The 4-(dimethylaminoalkyl)piperazine inhibitors of alpha-glucosidase: allosteric enzyme inhibition and identification of interacting chemical groups

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Ghani U., Ashraf S., Ul Haq Z., KAPLANCIKLI Z. A., DEMİRCİ F., ÖZKAY Y., ...More

TURKISH JOURNAL OF CHEMISTRY, vol.46, no.5, pp.1484-1492, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 46 Issue: 5
  • Publication Date: 2022
  • Doi Number: 10.55730/1300-0527.3453
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, TR DİZİN (ULAKBİM)
  • Page Numbers: pp.1484-1492
  • Keywords: Alpha-glucosidase inhibitor, dithiocarbamate, piperazine, noncompetitive, allosteric, MOLECULAR-DYNAMICS SIMULATIONS, IN-VITRO, DERIVATIVES, MECHANISM
  • Anadolu University Affiliated: Yes


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.