2. Academic Validation
  3. Unleashing new MTDL AChE and BuChE inhibitors as potential anti-AD therapeutic agents: In vitro, in vivo and in silico studies

Unleashing new MTDL AChE and BuChE inhibitors as potential anti-AD therapeutic agents: In vitro, in vivo and in silico studies

  • Int J Biol Macromol. 2024 May;268(Pt 1):131740. doi: 10.1016/j.ijbiomac.2024.131740.
Dalia Zaafar 1,  Nehal H Elghazawy 2,  Afnan Hassan 3,  Mohamed Y Mahmoud 4,  Alaa F Bakr 5,  Reem K Arafa 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 12974, Egypt. Electronic address: dalia.zaffar@pharm.mti.edu.eg.
  • 2 Drug Design and Discovery Lab, Zewail City of Science and Technology, Cairo 12578, Egypt.
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 12974, Egypt; Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo 12578, Egypt. Electronic address: afhassan@zewailcity.edu.eg.
  • 4 Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt. Electronic address: mohamed_yehia@cu.edu.eg.
  • 5 Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt.
  • 6 Drug Design and Discovery Lab, Zewail City of Science and Technology, Cairo 12578, Egypt; Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo 12578, Egypt. Electronic address: rkhidr@zewailcity.edu.eg.
PMID: 38653428 DOI: 10.1016/j.ijbiomac.2024.131740
Abstract

Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC50s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated β-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased Caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories.

Keywords

Acetyl choline esterase and Butyryl choline esterase inhibitors; Alzheimer's disease; Multi-target directed ligands.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z