Design, Synthesis, and Biological Evaluation of Novel Sulfonamide-Based 1,2,4-Triazole Derivatives as AChE Inhibitors with Potential Anti-Alzheimer’s Activity

This study designed, synthesized, and evaluated two series of sulfonamide-based 1,2,4-triazole derivatives (<b>5a–c</b> and <b>6a–c</b>) as potential anti-Alzheimer agents. Acetylcholinesterase (AChE) inhibition assays identified <b>6c</b> as the most potent inhibitor in the series (IC₅₀ = 3.66 ± 1.15 μg/mL), surpassing the reference drug donepezil (IC₅₀ = 5.69 ± 0.17 μg/mL).

Compounds <b>3a</b> (IC₅₀ = 5.51 ± 0.73 μg/mL) and <b>6b</b> (IC₅₀ = 6.25 ± 0.07 μg/mL) followed closely, showing inhibitory activity comparable to donepezil. Compound <b>4a</b> displayed moderate potency (IC₅₀ = 33.55 ± 0.41 μg/mL), assigning it at an intermediate level between the most active compounds and the weaker derivatives in the series. Cytotoxicity testing on BJ-1 fibroblasts revealed low toxicity for <b>6b</b> and <b>6c</b> (∼34.3% cell death) compared to doxorubicin (83.6%).