Background
Glucokinase activators (GKAs) are the new class of drugs which act on glucokinase (GK) enzyme and
show their antihyperglycemic activity. Moreover, till date there is no single drug in market without
any side effect as antidiabetic activity.
Objective
The present work was planned to design, synthesize and pharmacologically evaluate the antidiabetic
activity of a series of newer benzamide derivatives as potential GKAs.
Method
This work involved synthesis of newer benzamide derivatives from benzoic acid and their evaluation
by docking studies to determine the binding interactions for the best fit conformations in the binding
site of GK enzyme. Based on the results of docking studies, the selected molecules were tested for in
vitro GK enzyme assay and further tested for in vivo antidiabetic activity in animal models. Further
the in vitro pharmacokinetic studies were analyzed for oral activity.
Results
Among all designed and synthesized derivatives the compounds 5g, 5h, 5i, 5j, 5l, 5m and 5n showed
excellent GK activation fold in the in vitro GK assay. Among these selected molecules the compounds 5g and 5i possessed highest antihyperglycemic activity in oral glucose tolerance test
during in vivo studies. In addition, the results of antihyperglycemic activity and in silico docking
studies were found to support each other for all the synthesized molecules as glucokinase activators.
The synthesized derivatives were further in vitro analyzed for pharmacokinetic properties. This series
of compounds found appropriate for oral administration. These finding lead to the development of
orally active glucokinase activators as antidiabetic agents.
Conclusion
The newer series of 3-substituted benzamide derivatives were designed, synthesized, characterized,
and pharmacologically evaluated based on the structural requirements of the allosteric binding site of
the GK protein and previously reported pharmacophoric requirements. Amongst the several
synthesized derivatives, compounds 5g, 5h, 5i, 5j, 5l, 5m and 5n showed appreciable GK activation
profile in the in vitro enzymatic assay. In molecular docking studies the all the synthesized
compounds showed the H-binding interactions with the Arg63 residue of the allosteric site of the GK
protein. Amongst all the synthesized compounds tested in vivo for their antihyperglycemic activity,
the compounds 5g and 5i have highest activity. This series of compounds found appropriate for oral
administration. These findings lead to the development of safe, orally active and potent glucokinase
activators as antidiabetic agents.
Keywords: Antihyperglycemic activity, Benzamide derivatives, Glucokinase enzyme, GK
activators, In silico method, In vitro GK assay
Publication date: 01/08/21
https://ijbpas.com/pdf/2021/August/MS_IJBPAS_2021_5574.pdf
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https://doi.org/10.31032/IJBPAS/2021/10.8.5574
