Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of β-amyloid aggregation and inflammation mediated neurotoxicity
Graphical abstract
Introduction
Alzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder that affects millions of elderly people accompanied with cognitive impairment, memory loss, abnormal behavior and decline in language skills.1 The pathologic hallmarks of AD are the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain.2, 3 Although the precise etiology remain elusive, several factors, such as deposits of β-amyloid peptide (Aβ), low levels of acetylcholine (ACh), oxidative stress, inflammation and tau protein hyperphosphorylation play vital roles in the pathogenesis of AD.4 Moreover, several hypothesis based on the above factors have been suggested to make clear the mechanism of AD pathogenesis.5
At present, the hypothesis to explain the mechanism of AD development contain the classic ‘amyloid hypothesis’, conventional ‘cholinergic hypothesis’ and ‘inflammatory hypothesis’, etc.6, 7, 8 According to the ‘cholinergic hypothesis’, the recession of ACh level leads to cognitive and memory deficits. So, maintaining and recovering the cholinergic function is deemed to be beneficial to the disease.9, 10 Based on ‘amyloid hypothesis’, the accumulation of Aβ plaques in the central nervous system (CNS) plays a pivotal role in the pathology of AD.11 Aβ peptides include two main abundant isoforms, Aβ1–42 and Aβ1–40. They are accumulated through sequential cleaving of the amyloid precursor protein (APP) by β- and γ-secretase.12 Of the two forms of Aβ, Aβ1–42 exerts lower solubility and more toxic and has a higher propensity to form fibrillar aggregates. Aβ1–42 soluble oligomers and the assembly of its aggregates into fibrils cause strong neuronal toxicity. Therefore, finding compounds that ubiquitously slow or block the process of Aβ1–42 aggregation attracts much current attention.13
Converging lines of evidences supports the verdict that neuroinflammation is associated with AD pathology.14, 15, 16 The major players involved in the inflammatory process in AD are thought to be the microglia.17 Microglia, the immune cells of the CNS, plays crucial roles in defense against injury and tissue repair.18, 19 There exist a variety of transmembrane pattern-recognition receptors called Toll-like receptors (TLRs) expressed limited to microglia, astrocytes and in the brain. TLRs are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands.20 Recent findings indicate that TLRs/MyD88 signaling pathway is implicated in the pathogenesis of AD. In the CNS, microglia express several different TLRs that, when activate by corresponding pathogen-associated molecular patterns (PAMPs), induce the production of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, which may increase neuronal damage and results in neuronal cell death in the brain.21, 22 Many literatures also demonstrated that excess Aβ1–42 could trigger the inflammatory process in AD, gain the production of pro-inflammatory cytokines through the activation of TLRs/MyD88 signaling pathway, vice versa.23, 24
The complex nature of AD indicates that a unitary mechanism of action is unable to provide a comprehensive therapeutic approach to such multifaceted neurodegenerative disease. Thus, the efficient therapy is more likely to base on the ‘one molecule, multiple targets’ paradigm.25 This strategy is based on the evidence that a compound able to bind to different targets involved in the disease might be more suitable for the treatment.26, 27, 28 So, the designed molecules posses the following properties, like inhibition of self-mediated Aβ1–42 aggregation, reduction of the amount of pro-inflammatory factors and prevention of inflammation mediated toxicity, emerged as promising agent for AD treatment. The Liver X Receptor agonist (T0901317) could alleviate AD pathology by acting on amyloid deposition and brain inflammation.29 Additionally, Schmued LC group reported that the compound K114 could inhibit Aβ1–42 aggregation and inflammation in vitro and in vivo in AD/Tg mice.30
ST2825 (structure showed in Fig. 1), a peptidomimetic inhibitor of MyD88, could inhibit the homodimerization of MyD88 effectively, and thus block the TLRs/MyD88 signaling pathway. As a result, the nuclear transcription factor κB (NF-κB), a transcription factor downstream of MyD88 signaling pathway that allows production of essential effector molecules like pro-inflammatory cytokines for immune and inflammatory responses, will be suppressed.31, 32 Considering the complex structures and bad thermal stability of ST2825, and also its moderate bioactivity due to poor solubility, it is essential to search the non-peptidomimetic compounds with simple structures and owned good stability, as well as preferable solubility. Herein, a series of 2-piperidone derivatives were designed and synthesized. The pharmacological effects of these novel compounds were validated based on the multitarget-directed ligands strategy (MTDLs) by measurement of Aβ1–42 self-aggregation inhibitory activities, assessing the ability to regulate the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) stimulated by LPS in microglia and prevent the inflammation mediated toxicity in SH-SY5Y cells. Molecular modeling studies allowed to elucidate the interactions between target compounds and amino acid residues of the active site of MyD88.
Section snippets
Chemistry
The synthetic strategies to 2-piperidone derivatives (5a–5c, 6a–6b, 7a–7q and 8) were illustrated in Scheme 1. Intermediate 2a–2d was synthesized from aromatic aldehydes and malonic acid by Knoevenagel reaction with pyridine as catalyst.33 Use the p-toluenesulfonic acid (TsOH) as promoter to esterify the intermediate 2a–2d with ethanol provided high yields of intermediate 3a–3d.34 According to described methods, the ethyl 4-nitro-3-phenylbutanoate 4a–4d was synthesized from the intermediate 3a–
Conclusion
In conclusion, a series of 2-piperidone derivatives were designed, synthesized and biologically evaluated. Most of 2-piperidone derivatives showed a good inhibitory potency on Aβ1–42 self-aggregation. Especially compound 7q exhibited the highest inhibitory potency (59.11% at 20 μM), and inhibited Aβ1–42 self-aggregation in a concentration-dependent manner. Additionally, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity.
Chemistry
Melting points were measured on an uncorrected X-5 Digital melting point apparatus. IR (KBr-disc) spectra were detected by Bruker VERTEX 70 spectrometer one scanning 3500 and 350 cm−1. 1H NMR and 13C NMR spectra were recorded using TMS as the internal standard in DMSO-d6 on a Bruker spectrometer at 400 and 100 MHz, respectively. The mass spectra were recorded on a Finnigan LCQ Deca XP™ instrument with an ESI mass selective detector. Reactions were monitored by thin layer chromatography (TLC) on
Acknowledgement
This work was supported by Grants from the Key Project of Independent Innovation Research Fund of Huazhong University of Science and Technology (2014YGYL017) to Prof. Feng-Chao Jiang.
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