2. Academic Validation
  3. "Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors"

"Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors"

  • Bioorg Chem. 2025 Apr:157:108295. doi: 10.1016/j.bioorg.2025.108295.
Aya M Almatary 1,  Mohammad M Al-Sanea 2,  Eman E Nasr 3,  Abdullah Haikal 4,  Gary S Thompson 5,  Amira Abood 6,  Mahmoud A A Ibrahim 7,  Abdullah A Elgazar 8,  Abdelrahman Hamdi 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72388, Saudi Arabia. Electronic address: mmalsanea@ju.edu.sa.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4 Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 5 Wellcome Trust Biological NMR Facility, School of Biosciences, Division of Natural Sciences, University of Kent, Canterbury, Kent CT2 7NZ, UK.
  • 6 Chemistry of Natural and Microbial Products Department, National Research Center, Dokki, Cairo, Egypt; School of Bioscience, University of Kent, Canterbury, Kent CT2 7NZ, UK.
  • 7 Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt; School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa.
  • 8 Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: abdelrahmanhamdi2012@yahoo.com.
PMID: 40010133 DOI: 10.1016/j.bioorg.2025.108295
Abstract

Novel 2,4-thiazolidinedione-benzothiazole-triazole hybrids (7a-7l) were designed and synthesized as therapeutic agents with pleotropic activity for Alzheimer's disease (AD). These compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Compound 7k, exhibited exceptional AChE inhibition (IC₅₀ = 0.083 μM), while compound 7d, showed potent activity (IC₅₀ = 0.119 μM). Kinetic studies revealed that 7k was able to exert its action through mixed types of inhibition. Also, the anti-inflammatory potential of these lead compounds was assessed in LPS-stimulated RAW 264.7 macrophages. Both compounds demonstrated significant dose-dependent inhibition of key inflammatory mediators, including NO, TNF-α, IL-6, and IL-1β at non-cytotoxic concentrations (≤10 μM). Notably, compound 7k exhibited superior anti-inflammatory activity, achieving 92 % NO inhibition, 65 % TNF-α reduction, and 61.1 % IL-1β suppression at 10 μM. Moreover, compound 7k exerted neuroprotective activity against H2O2 induced neurotoxicity in SH-Sy5y cell line leading to reduction in LDH, ROS levels and improving cell survival. Finally, compound 7k was able to prevent Aβ aggregation at IC50 = 5 μM. Molecular docking studies provided structural insights into the possible binding interactions of compounds 7d and 7k within the AChE active site. The stability and binding energies of compounds 7d and 7k complexed with AChE were assessed over 100 ns molecular dynamics simulations and compared with Donepezil. The MM/GBSA binding energy calculations indicated that compound 7k exhibited a higher affinity for AChE in comparison with compound 7d and Donepezil, with ΔGbinding values of -46.1, -42.6, and - 24.0 kcal/mol, respectively. These findings suggest that these novel hybrid molecules represent promising multi-target therapeutic candidates for AD treatment, effectively addressing both cholinergic dysfunction and neuroinflammation.

Keywords

Acetylcholinesterase inhibition; Alzheimer's disease; Anti-inflammatory agents; Molecular docking.; Multi-target therapeutic strategy; Thiazolidinedione-benzothiazole hybrids.

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