Abstract
In continuation of our interest in identifying new alpha-glucosidase inhibitors with potential to become antidiabetic drugs, this work focuses on the study of 4-(dimethylaminoalkyl)piperazine-1-carbodithioate derivatives as alpha-glucosidase inhibitors. The eight heterocyclic piperazine-dithiocarbamate complexes studied in this work contain a variety of substitutions on their benzene ring exhibiting potent, noncompetitive inhibition of alpha-glucosidase. Dithiocarbamate and piperazine moieties are important pharmacophores with promising therapeutic prospects featuring facilitated drug delivery due to their lipophilic nature in addition to their alpha-glucosidase inhibitory activity. Enzyme kinetics, molecular dynamics simulations, and docking studies revealed that the target compounds bind to a new allosteric site that is located near the active site of alpha-glucosidase. Majority of molecular interactions of the compounds with the enzyme are mediated by hydrophobic contacts in addition to a number of important polar interactions. The current work identifies a number of chemical groups in the compounds that are responsible for potent inhibition of alpha-glucosidase. Moreover, it also provides new insights into understanding alpha-glucosidase inhibition by dithiocarbamate and piperazine-containing compounds that can be promising for development of new antidiabetic drugs.