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.

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 IC(50): 20.16 ± 1.07-175.40 ± 6.97 nM) compared to the reference inhibitor epalrestat (K (I): 837.70 ± 53.87 nM, IC(50): 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 IC(50): 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, IC(50): 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.