Rani Payal, Chahal Sandhya, Ranolia Anju, Kumar Devendra, Kataria Ramesh, Kumar Parvin, Singh Devender, Duhan Anil, Jha Vibhu, Wahajuddin Muhammad, Joshi Gaurav, Sindhu Jayant
Department of Chemistry, COBS&H, CCS Haryana Agricultural University Hisar 125004 India
Department of Chemistry, Chaudhary Ranbir Singh University Jind 126102 India.
RSC Med Chem. 2025 Apr 17. doi: 10.1039/d5md00069f.
Current therapeutic regimens approved to treat Alzheimer's disease (AD) provide symptomatic relief by replenishing the acetylcholine levels in the brain by inhibiting AChE. However, these drugs don't halt or slow down the progression of Alzheimer's disease, which remains a major challenge. Evidence suggests a significant increase in BuChE activity with a decrease in AChE activity as the AD progresses along with the Aβ aggregation. To address this unmet need, we rationally developed sulfenylated 5-aminopyrazoles (3a-3o) electro-organic synthesis in good to excellent yields (68-89%) and duly characterized them using spectrophotometric techniques. The compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, with 3b (4-NO) showing the highest potency. It exhibited IC values of 1.634 ± 0.066 μM against AChE and 0.0285 ± 0.019 μM against BuChE, outperforming donepezil and tacrine. Admittedly, 3b effectively inhibited Aβ aggregation and enhanced working memory, as indicated by the Y-maze test, besides portraying no cytotoxicity. The outcome was further corroborated using techniques, leading to the elucidation of plausible inhibition and metabolism mechanisms.
目前批准用于治疗阿尔茨海默病（AD）的治疗方案，通过抑制乙酰胆碱酯酶（AChE）来补充大脑中的乙酰胆碱水平，从而缓解症状。然而，这些药物并不能阻止或减缓阿尔茨海默病的进展，这仍然是一个重大挑战。有证据表明，随着AD的进展以及淀粉样β蛋白（Aβ）的聚集，丁酰胆碱酯酶（BuChE）活性显著增加，而AChE活性降低。为了满足这一未被满足的需求，我们合理地开发了亚磺酰化5-氨基吡唑（3a - 3o），通过有机电合成以良好至优异的产率（68 - 89%）得到，并使用分光光度技术对其进行了充分表征。对这些化合物进行了乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制测试，其中3b（4 - NO）显示出最高的效力。它对AChE的IC值为1.634 ± 0.066 μM，对BuChE的IC值为0.0285 ± 0.019 μM，优于多奈哌齐和他克林。诚然，3b除了没有细胞毒性外，还能有效抑制Aβ聚集，并通过Y迷宫试验表明能增强工作记忆。使用相关技术进一步证实了这一结果，从而阐明了可能的抑制和代谢机制。
