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 4a-4p and 5a-5n 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 5k, 4h, 5h, 4d, 4b, and 5i showed potent inhibition in the range of 0.93 to 10.26 µM, respectively, whereas fifteen compounds 4c, 4g, 4i, 4j, 4l, 4m, 4o, 4p, 5c, 5d, 5j, 5l, 5m, 5n and 1 exhibited significant inhibitory activity with IC₅₀ in range of = 11.42 to 48.39 µM. In addition, compounds 5g, 5f, 4k, 4n, and 4f 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.

Keywords: (S)-flurbiprofen; Schiff’s bases; molecular docking; α-glucosidase inhibition.

Figure 1

Reported α-glucosidase inhibitors [15,28,29].

Scheme 1

Schiff’s base derivatives of flurbiprofen.

Figure 2

Substitution influence on the Schiff’s base derivatives of flurbiprofen.

Figure 3

(A) The docked orientations of all the active compounds are shown in the active site of α-glucosidase enzyme. The entrance of the active site and the hydrophobic pocket is displayed in the surface model, the compounds are presented in cyan ball and stick model. (B) The binding mode of the most active compound (5k, shown in magenta ball and stick model) is displayed in the active site of α-glucosidase. The active site residues are presented in orange stick model, and the protein is shown in gold ribbon. The H-bonds are displayed in green dotted line.

Figure 3

(A) The docked orientations of all the active compounds are shown in the active site of α-glucosidase enzyme. The entrance of the active site and the hydrophobic pocket is displayed in the surface model, the compounds are presented in cyan ball and stick model. (B) The binding mode of the most active compound (5k, shown in magenta ball and stick model) is displayed in the active site of α-glucosidase. The active site residues are presented in orange stick model, and the protein is shown in gold ribbon. The H-bonds are displayed in green dotted line.