Synthesis, characterization, crystallographic, binding, in silico and antidiabetic studies of novel 2,4-thiazolidinedione-phenothiazine molecular hybrids

Abstract

2,4-thiazolidinedione-phenothiazine molecular hybrids, 9a–9t were synthesized, characterized and screened for antidiabetic activities viz., α -amylase inhibition and glucose uptake assay. The synthesized compounds were characterized by spectroscopic techniques. The molecule 9p was grown into single crystals, and its crystal structure and refinement data were deliberated. Most of the compounds displayed a significant to moderate α-amylase inhibition and glucose uptake activity. The compounds, 9m-9p showed a significant α-amylase inhibition with IC50 values (83.7 ± 0.7 - 60.8 ± 0.8 µM), which are greater than that of the standard, acarbose (101.7 ± 2.0 µM). Most of the compounds showed good glucose uptake assay and compounds, 9a-9 g showed IC50 values in the range of 169.8 ± 1.2 - 213.3 ± 0.5 µM which are ∼2-fold greater compared to that of the standard, metronidazole (441.5 ± 2.1 µM). The compound, 9l showed acceptable values for both α-amylase inhibition (IC50 = 130.6 ± 2.0 µM) and glucose uptake assay (IC50 = 459.3 ± 2.2 µM) compared to those of the standard. Molecular docking studies confirmed interactions of the compounds with the human pancreatic α-amylase protein with PDB ID: 2QV4. Further, the interactions of 9o and 9p with human serum albumin were also investigated.