Abstract
Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a–t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.
Graphical abstract
A series of 20 benzothiazole-appended indenopyrazoles were synthesized in good yields.
Structural confirmation of the newly synthesized compounds was ascertained by spectral analysis data and finally by single-crystal x-ray crystallography.
The titled compounds were screened for their in vitro antidiabetic activity.
Among all the derivatives, 3p and 3r exhibited promising inhibitory activity against both enzymes, α-amylase and α-glucosidase.
Enzymatic inhibition was supported by docking studies of compounds 3p with binding energies of -10.3 and -10.4 kcal/mol and 3r with binding energies of -10.3 and -10.7 kcal/mol for α-amylase and α-glucosidase, respectively.
The docked complexes of the most active compound, 3r, with α-amylase and α-glucosidase were subjected to molecular dynamics study to check the complex stability and the ligand–target interactions at the active sites of the enzymes.
Financial disclosure
The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
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No writing assistance was utilized in the production of this manuscript.