The use of dual acetylcholinesterase (AChE)–monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a–4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the in vitro fluorometric method. Additionally, amyloid beta (Aβ)-aggregation inhibitory effects of active compounds were evaluated by means of an in vitro kit-based method. The biological evaluation showed that compounds 4a, 4d, 4f, 4h, 4k and 4m displayed significant activity against AChE and MAO-B enzymes. Compound 4f displayed inhibitory activity against AChE and MAO-B enzyme with IC50 values of 23.4 ± 1.1 nM and 40.3 ± 1.7 nM, respectively. It has been revealed that compound 4f may have the potential to inhibit AChE and MAO-B enzymes, as well as the ability to prevent the formation of beta amyloid plaques accumulated in the brains of patients suffering from AD. In silico studies also support the obtained biological activity findings. Compound 4f provided strong interactions with the active site of both enzymes. In particular, the interaction of compound 4f with flavin adenine dinucleotide (FAD) in the MAO-B enzyme active site is a promising and exciting finding.

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

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

Synthesis, structural elucidation, in vitro antibacterial activity, DFT calculations, and molecular docking aspects of mixed-ligand complexes of a novel oxime and phenylalanine.

A series of quinazolin-4(3H)-one derivatives was designed through scaffold-hopping strategy and synthesized as novel multifunctional anti-AD agents demonstrating both cholinesterase inhibition and anti-inflammatory activities. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated, and the enzyme kinetics study as well as detailed binding mode via molecular docking were performed for selected compounds. MR2938 (B12) displayed promising AChE inhibitory activity with an IC50 value of 5.04 μM and suppressed NO production obviously (IC50 = 3.29 μM). Besides, it was able to decrease the mRNA levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CCL2 at 1.25 μM. Further mechanism study suggested that MR2938 suppressed the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. All these results indicate that MR2938 is a good starting point to develop multifunctional anti-AD lead compounds. 

Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities.

An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC50 of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5-120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10-6 cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs. 

Run-Ze Liu

Papers

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