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

Ren, Bo; Guo, Cong; Liu, Run-Ze; Bian, Zhao-Yuan; Liu, Rong-Chun; Huang, Lan-Fang; Tang, Jiang‐Jiang

doi:10.1016/j.ejmech.2021.114031

Cited by 16 publications

(2 citation statements)

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“… 3 Several FDA-approved anti-AD drugs currently available clinically (such as cholinesterase inhibitors: donepezil, rivastigmine, galantamine) provide only partial relief of symptoms and cannot stop or reverse disease progression. 4 Donepezil works in Alzheimer's disease specifically as an acetylcholinesterase (AChE) inhibitor at mild to moderate levels. However, donepezil has side effects such as nausea, diarrhea, weakness, dizziness, urinary incontinence, and insomnia.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

et al. 2022

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“…Since oximes, including derivatives of 11 H -indeno[1,2- b ]quinoxalin-11-ones and related tryptanthrin analogs, could form complexes with different metal ions, and the ion-chelating properties of ligands can alter to their biological activities [ 38 , 39 , 40 ], we hypothesized that other salts of IQ-1 may lead to a change in therapeutic potential of the resulting ion complexes. In particular, we evaluated lithium salts of IQ-1 because Li + is also a promising candidate for the treatment of ischemic stroke [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion

et al. 2022

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The c-Jun N-terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11H-indeno[1,2-b]quinoxaline-11-one oxime (IQ-1L) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li+ ion stabilizes the six-membered ring with the 11H-indeno[1,2-b]quinoxaline-11-one (IQ-1) oximate better than Na+. Molecular docking showed that the Z isomer of the IQ-1 oximate should bind JNK1 and JNK3 better than (E)-IQ-1. Indeed, experimental analysis showed that IQ-1L exhibited higher JNK1-3 binding affinity in comparison with IQ-1S. IQ-1L also was a more effective inhibitor of lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue monocytes and was a potent inhibitor of proinflammatory cytokine production by MonoMac-6 monocytic cells. In addition, IQ-1L inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. In a rat model of focal cerebral ischemia (FCI), intraperitoneal injections of 12 mg/kg IQ-1L led to significant neuroprotective effects, decreasing total neurological deficit scores by 28, 29, and 32% at 4, 24, and 48 h after FCI, respectively, and reducing infarct size by 52% at 48 h after FCI. The therapeutic efficacy of 12 mg/kg IQ-1L was comparable to that observed with 25 mg/kg of IQ-1S, indicating that complexation with Li+ improved efficacy of this compound. We conclude that IQ-1L is more effective than IQ-1S in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.

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Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation

Yin

et al. 2023

Angewandte Chemie

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(−)‐Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X‐ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio‐ and stereoselective hydrogenation, and subsequent merged MBH–Tsuji–Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)‐euptox A (2) in 8 steps from commercially available monoterpene (−)‐carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2O2‐treated SH‐SY5Y and PC12 cells.

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

Cited by 16 publications

References 60 publications

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation

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