Dual-target ligand discovery for Alzheimer’s disease: triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and β-amyloid aggregation

Abstract

Alzheimer disease (AD) is one of the major neurodegenerative diseases that could not be prevented or completely cured and may lead to death. Here, we target AChE and β-amyloid proteins. Synthesising new triphenylphosphporanylidene derivatives based on the surveyed literature and testing their biological activity revealed promising results especially for the acetyl triphenylphosphoranylidene derivative 8c , which showed good inhibitor activity against AChE enzyme with IC 50 in the nanomolar range (97.04 nM); on the other hand, it showed poor selectivity for AChE versus butyrylcholinesterase but with some futural structural modification, this selectivity can be improved. 8c showed MMP-2 IC 50 of 724.19 nM and Aβ 1-42 aggregation IC 50 of 302.36 nM. A kinetic study demonstrated that compound 8c uncompetitively inhibited AChE. Moreover, derivative 8c showed low cytotoxicity, good in vivo behavioural studies including Y-maze and passive avoidance tests with activity similar to that of donepezil. Finally, in silico studies for 8c predict its good penetration into BBB and good binding affinity in the AChE binding site.

Major Bioactive Prenylated Flavonoids from Humulus lupulus L., Their Applications in Human Diseases and Structure-Activity Relationships (SAR) – A Review

“…111 According to the recently reported studies, among the in silico results of FDA-approved drugs, the binding energies of donepezil were reported between -19.71 kcal/mol and -8.4 kcal/mol calculated by using various algorithms such as AutoDock Vina, Glide/ SP/XP, and MOE etc. [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128] Furthermore, docking scores were given as -10.46 kcal/mol and -7.64 kcal/mol for donepezil and rivastigmine, respectively, by using Glide/ SP. 129 In our previously reported study, we calculated induced fit docking (IFD) and quantum polarized ligand docking (QPLD) scores as -12.20 kcal/mol and -9.54 kcal/mol for known inhibitor neostigmine, respectively, against AChE.…”

“…with donepezil have been reported in various recently reported studies. [138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155] The interactions between the target protein and drug was reported as H bonds with Tyr122, Phe293, Arg294, alkyl bonds with Leu287, Trp284, and pipi stacking with Trp84, and carbon-hydrogen bond with Ser291, Val292, Tyr335. 156 The main interactions for donepezil were reported for H bonds, hydrophobic and pi-interactions with Trp88, Trp279, Phe288, Phe290, Phe330, Tyr334, Arg289.…”

Inhibition of Enzymes Involved in Neurodegenerative Disorders and Aβ1–40 Aggregation by Citrus limon Peel Polyphenol Extract

“…Therefore, a great effort has been devoted to identifying compounds able to prevent or delay the insurgence of the disease. Furthermore, because AD and PD are multifactorial diseases, pharmacological strategies for their treatment aimed for a multitargeting approach that provides the identification of ligands able to interact and affect the activity of two or more molecular targets [11,37,38].…”