Design, synthesis and biological evaluation of novel phthalimide-Schiff base-coumarin hybrids as potent α-glucosidase inhibitors

Abstract

We have designed and synthesized phthalimide-Schiff base-coumarin hybrids 8a–b, 9a–d, 10a–b, and 11a–d and evaluated them for α-glucosidase inhibitory potential against yeast form of this enzyme. For the synthesis of title compounds 4-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 2-hydroxybenzaldehyde, 2-hydroxybenzaldehyde derivatives, coumarin-3-carbohydrazide, and coumarin-7-yloxy-acetohydrazide were used. In vitro α-glucosidase inhibition revealed that all the synthesized compounds exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 85.2 ± 1.7 and 577.7 ± 7.5 µM when compared with the standard inhibitor acarbose having IC50 value 750.0 ± 12.0 µM. The most potent compounds were 4-hydroxybenzaldehyde derivative 8a with coumarin-3-carbohydrazide moiety, 2-hydroxy-5-nitrobenzaldehyde derivative 11d with coumarin-7-yloxy-acetohydrazide moiety, and 2-hydroxy-5-nitrobenzaldehyde derivative 9d with coumarin-3-carbohydrazide moiety. Molecular docking studies were carried out to understand the interaction modes and binding energies of the most active compounds and standard drug acarbose. This studies predicted that compounds 8a, 11d, and 9d (respectively with binding energies = − 10.77, − 8.65, and − 8.66 kcal/mol) bind to active site α-glucosidase more easily than acarbose (binding energy = − 4.04 kcal/mol).