Design, synthesis and structure-activity relationship studies of 3-phenylpyrazino[1,2-a]indol-1(2H)-ones as amyloid aggregation and cholinesterase inhibitors with antioxidant activity

Gujral, Sarbjeet Singh; Shakeri, Arash; Hejazi, Leila; Rao, Praveen P.N.

doi:10.1016/j.ejmcr.2022.100075

Cited by 2 publications

(1 citation statement)

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“…The neuroprotective effect of compounds 7a and 7b on cell death induced by Aβ42 was evaluated in vivo using a mouse hippocampal HT22 cell line. , The cells were cultured in Dulbecco’s modified Eagle's media (DMEM) and Ham’s F12 (1:1) with the addition of glutamate (2.5 mM) supplemented with 10% fetal bovine serum (FBS), and 1% penicillin and streptomycin at 37 °C, in 5% CO 2 until 70–80% confluence. Then, the cells were seeded at a density of 50,000 cells/1 mL to a 96-well plate.…”

Section: Methodsmentioning

confidence: 99%

Small Molecules N-Phenylbenzofuran-2-carboxamide and N-Phenylbenzo[b]thiophene-2-carboxamide Promote Beta-Amyloid (Aβ42) Aggregation and Mitigate Neurotoxicity

Zhao,

Rao

2023

ACS Chem. Neurosci.

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This study reports the unusual ability of small molecules N-phenylbenzofuran-2-carboxamide (7a) and Nphenylbenzo[b]thiophene-2-carboxamide (7b) to promote and accelerate Aβ42 aggregation. In the in vitro aggregation kinetic assays, 7a was able to demonstrate rapid increases in Aβ42 fibrillogenesis ranging from 1.5-to 4.7-fold when tested at 1, 5, 10, and 25 μM compared to Aβ42-alone control. Similarly, compound 7b also exhibited 2.9-to 4.3-fold increases in Aβ42 fibrillogenesis at the concentration range tested. Electron microscopy studies at 1, 5, 10, and 25 μM also demonstrate the ability of compounds 7a and 7b to promote and accelerate Aβ42 aggregation with the formation of long, elongated fibril structures. Both 7a and 7b were not toxic to HT22 hippocampal neuronal cells and strikingly were able to prevent Aβ42-induced cytotoxicity in HT22 hippocampal neuronal cells (cell viability ∼74%) compared to the Aβ42-treated group (cell viability ∼20%). Fluorescence imaging studies using BioTracker 490 green, Hoeschst 33342, and the amyloid binding dye ProteoStat further demonstrate the ability of 7a and 7b to promote Aβ42 fibrillogenesis and prevent Aβ42-induced cytotoxicity to HT22 hippocampal neuronal cells. Computational modeling studies suggest that both 7a and 7b can interact with the Aβ42 oligomer and pentamers and have the potential to modulate the selfassembly pathways. The 8-anilino-1-naphthalenesulfonic acid (ANS) dye binding assay also demonstrates the ability of 7a and 7b to expose the hydrophobic surface of Aβ42 to the solvent surface that promotes self-assembly and rapid fibrillogenesis. These studies demonstrate the unique ability of small molecules 7a and 7b to alter the self-assembly and misfolding pathways of Aβ42 by promoting the formation of nontoxic aggregates. These findings have direct implications in the discovery and development of novel small-molecule-based chemical and pharmacological tools to study the Aβ42 aggregation mechanisms, and in the design of novel antiamyloid therapies to treat Alzheimer's disease.

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Section: Methodsmentioning

confidence: 99%