Novel 2-indolinone benzylpiperidine- thiosemicarbazone hybrids as cholinesterase inhibitors: Design, synthesis and biological evaluation

  • Bioorg Chem. 2026 Jun 24:180:110150. doi: 10.1016/j.bioorg.2026.110150.
Zekiye Şeyma Sevinçli  1 ,  Özge Soylu-Eter  2 ,  Gozde Hasbal-Celikok  3 ,  Gulsum Altiparmak-Ulbegi  3 ,  Ece Bayır  4 ,  Aylin Şendemir  5 ,  Pinar Aksoy-Sagirli  3 ,  Nilgün Karalı  6
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yuzuncu Yil University, 65080, Van, Türkiye. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Technology, Faculty of Pharmacy, Fırat University 23119, Elazığ, Türkiye.
  • 3. Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116, Istanbul, Türkiye.
  • 4. Central Research Testing and Analysis Laboratory Research and Application Center, Ege University, 35100, Izmir, Türkiye.
  • 5. Department of Bioengineering, Faculty of Engineering, Ege University, 35040, Izmir Türkiye; Department of Biomedical Technologies, Graduate School of Natural and Applied Sciences, Ege University, 35040, Izmir, Türkiye.
  • 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, 34116, Istanbul, Türkiye.
PMID: 42372459 DOI: 10.1016/j.bioorg.2026.110150
Abstract

The design of this study was based on donepezil, a selective acetylcholinesterase (AChE) inhibitor used in the treatment of AD, consisting of an 1-indanone ring and a benzylpiperidine moiety. For this purpose, the 1-indanone ring was replaced with a 2-indolinone ring and new hybrid compounds were designed by connecting the benzylpiperidine residue to the 2-indolinone ring via the thiosemicarbazone bridge. Based on the results of in silico studies, 29 new 2-indolinone benzylpiperidine-thiosemicarbazone hybrid compounds (10a-n and 11a-o) were selected and synthesized. The in vitro anti-cholinesterase (ChE) activities of the compounds were determined and compared with donepezil (IC50 = 0.44 μM for AChE and IC50 = 4.70 μM for BuChE). Compound 11e showed the strongest inhibition (IC50 = 0.91 μM for AChE and IC50 = 30.97 μM for BuChE), while compounds 11a, 11b, 11d, 11g, 11k, 11l and 11n also displayed strong AChE inhibitory activity (range of IC50 = 1.15-3.13 μM). Compounds showed weak or no inhibition against BuChE. The cytotoxic effects of the active compounds were evaluated in HUVEC cell lines, and non-cytotoxic effects were observed for compounds 11b, 11d, 11e and 11k. Neuroprotective effect studies of active and non-cytotoxic compounds in HUVEC cells were performed in SH-SY5Y cells exposed to H2O2-induced damage. According to the results, compounds 11e and 11k exhibited significant neuroprotective effects in damaged SH-SY5Y cells, with the compound 11e showing higher protective effect than compound 11k. Compound 11e exhibited a markedly higher permeability across the blood-brain barrier (BBB) model. Compound 11e was selected as the lead candidate based on mechanistic findings. Molecular dynamics simulation of compound 11e was performed on the AChE binding pocket.

Keywords
2-Indolinone; Anti-cholinesterase; Benzylpiperidine; Blood-brain barrier; Neuroprotection; Thiosemicarbazone.
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