Novel Benzimidazole–Isatin Hybrids as Potential Therapeutics for Alzheimer’s Disease: Design, Microwave-Assisted Synthesis, and Structure–Activity Relationship

Creative Commons License

Yılmaz F., Akyüz G.

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, cilt.52, sa.5, ss.139, 2026 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 52 Sayı: 5
  • Basım Tarihi: 2026
  • Doi Numarası: 10.1134/s1068162025604355
  • Dergi Adı: RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Scopus, Materials Science & Engineering Collection (ProQuest), Technology Collection (ProQuest), Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, Chemical Abstracts Core
  • Sayfa Sayıları: ss.139
  • Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
  • Recep Tayyip Erdoğan Üniversitesi Adresli: Evet

Özet

Abstract—Objective: A novel series of benzimidazole–isatin hybrid compounds was designed and synthesized to evaluate their inhibitory activity against acetylcholinesterase (AChE) and establish comprehensive structure activity relationships (SAR). Methods: Target hybrids and intermediate precursors were synthesized using both conventional heating and microwave-assisted protocols. Structural elucidation of all synthesized compounds was unequivocally performed using 1H, 13C NMR, high-resolution mass spectrometry (HRMS), and elemental analy sis. Results and Discussion: Biological evaluation revealed that integration of the isatin scaffold significantly enhanced AChE inhibitory potency compared with that of the isatin-free intermediate precursors. Notably, several hybrid derivatives displayed superior inhibitory activity relative to the reference drug galantamine (IC50 = 56.4 ± 0.7 µM). SAR analysis demonstrated that electron-withdrawing substituents on the benzyl moiety, in synergy with halogenation on the isatin ring, substantially boosted AChE inhibition. Conclusions: This study underscores microwave irradiation as a highly efficient and superior synthetic approach, establishing benzimidazole–isatin hybrids—most notably compound Vi—as promising pharmacophoric scaffolds for drug development targeting Alzheimer’s disease.