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 (<i>K</i> _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 (<i>K</i> _I: 837.70 ± 53.87 nM, IC₅₀: 265.00 ± 2.26 nM). Furthermore, compounds <b>6a</b>, <b>6g</b>, <b>6h</b>, <b>6j</b>, <b>6o</b>, <b>6p</b>, and <b>6q</b> showed significantly higher inhibitory activity (<i>K</i> _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 (<i>K</i> _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 <b>6h</b> (<i>K</i> _<i>I</i> : 4.48 ± 0.25 μM), interacts with the target protein 5NN8 through hydrogen bonds as in acarbose. On the other hand, compounds <b>6o</b> (<i>K</i> _I: 15.39 ± 1.61 nM) and <b>6p</b> (<i>K</i> _I: 23.86 ± 2.41 nM), the most potent inhibitors for AR, establish hydrogen bonds with the target protein 4JIR like epalrestat. <i>In silico</i> ADME/T analysis was performed to predict their drug-like properties. A cytotoxicity study was carried out with the L929 fibroblast cell line <i>in vitro</i>, revealing that all of the synthesized compounds were noncytotoxic. Furthermore, AMES test has been added to show the low mutagenic potential of the compounds <b>6h</b> and <b>6o</b>.