Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel alpha-amylase inhibitors

In a sustained search for novel alpha-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spim [pyrrolidine-2,3'-oxindoles]. They were obtained by one-pot three component [3 + 2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their alpha-amylase inhibitory activity and showed good alpha-amylase inhibition with IC50 values ranging between 1.49 +/- 0.10 and 3.06 +/- 0.17 mu M, with respect to the control drug acarbose (IC50 = 1.56 mu M). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelled by means of molecular in silico docking studies. The most potent compounds 5 g, 5 k, 5 s and 5 1 were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spimpyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.