Spiroindolone Analogues as Potential Hypoglycemic with Dual Inhibitory Activity on α-Amylase and α-Glucosidase

Abstract

Inhibition of α-amylase and α-glucosidase by specified synthetic compounds during the digestion of starch helps control post-prandial hyperglycemia and could represent a potential therapy for type II diabetes mellitus. A new series of spiroheterocyclic compounds bearing oxindole/benzofuran/pyrrolidine/thiazolidine motifs were synthesized via a 1,3-dipolar cyclo-addition reaction approach. The specific compounds were obtained by reactions of chalcones having a benzo[b]furan scaffold (compounds 2a–f), with a substituted isatin (compounds 3a–c) and heterocyclic amino acids (compounds 4a,b). The target spiroindolone analogues 5a–r were evaluated for their potential inhibitory activities against the enzymes α-amylase and α-glucosidase. Preliminary results indicated that some of the target compounds exhibit promising α-amylase and α-glucosidase inhibitory activity. Among the tested spiroindolone analogues, the cycloadduct 5r was found to be the most active (IC50 = 22.61 ± 0.54 μM and 14.05 ± 1.03 μM) as α-amylase and α-glucosidase inhibitors, with selectivity indexes of 0.62 and 1.60, respectively. Docking studies were carried out to confirm the binding interaction between the enzyme active site and the spiroindolone analogues.

Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[pyrrolidine-thiazolo-oxindoles] Derivatives

“…One of the most privileged aza-heterocyclic scaffolds is spiro[pyrrolidine-oxindole] [2], which is present in natural products and useful as a building block for the synthesis of significant biologically active compounds. This class of aza-heterocyclic compounds has gained great interest, owing to several reports of its pharmaceutical potency, including anticancer [3], antitumor [4], 5-HT3 receptor antagonist [5], acetylcholinesterase-inhibitory [6], antibacterial [7], antibiotic [8], and MDM2-p53 inhibitor [9] effects; selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors [10]; and potential hypoglycemic dual inhibitory activity against α-amylase and α-glucosidase [11] (Figure 1). To date, prolonged efforts have been exerted to expand divergent complexity and to develop efficient synthetic routes for these valuable privileged aza-heterocyclic scaffolds, which would remarkably enhance their bioactivity [1,12].…”

“…Sci. 2020, 10, x FOR PEER REVIEW 2 of 10 antagonist [5], acetylcholinesterase-inhibitory [6], antibacterial [7], antibiotic [8], and MDM2-p53 inhibitor [9] effects; selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors [10]; and potential hypoglycemic dual inhibitory activity against α-amylase and α-glucosidase [11] (Figure 1). To date, prolonged efforts have been exerted to expand divergent complexity and to develop efficient synthetic routes for these valuable privileged aza-heterocyclic scaffolds, which would remarkably enhance their bioactivity [1,12].…”

Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

“…In particular, a series of spiro-oxindole-tethered benzo[ b ]thiophene scaffolds consisting of a single regio- and diastereo-selective isomer were synthesized from benzo[ b ]thiophene-based chalcones ( 2a – e ), which were in turn prepared through an aldol condensation of the corresponding substituted acetophenones ( 1a – e ) with benzo[ b ]thiophene-2-carboxaldehyde. Following the 1,3-dipolar cycloaddition reaction protocol [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], 2a – e reacted with 5-substituted isatins ( 3a – c ) and secondary amino acids, such as thioproline ( 4a ) and octahydro-1 H -indole-2-carboxylic acid ( 4b ), forming the corresponding spiro-oxindole analogs IIa–n in high yields after purification by short column chromatography. The chemical features of the target compounds were assigned based on the NMR spectrum.…”

“…The chalcone derivatives 2a – e were synthesized based on a reported procedure [ 27 , 28 ] using benzo[ b ]thiophene-2-carboxaldehyde (1.0 eq.) in ethanol and the corresponding substituted acetophenone (acetopehnone, p -Cl- acetopehnone, p -Br-acetopehnone, p -F-acetopehnone and p -CF 3 -acetopehnone) (1.0 eq.)…”

Regio- and Stereoselective Synthesis of a New Series of Spirooxindole Pyrrolidine Grafted Thiochromene Scaffolds as Potential Anticancer Agents

“…These spiro-heterocycles with oxindole and pyrrolidine scaffolds possesses wide spectrum pharmacological activities, such as Barakat et al reported the synthesis and biological activities of several spirooxindoles they exhibited interesting pharmacological activities as MDM2-p53 protein-protein interaction inhibitors, phosphodiesterase 1, and as selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors. These spirooxindoles were reported to have potential hypoglycemic activity with inhibitory activities against α-amylase and α-glucosidase, and other pharmacological targets [26][27][28][29][30][31][32][33][34].…”