-4(5H)-one-appended isatin–triazole hybrids with protective effects against inflammation, oxidative stress, and lymphocyte infiltration in a type 1 diabetic rat model

Pancreatic inflammation plays a critical role in the development and progression of type 1 diabetes (T1D). In this study, a series of novel 1,2,3-triazole-linked isatin-thiazol-4(5H)-one hybrids were rationally designed and synthesized via a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, affording the target compounds in good to excellent yields. The compounds were structurally characterized using 1D and 2D NMR spectroscopy. Their anti-inflammatory potential was evaluated both in vitro and in vivo by assessing their inhibitory effects on key enzymes involved in pancreatic inflammation, namely phospholipase A2 (PLA2), myeloperoxidase (MPO), and elastase (ELA). Triazoles 8h and 8i showed the most potent activities. Compound 8h exhibited IC₅₀ values of 19.3, 7.9, and 18.2 µg/mL, respectively, against PLA2, MPO, and ELA, outperforming the reference drug indomethacin. In alloxan-induced diabetic rats, oral administration of 8i (25 mg/kg) reduced pancreatic PLA2, MPO, and ELA activities by 54 %, 62 %, and 56 %, respectively. Analog 8h also significantly decreased oxidative stress markers (H₂O₂ and TBARS) by 62 % and 58 % and improved glycemic control, lowering fasting blood glucose and HbA1c by 54 % and 25 %. Histological analysis confirmed protection of pancreatic tissue, with reduced lymphocyte infiltration and preserved β-cell architecture. Molecular docking studies revealed strong binding affinities of 8h and 8i to PLA2, MPO, and porcine pancreatic elastase, with better binding energies than indomethacin. In silico ADME-Tox predictions supported their drug-likeness and oral bioavailability. These findings highlight 8h and 8i as promising candidates for managing pancreatic inflammation and oxidative stress associated with T1D.