2026-10-12T18:36:32Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34041796 2026-10-01T09:23:19Z category_4 category_12 category_15 category_19 category_21 category_873 category_46 category_122 portal_87 item_type_6 month_year_10_2026

Design, Synthesis, and Biological Evaluation of Novel Sulfonamide-Based 1,2,4-Triazole Derivatives as AChE Inhibitors with Potential Anti-Alzheimer’s Activity Hala A. Elreedy (25155625) Asmaa M. Elfiky (25155628) Ahmed M. Salem (25155631) Khadiga S. Ibrahim (25155634) Heba Mahdy-Abdallah (25155637) Mohamed A. Ghazy (16939952) Asmaa A. Mahmoud (9645503) Heba M. Abo-Salem (25155640) Biochemistry Cell Biology Neuroscience Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Mental Health Sulfonamide 1,2,4-triazole acetylcholinesterase BACE1 molecular docking Alzheimer’s disease Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder involving multiple pathological pathways. This study designed, synthesized, and evaluated two series of sulfonamide-based 1,2,4-triazole derivatives (5a–c and 6a–c) as potential anti-Alzheimer agents. Acetylcholinesterase (AChE) inhibition assays identified 6c 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 3a (IC50 = 5.51 ± 0.73 μg/mL) and 6b (IC50 = 6.25 ± 0.07 μg/mL) followed closely, showing inhibitory activity comparable to donepezil. Compound 4a 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 6b and 6c (∼34.3% cell death) compared to doxorubicin (83.6%). Acute oral toxicity of 6c (5 g/kg) in mice caused no mortality or clinical signs of toxicity, with only minor changes in serum urea and mean corpuscular volume. In an aluminum chloride-induced rat model of AD, 6c significantly improved cognitive function, reduced hippocampal amyloid β plaque aggregation, and downregulated expression of APP, BACE1, FAS, FADD, CASP8, and BID genes. Molecular docking confirmed strong binding of 6c to AChE (−9.4 kcal/mol) and BACE1 (−7.4 kcal/mol) via hydrogen bonding and hydrophobic interactions. These findings position 6c as a promising AChE inhibitor for AD treatment, guiding future development of sulfonamide–1,2,4-triazole therapeutics. 2026-10-01T09:23:19Z Text Journal contribution 10.6084/m9.figshare.34041796.v1 https://figshare.com/articles/journal_contribution/Design_Synthesis_and_Biological_Evaluation_of_Novel_Sulfonamide-Based_1_2_4-Triazole_Derivatives_as_AChE_Inhibitors_with_Potential_Anti-Alzheimer_s_Activity/34041796 CC BY 4.0