Novel benzothiazole-based cholinesterase inhibitors with amyloid beta disaggregation and antioxidant activity against Alzheimer's disease

  • Eur J Med Chem. 2025 Nov 15:298:118047. doi: 10.1016/j.ejmech.2025.118047.
Bhagwati Bhardwaj  1 ,  Sachin Kumar Vishwakarma  1 ,  Abhinav Singh  1 ,  Hansal Kumar  1 ,  T A Gajendra  2 ,  Akash Verma  3 ,  Sairam Krishnamurthy  2 ,  Vincent Jo Davisson  4 ,  Sushant Kumar Shrivastava  5
Affiliations
  • 1. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
  • 2. Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
  • 3. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India; Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, U.P., India.
  • 4. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
  • 5. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India. Electronic address: [email protected].
PMID: 40784304 DOI: 10.1016/j.ejmech.2025.118047
Abstract

The development of multi-targeted therapeutic agents has gained significant attention as a promising approach for managing Alzheimer's disease. This study reported the synthesis of a series of novel benzothiazole-piperazine derivatives and assessment of their efficacy against cholinesterase Enzymes and anti-β-amyloid (Aβ) aggregation activity. Compound LB05 emerged as the most effective, demonstrating potent inhibition of acetylcholinesterase (AChE) with an IC50 = 0.40 ± 0.01 μM and an inhibition constant (Ki) of 0.28 μM. Enzyme kinetics and PI displacement assays revealed that LB05 acts as a mixed-type AChE Inhibitor. LB05 demonstrated significant efficacy in preventing both self-induced and AChE-mediated aggregation of Aβ1-42. The isothermal calorimetric titration results indicated that LB05 exhibits a moderate binding affinity for Aβ. Additionally, compound LB15 demonstrated significant antioxidant activity, showing 50.72 % DPPH radical scavenging at a concentration of 25 μM along with notable metal-chelating capabilities. In-silico assessments suggested that these compounds possess favorable drug-like properties and blood-brain barrier (BBB) permeability confirmed using the PAMPA-BBB assay. Notably, compound LB05 exhibited a strong safety profile in acute toxicity testing. It effectively alleviated cognitive and memory deficits in a scopolamine-induced amnesic model, demonstrating efficacy similar to that of Donepezil. Therefore, we propose that LB05 has the potential to be a promising lead candidate for further development as a therapeutic agent for Alzheimer's disease.

Keywords
Acetylcholinesterase (AChE); Alzheimer's disease; Amyloid-β; Antioxidant; Butyrylcholinesterase (BChE); Structure-based drug design.
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