2. Academic Validation
  3. Design and development of sulfenylated 5-aminopyrazoles as inhibitors of acetylcholinesterase and butyrylcholinesterase: exploring the implication for Aβ1-42 aggregation inhibition in Alzheimer's disease

Design and development of sulfenylated 5-aminopyrazoles as inhibitors of acetylcholinesterase and butyrylcholinesterase: exploring the implication for Aβ1-42 aggregation inhibition in Alzheimer's disease

  • RSC Med Chem. 2025 Apr 17. doi: 10.1039/d5md00069f.
Payal Rani 1,  Sandhya Chahal 2,  Anju Ranolia 1,  Kiran 1,  Devendra Kumar 3 4,  Ramesh Kataria 5,  Parvin Kumar 6,  Devender Singh 7,  Anil Duhan 1,  Vibhu Jha 8,  Muhammad Wahajuddin 8,  Gaurav Joshi 8 9,  Jayant Sindhu 1
Affiliations

Affiliations

  • 1 Department of Chemistry, COBS&H, CCS Haryana Agricultural University Hisar 125004 India jayantchem@gmail.com.
  • 2 Department of Chemistry, Chaudhary Ranbir Singh University Jind 126102 India.
  • 3 School of Pharmacy, Narsee Monjee Institute of Management Studies (NMIMS) Dist. Dhule Maharashtra-42400 India.
  • 4 Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University) Varanasi 221005 India.
  • 5 Department of Chemistry at Panjab University Chandigarh-160014 India.
  • 6 Department of Chemistry, Kurukshetra University Kurukshetra-136119 India.
  • 7 Department of Chemistry, Maharshi Dayanand University Rohtak-124001 India.
  • 8 Institute of Cancer Therapeutics School of Pharmacy and Medical Sciences, University of Bradford UK garvpharma29@gmail.com gjoshi@bradford.ac.uk.
  • 9 Department of Pharmaceutical Sciences, Chauras Campus, HNB Garhwal University (A Central University) Srinagar Uttarakhand 246174 India.
PMID: 40256309 DOI: 10.1039/d5md00069f
Abstract

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 Aβ1-42 aggregation. To address this unmet need, we rationally developed sulfenylated 5-aminopyrazoles (3a-3o) via 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-NO2) showing the highest potency. It exhibited IC50 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 Aβ1-42 aggregation and enhanced working memory, as indicated by the Y-maze test, besides portraying no cytotoxicity. The outcome was further corroborated using in silico techniques, leading to the elucidation of plausible inhibition and metabolism mechanisms.

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