Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 1,3,4-Thiadiazole Derivatives Targeting Both Aldose Reductase and α-Glucosidase for Diabetes Mellitus

Abstract

We have developed new 1,3,4-thiadiazole derivatives and examined their ability to inhibit aldose reductase and α-glucosidase. All of the members of the series showed a higher potential of aldose reductase inhibition (K _I: 15.39 ± 1.61-176.50 ± 10.69 nM and IC₅₀: 20.16 ± 1.07-175.40 ± 6.97 nM) compared to the reference inhibitor epalrestat (K _I: 837.70 ± 53.87 nM, IC₅₀: 265.00 ± 2.26 nM). Furthermore, compounds 6a, 6g, 6h, 6j, 6o, 6p, and 6q showed significantly higher inhibitory activity (K _I: 4.48 ± 0.25 μM-15.86 ± 0.92 μM and IC₅₀: 4.68 ± 0.23 μM-34.65 ± 1.78 μM) toward α-glucosidase compared to the reference acarbose (K _I: 21.52 ± 2.72 μM, IC₅₀: 132.51 ± 9.86 μM). Molecular docking studies confirmed that the most potent inhibitor of α-GLY, compound 6h (K _I : 4.48 ± 0.25 μM), interacts with the target protein 5NN8 through hydrogen bonds as in acarbose. On the other hand, compounds 6o (K _I: 15.39 ± 1.61 nM) and 6p (K _I: 23.86 ± 2.41 nM), the most potent inhibitors for AR, establish hydrogen bonds with the target protein 4JIR like epalrestat. In silico ADME/T analysis was performed to predict their drug-like properties. A cytotoxicity study was carried out with the L929 fibroblast cell line in vitro, revealing that all of the synthesized compounds were noncytotoxic. Furthermore, AMES test has been added to show the low mutagenic potential of the compounds 6h and 6o.

Scheme 1. Figure Shows the Metabolism of Glucose via the Polyol Pathway and Its Contribution to Diabetic Complications

Glucose is converted to sorbitol via the enzyme aldose reductase, consuming NADPH, which leads to a decrease in the antioxidant capacity of the cell. Sorbitol is oxidized to fructose via the enzyme sorbitol dehydrogenase, and NADH accumulates during this reaction. The accumulation of NADH leads to the formation of ROS via the enzyme NADH oxidase. The increase in ROS and the formation of AGEs by fructose contribute to diabetic complications such as retinopathy, nephropathy and neuropathy. Glucosidase inhibitors prevent the conversion of complex carbohydrates into glucose, while aldose reductase inhibitors help prevent complications by limiting the activity of polyol metabolism.^, (NADPH: Nicotinamide adenine dinucleotide phosphate, NADH: Nicotinamide adenine dinucleotide, ROS: Reactive oxygen species, AGE: Advanced glycation end products).

Figure 1

Structures of the designed compounds (6a–6q).

Scheme 2. Synthetic Routes for Preparing Title Compounds (6a–6q)

Reagents and conditions; i: hydrazine hydrate, ethanol, rt; 4 h ii: (1) carbon disulfide, potassium hydroxide, ethanol, reflux, 10 h (2) hydrochloric acid, pH 4–5; iii: acetic acid, ethanol, reflux, 8 h; iv: sodium borohydride, methanol, rt; 10 h; v: chloroacetyl chloride, triethylamine, tetrahydrofuran, ice-bath, 5 h; vi: potassium hydroxide, acetone, rt, 8 h.

Figure 2

SAR study of compounds 6a–6q.

Figure 3

Protein–ligand interaction (3D and 2D). α-GLY, represented by 5NN8, was subjected to molecular docking studies with compound 6h, 6p, and acarbose.

Figure 4

Protein–ligand interaction (3D and 2D). AR, represented by 4JIR, was subjected to molecular docking studies with compound 6o, 6p and epalrestat.

Figure 5

Radar graph showing the chemical structure and physicochemical properties of compounds (6h, 6o, and 6p) and acarbose, epalrestat.

Figure 6

Cell viability of the synthesized compounds (6a–6q) at maximum dose (100 μM) for 24 h.

Figure 7

Average number of positive wells at effective concentrations.