Hybridization-based design of novel anticholinesterase indanone-carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies


Shahrivar-Gargari M., Hamzeh-Mivehroud M., Hemmati S., Mojarrad J. S., TÜYLÜ KÜÇÜKKILINÇ Z. T., AYAZGÖK B., ...Daha Fazla

ARCHIV DER PHARMAZIE, cilt.354, sa.7, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 354 Sayı: 7
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1002/ardp.202000453
  • Dergi Adı: ARCHIV DER PHARMAZIE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: acetylcholinesterase inhibitor, Alzheimer&apos, s disease, amyloid&#8208, &#946, self&#8208, aggregation, indanone&#8211, carbamate hybrid, partial noncompetitive mixed&#8208, type inhibition
  • Hacettepe Üniversitesi Adresli: Evet

Özet

Inspired by the structures of donepezil and rivastigmine, a novel series of indanone-carbamate hybrids was synthesized using the pharmacophore hybridization-based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 mu M; compound 4b: IC50 = 4.64 mu M). Moreover, the results of the A beta(1-40) aggregation assay revealed that compound 4b is a potent A beta(1-40) aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype-selective enzyme inhibitors. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multitargeted anti-Alzheimer agents.