New spiropyrrolothiazole derivatives bearing an oxazolone moiety as potential antidiabetic agent: Design, synthesis, crystal structure, Hirshfeld surface analysis, ADME and molecular docking studies

Abstract

In a sustained search for novel and effective antihyperglycemics, a new series of fifteen isomeric oxazolone-fused dispiropyrrolothiazoles resulting from one-pot three component reaction between L-4-thiazolidine carboxylic acid, arylidene-oxazolones and isatin (or acenaphthenequinone) has been synthesized. Four crystal structure determinations further corroborate the proposed stereochemistry and composition of these spirocompounds. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. Results showed the main contribution of H···H and C···H/ H···C contacts for the crystal structures 4b, 5c, 6a and 6e as well as those of O···H/ H···O contacts followed by the S···H/ H···S contacts. Furthermore, the hypoglycemic potency of these heterocycles has been evaluated against both α-amylase from human saliva (HAA) and α-glucosidase from Saccharomyces cerevisiae (SCAG). Among the spiropyrrolothiazole derivatives, the high significantly were 4b (IC50 (HAA) = 1.76 ± 0.14 μM; IC50 (SCAG) = 4.81 ± 0.24 μM) and 5d (IC50 (HAA) = 2.88 ± 0.19 μM; IC50 (SCAG) = 7.78 ± 0.37 μM), while in dispiropyrrolothiazole analogues, those of 6f (IC50 (HAA) = 2.18 ± 0.17 μM), 6e (IC50 (HAA) = 2.28 ± 0.18 μM) and 6c (IC50 (HAA) = 2.49 ± 0.20 μM) and 6e (IC50 (SCAG) = 6.41 ± 0.25 μM), 6f (IC50 (SCAG) = 6.93 ± 0.34 μM) and 6c (IC50 (SCAG) = 7.11 ± 0.31 μM) were found to be the most active, respectively as compared to the standard drug, acarbose (IC50 (HAA) = 1.28 ± 0.13 μM; IC50 (SCAG) = 2.80 ± 0.20 μM). Structural activity relationships (SARs) and molecular dockings of the most active inhibitors into the binding sites of HAA (1B2Y) and SCAG (3W37) were also established. Furthermore, pharmacokinetic studies indicate that the heterocycles exhibit acceptable predictive ADME properties and good drug ability. Overall, our results indicate that these derivatives could be a promising template to design potent dual HAA and SCAG inhibitors.