A new neuroprotective candidate TJ1 targeting amyloidogenesis in 5xFAD Alzheimer's disease mice.

As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) 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 Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- 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 Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß 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.

Trienomycin A-simplified analogs: Synthesis and anti-neuroinflammatory activity.

A series of novel trienomycin A (TA)-mimetic compounds (5a-p) have been designed, synthesized, and evaluated for their in vitro anti-neuroinflammatory and neuroprotective activities. Among them, compounds 5h, 5n, and 5o exhibits relatively strong NO inhibitory activity in LPS-activated BV-2 cells with the EC50 values of 12.4, 17.3, and 8.9 µM, respectively. Moreover, 5h showed evidently neuroprotective effect against H2O2-induced PC-12 cells without cytotoxicity at 20 µM. Overall, these compounds can provide a better understanding of the structure-activity relationship of TA and furnish research ideas for anti-neuroinflammatory and neuroprotective agents.

Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity relationships.

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 EC50 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 H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. 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.