Discovery of chalcone derivatives as potential α-glucosidase and cholinesterase inhibitors: Effect of hyperglycemia in paving a path to dementia

Abstract

In the present study, a series of fascinating chalcone derivatives 1C-14C has been designed and synthesized by Claisen-Schmidt condensation. The target compounds were screened for in vitro α-glucosidase and cholinesterase inhibitory activities. For the first time, the enzyme inhibitory activities of the target derivatives were assessed for antihyperglycemic and neuroprotective activities on streptozotocin (STZ) induced diabetic animal models using in vivo mechanism-based assays. Based on α-glucosidase and cholinesterase inhibitory activities, the compounds 2C, 3C, 13C and 14C were chosen in vivo for further evaluation of antidiabetic and neuroprotective activities in STZ-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic and antiamnesic activities and found nontoxic in nature. The target compounds were then tested in vivo for cognitive function in a STZ-induced amnesic animal paradigm, where four compounds 2C, 3C, 13C, and 14C considerably reduced the amnesic effects as measured by the Y-Maze Paradigm and novel object discrimination (NOD) tasks. Furthermore, the structure-activity relationship of these substituted chalcone derivatives was established. According to kinetic studies, 2C and 7C have Ki values of 0.017±0.00078 µM and 0.00060±0.00004 µM, respectively, and were competitive inhibitors of cholinesterase and α-glucosidase. Molecular docking study revealed that the co-crystallized ligand and potent compounds exhibited same binding orientation within the target enzyme's active site (α-glucosidase (PDB ID: 3AJ7), AChE (PDB ID: 1ACL) and BChE (PDB ID: 4TPK)). The QSAR studies were conducted based on anti-glucosidase and anti-cholinesterases (AChE, BChE) assays. The value of coefficient of multiple determinant (R2) 0.9999 depicts a strong relationship between 1C-14C structures and selected properties. Most of these substances are selective inhibitors of cholinesterase that may be used for age-related problems and to treat the progressive neurodegenerative disorder.