Medicinal approaches toward diabetes mellitus based on chloro-1H -indazole-derived triazolo-thiadiazole hybrid derivatives: design, synthesis, characterization, in vitro and in silico insights
摘要
A new series of chloro-1H-indazole-based fused triazole-thiadiazole analogs (1–15) were developed and characterized via 13C-NMR, 1H-NMR, and HREI-MS. The synthesis proceeded with good yields (54–77%) over reaction times of 4 and 14 h, yielding predominantly greenish solid compounds with melting points ranging from 153 to 187 °C. The anti-diabetic potential of the synthesized analogs was evaluated through in vitro inhibition of α-amylase and α-glucosidase enzymes, using Acarbose as the reference inhibitor (IC₅₀ = 3.74 ± 0.33 µM for α-amylase; 4.65 ± 1.98 µM for α-glucosidase). Several synthesized analogs (10, 12, 3, 4, 5, and 13) demonstrated superior inhibitory activity compared to the standard drug. Notably, analog-10, featuring a para-fluoro substitution, exhibited the most potent inhibition with IC50 values of 1.17 ± 1.32 µM (α-amylase) and 1.73 ± 0.19 µM (α-glucosidase). Molecular docking studies revealed that hydrogen bonding interactions significantly contributed to the enhanced binding affinity of these compounds. Additionally, ADMET analysis predicted favorable pharmacokinetic properties, suggesting high drug-likeness, bioavailability, and metabolic stability. These findings provide a strong foundation for the future design and development of novel anti-diabetic agents, with potential for further optimization and preclinical evaluation.