Bio-Oriented Synthesis of Novel (S)-Flurbiprofen Clubbed Hydrazone Schiff’s Bases for Diabetic Management: In Vitro and In Silico Studies

Abstract

A new series of (S)-flurbiprofen derivatives <b>4a</b>-<b>4p</b> and <b>5a</b>-<b>5n</b> were synthesized with different aromatic or aliphatic aldehydes and ketones to produce Schiff's bases and their structures were confirmed through HR-ESI-MS, ¹H, and ¹³C-NMR spectroscopy. The α-glucosidase inhibitory activities of the newly synthesized compounds were scrutinized, in which six compounds <b>5k</b>, <b>4h</b>, <b>5h</b>, <b>4d</b>, <b>4b,</b> and <b>5i</b> showed potent inhibition in the range of 0.93 to 10.26 µM, respectively, whereas fifteen compounds <b>4c, 4g, 4i, 4j, 4l, 4m, 4o, 4p, 5c, 5d, 5j, 5l, 5m, 5n</b> and <b>1</b> exhibited significant inhibitory activity with IC₅₀ in range of = 11.42 to 48.39 µM. In addition, compounds <b>5g, 5f</b>, <b>4k</b>, <b>4n</b>, and <b>4f</b> displayed moderate-to-low activities. The modes of binding of all the active compounds were determined through the molecular docking approach, which revealed that two residues, specifically Glu277 and His351 are important in the stabilization of the active compounds in the active site of α-glucosidase. Furthermore, these compounds block the active site with high binding energies (-7.51 to -3.36 kcal/mol) thereby inhibiting the function of the enzyme.