Novel hybrid indazole-based 2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives: design, synthesis, spectroscopic characterization, SAR, molecular docking, pharmacokinetics and toxicological activities
There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of indazole-based 2,4-dihydro-3H-1,2,4-triazole-3-thone derivatives (1-17) and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H NMR, 13C NMR, and HRMS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure–activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions on the phenyl ring. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values of for α-glucosidase (3.42 ± 1.43 μM to 29.34 ± 0.79 μM) and α-amylase (3.44 ± 0.18 μM to 31.77 ± 0.90 μM), respectively. The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 μM for α-amylase and IC50 = 9.80 ± 0.20 μM for α-glucosidase). Specifically, among the synthesized analogs, seven compounds (1, 5, 6, 8, 11,15, and 16) demonstrated superior inhibitory activity, surpassing acarbose with IC50 values ranging from for α-glucosidase and for α-amylase respectively. The outcome was further corroborated using in silico techniques, leading to the elucidation of plausible inhibition and metabolism mechanisms. These findings reveal that triazole-containing bis-hydrazones act as α-glucosidase and α-amylase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.
