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As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-β (Aβ) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aβ 42 -induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aβ 42 -induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aβ 42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aβ 42 -stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H 2 O 2 - and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aβ 42 by acting on Aβ oligomerization and fibrilization. Besides, TJ1 reversed Aβ-, H 2 O 2 - and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aβ 42 and Aβ plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,6-O,O-diacetylbritannilactone (OABL), a 1,10-seco-eudesmane sesquiterpene lactone isolated from the herb Inula britannica L., exhibited strong anti-inflammatory activity in vitro as well as favorable BBB penetration property. OABL reduced LPS-induced neuroinflammation in BV-2 microglial cells as assessed by effects on the levels of inflammatory mediators including NO, PGE 2 , TNF-α, iNOS, and COX-2, as well as the translocation of NF-κB. Besides, OABL also exhibited pronounced neuroprotective effects against oxytosis and ferroptosis in the rat pheochromocytoma PC12 cell line. For in vivo research, OABL (20 mg/kg B.W., i.p.) for 21 d attenuated the impairments in cognitive function observed in 6-month-old 5xFAD mice, as assessed with the Morris water maze test. OABL restored neuronal damage and postsynaptic density protein 95 (PSD95) expression in the hippocampus. OABL also significantly reduced the accumulation of amyloid plaques, the Aβ expression, the phosphorylation of Tau protein, and the expression of BACE1 in AD mice brain. In addition, OABL attenuated the overactivation of microglia and astrocytes by suppressing the expressions of inflammatory cytokines, and increased glutathione (GSH) and reduced malondialdehyde (MDA) and super oxide dismutase (SOD) levels in the 5xFAD mice brain. In conclusion, these results highlight the beneficial effects of the natural product OABL as a novel treatment with potential application for drug discovery in AD due to its pharmacological profile., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC 50 value of 0.57 μM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H 2 O 2 -induced PC12 cells damage and ferroptosis without cytotoxicity at 10 μM, as well as selectively metal chelating properties via chelating Cu 2+ . In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)