Design, Synthesis, Biological and Computational Studies of Isatin-Based Thiourea Analogues as Dual Inhibitors of α-amylase and α-glucosidase

Acarbose is a recognized inhibitor of α-amylase and α-glucosidase used in the treatment of diabetes mellitus. However, these established and therapeutically utilized inhibitors are also associated with numerous undesirable effects. Consequently, there is a need to develop safer therapies. Despite the wide range of biological activities of isatin and thiourea, their potential for α-amylase and α-glucosidase inhibition has been infrequently investigated. This study focuses on the synthesis and biological evaluation of isatin-based thiourea analogues (1-18) for their α-amylase and α-glucosidase inhibitory activities. The structures of the synthesized analogues were confirmed using various spectroscopic techniques, including 1 HNMR, 13 CNMR, and HR-EIMS. All the analogues exhibited excellent inhibitory potential against α-amylase and α-glucosidase enzymes, with IC 50 values ranging from 0.30 ± 0.05 to 23.70 ± 0.50 µM (α-amylase) and 0.40 ± 0.05 to 25.70 ± 0.50 µM (α-glucosidase) compared to the standard drug acarbose (IC 50 = 8.90 ± 0.10 and 9.10 ± 0.10 µM, respectively). Among these, analogues 2, 8, 11, and 17 demonstrated remarkable potency, significantly outperforming acarbose. Structure-activity relationship analysis revealed that different substitutions on the compounds significantly impacted their inhibitory potential. Additionally, in silico studies identified key structural features responsible for interactions with the active sites of α-amylase and α-glucosidase enzymes.