Benzodioxole grafted spirooxindole pyrrolidinyl derivatives: synthesis, characterization, molecular docking and anti-diabetic activity

Abstract

A highly stereoselective, three-component method has been developed to synthesize pyrrolidine and pyrrolizidine containing spirooxindole derivatives. The interaction between the dipolarophile α,β-unsaturated carbonyl compounds and the dipole azomethine ylide formed in situ by the reaction of 1,2-dicarbonyl compounds and secondary amino acids is referred to as the 1,3-dipolar cycloaddition reaction. The reaction conditions were optimized to achieve excellent stereo- and regioselectivity. Shorter reaction time, simple work-up and excellent yields are the salient features of the present approach. Various spectroscopic methods and single crystal X-ray diffraction examinations of one example of compound 6i validated the stereochemistry of the expected products. The anti-diabetic activity of the newly synthesized spirooxindole derivatives was tested against the α-glucosidase and α-amylase enzymes. Compound 6i was found to exhibit potent inhibition activity against α-glucosidase and α-amylase enzymes which is further evidenced by molecular docking studies.

Fig. 1. Spirooxindole core consisting of some bioactive compounds.

Fig. 2. Selected ¹H and ¹³C NMR chemical shifts of spirooxindole pyrrolidine 5c.

Fig. 3. Selected ¹H and ¹³C NMR chemical shifts of spirooxindole pyrrolizidine 6c.

Fig. 4. ORTEP diagram of compound 6i.

Scheme 1. Proposed reaction mechanism for the synthesis of 5.

Fig. 5. (A) Inhibitory effects of series 5 spirooxindole pyrrolidine derivatives on AGE formation at diverse concentrations. (B) Inhibitory effects of series 6 spirooxindole pyrrolizidine derivatives on AGE formation at diverse concentrations.

Fig. 6. The 3D and 2D interaction view of compound 6i with the binding sites of α-glucosidase.

Fig. 7. The 3D and 2D interaction view of compound 6i with the binding sites of α-amylase.

Fig. 8. The 3D and 2D interaction view of compound 6i with the binding site of Human serum albumin.

Fig. 9. Analysis of RMSD, RMSF, Rg, SASA, and number of hydrogen bonds of 6i (black) and acarbose (red) with α–glucosidase (green) at 100 ns. (A) Time evolution of backbone RMSD of the complex structure. (B) RMSF of protein and ligand. (C) The radius of gyration (Rg) (D) SASA (E) Hydrogen bonds occurring over the time of simulation between protein and ligand.

Fig. 10. Analysis of RMSD, RMSF, Rg, SASA, and number of hydrogen bonds of 6i (black) and acarbose (red) with α-amylase (green) at 100 ns. (A) Time evolution of backbone RMSD of the complex structure. (B) RMSF of protein and ligand. (C) The radius of gyration (Rg) (D) SASA (E) Hydrogen bonds occurring over the time of simulation between protein and ligand.

Fig. 11. Analysis of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds of 6i (black) and Aminoguanidine (red) with Human serum albumin (green) at 100 ns. (A) Time evolution of backbone RMSD of the complex structure. (B) RMSF of protein and ligand. (C) The radius of gyration (Rg) (D) SASA (E) hydrogen bonds occurring over the time of simulation between protein and ligand.