Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase

Jeelan Basha Shaik, Daniel Pushparaju Yeggoni, Yelamanda Rao Kandrakonda, Mohan Penumala, Raveendra Babu Zinka, Kasi Viswanath Kotapati, Mark Manidhar Darla, Dinakara Rao Ampasala, S. Rajagopal, Damu Gangaiah Amooru

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Abstract

In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q)were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 10 4 , 2.22 × 10 4 , 1.18 × 10 4 , 9.8 × 10 3 and 3.2 × 10 4 M −1 and free energy change as −5.83, −5.91, −5.51, −5.41 and −6.12 kcal M −1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.

Original languageEnglish
Article number102960
JournalBioorganic Chemistry
Volume88
DOIs
Publication statusPublished - Jul 1 2019

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Keywords

  • Alzheimer's disease
  • Cyanoacetamide
  • Interaction with AChE
  • Methoxyflavones
  • MTDLs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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