Fluorenone–thiazolidine-4-one scaffolds as antidiabetic and antioxidant agents: design, synthesis, X-ray crystal structures, and binding and computational studies

Abstract

Using 2-(9H-fluoren-9-ylidene)hydrazinyl)thiazol-4(5H)-one and substituted benzaldehydes, a new library of fluorenone–thiazolidine-4-one scaffolds (5a–u) were synthesized and characterized using FT-IR, ¹H NMR, ¹³C NMR and mass spectral data. Single crystals of compound 5s were developed and crystallographic data were collected. Hirshfeld surface evaluation was used to investigate the intermolecular interactions that exist within the crystals. The synthesized compounds were screened for in vitro antioxidant and anti-diabetic properties by DPPH scavenging activity and α-glucosidase inhibition, respectively. Compounds 5a–l exhibited promising DPPH scavenging activity. Compound 5l showed an IC₅₀ value of 27.70 ± 0.8 μM, which is 4.25-fold greater as compared to that of the standard, gallic acid (an IC₅₀ value of 117.92 ± 2.8 μM). Compound 5g exhibited good α-glucosidase inhibition with an IC₅₀ value of 114.58 ± 1.6 μM, which is less than that of the standard inhibitor, acarbose, with an IC₅₀ value of 115.49 ± 2.2 μM. The mechanism of binding of compound 5g with human serum albumin (HSA) and calf thymus DNA (Ct-DNA) was studied by fluorescence spectroscopy. Furthermore, the ADME properties of the designed compounds were studied using the SwissADME online tool. The molecular docking studies of the compounds were performed against acid-α-glucosidase, in complex with 1-deoxynojirimycin (PDB ID: 5NN5).