Synthesis, Characterization, Antiglycation Evaluation, Molecular Docking, and ADMET Studies of 4-Thiazolidinone Derivatives

Abstract

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one (1-4) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2H-1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one (3) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational changes in the α-helix and β-sheet (due to hyperglycemia) were also found to be reversed upon the addition of (3). Experimental findings were complemented by computational [molecular docking, ADME/Tox, and density functional theory (DFT)] studies. The docking scores of the compounds were in order 1 > 3 > 2 > 4, indicating the importance of the polar group at the 5-arylidene moiety. The results of ADME/Tox and DFT calculations revealed the safe nature of the compounds with high drug-likeness and stability. Overall, we speculate that the results of this study could provide valuable insights into the biological activity of 4-thiazolidinones.

Scheme 1. Synthesis of 4-Thiazolidinone Derivatives

Figure 1

Compounds 1 (A), 2 (B), 3 (C), and 4 (D) were used as inhibitors in the glycation reactions with varying concentrations (0.78–400 μg/mL). Each value is the mean ± SD of three independent assays.

Figure 2

Inhibition of UV intensities of the glycation reactions using compounds (1–4) at a concentration of 200 μg/mL. Each value is the mean ± SD of three independent assays. Significance was defined by p < 0.05, p < 0.01, and p = ns. The “ns” represents nonsignificant.

Figure 3

Tryptophan-specific fluorescence of the glycation reactions using compounds (1–3) at a 200 μg/mL concentration. Each value is the mean ± SD of three independent assays. Significance was defined by p < 0.05.

Figure 4

Pentosidine-specific fluorescence in N-HSA and G-HSA. The G-HSA reactions were incubated in the presence of compounds (1–3). The concentration of compounds was set at 200 μg/mL. Each value is the mean ± SD of three independent assays. Significance was defined by p < 0.05 and p < 0.01.

Figure 5

Inhibition of ketoamine formation using compounds (1–3). The concentration of 200 μg/mL of compounds was used to coincubate in the glycation reactions. Each value is the mean ± SD of three independent assays. Significance was defined by p < 0.05.

Figure 6

Inhibition in the generation of carbonyl compounds in the presence of the compounds (1–3). A concentration of 200 μg/mL of compounds was used to coincubate in the glycation reactions. Each value is the mean ± SD of three independent assays. Significance was defined by p < 0.05 and p < 0.01.

Figure 7

CD analysis of the N-HSA and G-HSA samples. A reduction in glycation was observed with compounds 1 (G-HSA + 1), 2 (G-HSA + 2), and 3 (G-HSA + 3). The compound concentration of 200 μg/mL was added with 2.2 μM of HSA in all the samples. N-HSA and G-HSA samples were served as negative and positive controls. Each spectrum is the average of three independent assays.

Figure 8

Molecular docking outcomes for compounds (A) 1, (B) 2, (C) 3, and (D) 4. Only the residues involved in H-bond formation, π–π stacking, and salt bridge interactions are shown.

Figure 9

DFT-calculated HOMO–LUMO orbitals and the ESP map of compounds 1 (A), 2 (B), 3 (C), and 4 (D).