Synthesis and molecular modeling studies of 1-benzyl-2-indolinones as selective AChE inhibitors

Apaydın Ç. B., Soylu Eter Ö., Eraslan-Elma P., Özsoy N., Karall N. L.

Future Medicinal Chemistry, cilt.14, sa.23, ss.1705-1723, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 14 Sayı: 23
  • Basım Tarihi: 2022
  • Doi Numarası: 10.4155/fmc-2022-0139
  • Dergi Adı: Future Medicinal Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.1705-1723
  • Anahtar Kelimeler: acetylcholinesterase inhibitors, molecular docking, molecular dynamics, sulfonamides, synthesis, 2-indolinones
  • İstanbul Üniversitesi Adresli: Evet

Özet

Background: Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H2S donors, thioamide, thiocarbamate and thiourea groups are also critically important. Materials & methods: The 1-benzyl-2-indolinones 6a-n were designed using molecular modeling and synthesized, and their acetylcholinesterase and butyrylcholinesterase inhibitory effects were then investigated. Results: The compounds 6h (inhibition constant [Ki] = 0.22 μM; selectivity index [SI] = 26.22), 6i (Ki = 0.24 μM; SI = 25.83), 6k (Ki = 0.22 μM; SI = 28.31) and 6n (Ki = 0.21 μM; SI = 27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterase compared with donepezil (Ki = 0.41 μM; SI = 2.12). Analysis of molecular dynamics simulations with compounds 6k and 6n indicated that the preferred binding might be at allosteric binding pocket 4 of the enzyme. Conclusion: Benzyl substitution at the 1-position of the indole ring significantly increased potency and selectivity.