•Indanones display potential neuroprotective effects by targeting multiple mechanistic pathways of neurodegeneration.•Molecular docking studies and the structure–activity relationship of indanone ...analogs in regulating various neuronal enzymes are presented.•We provide valuable insights that will facilitate future drug design, eventually leading to the development of novel indanone-based neuroprotective therapeutics.
Indanone is a versatile scaffold that has a number of pharmacological properties. The successful development and ensuing approval of indanone-derived donepezil as a drug of choice for Alzheimer’s disease attracted significant scientific interest in this moiety. Indanones could act as small molecule chemical probes as they have strong affinity towards several critical enzymes associated with the pathophysiology of various neurological disorders. Inhibition of these enzymes elevates the levels of neuroprotective brain chemicals such as norepinephrine, serotonin and dopamine. Further, indanone derivatives are capable of modulating the activities of both monoamine oxidases (MAO-A and -B) and acetylcholinesterase (AChE), and thus could be useful in various neurodegenerative diseases. This review article presents a panoramic view of the research carried out on the indanone nucleus in the development of potential neuroprotective agents.
Alzheimer’s disease (AD) is an age-related multifactorial neurodegenerative disorder characterized by severe central cholinergic neuronal loss, gradually contributing to cognitive dysfunction and ...impaired motor activity, resulting in the brain’s cell death at the later stages of AD. Although the etiology of AD is not well understood, however, several factors such as oxidative stress, deposition of amyloid-β (Aβ) peptides to form Aβ plaques, intraneuronal accumulation of hyperphosphorylated tau protein, and low level of acetylcholine are thought to play a major role in the pathogenesis of AD. There is practically no drug for AD treatment that can address the basic factors responsible for the neurodegeneration and slow down the disease progression. The currently available therapies for AD in the market focus on providing only symptomatic relief without addressing the aforesaid basic factors responsible for the neurodegeneration. Ferulic acid (FA) is a phenol derivative from natural sources and serves as a potential pharmacophore that exerts multiple pharmacological properties such as antioxidant, neuroprotection, Aβ aggregation modulation, and anti-inflammatory. Several FA based hybrid analogs are under investigation as a multi-target directed ligand (MTDLs) to develop novel hybrid compounds for the treatment of AD. In the present review article, we are focused on the critical pathogenic factors responsible for the onset of AD followed by the developments of FA pharmacophore-based hybrids compounds as a novel multifunctional therapeutic agent to address the limitations associated with available treatment for AD. The rationale behind the development of these compounds and their pharmacological activities in particular to their ChE inhibition (ChEI), neuroprotection, antioxidant property, Aβ aggregation modulation, and metal chelation ability, are discussed in detail. We have also discussed the discovery of caffeic and cinnamic acids based MTDLs for AD. This review paper provides an in-depth insight into the research progress and current status of these novel therapeutics in AD and prospects for developing a druggable molecule with desired pharmacological affinity and reduced toxicity for the management of AD.
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•This review article summarizes the development of druggable Ferulic acid (FA) and analogs-derivatives to manage Alzheimer’s disease (AD).•The potential impact of the developed compounds on various critical aspects of AD are discussed in detail.•The current research on the development of FA will hopefully add disease-modifying properties to symptomatic treatment for AD.
Insufficient acetylcholine (ACh) can cause cognitive and memory dysfunction, clinically known as, Alzheimer's disease (AD). Acetylcholinesterase (AChE) can hydrolyze ACh into acetic acid and ...inactivate choline. Therefore, inhibiting the activity of AChE would help to improve the effectiveness of AD treatment. Currently, the methods for rapid screening of AChE inhibitors are limited. This study reports the application of AChE-immobilized magnetic nanoparticles as a drug screening tool to screen AChE inhibitors for natural products. First, AChE was immobilized on a surface of amino-modified magnetic nanoparticles using covalent binding and the AChE concentration, and the pH as well as time was optimized to obtain the maximum enzyme immobilization yield (61.4 μg/mg), and the kinetic model indicated that AChE-immobilized magnetic nanoparticles and the substrate had the high affinity and specificity. Then, a ligand fishing experiment was carried out using a mixed model of tacrine (an inhibitor of AChE) and caffeic acid (a non-inhibitor of AChE) to verify the specificity of the immobilized AChE, and the conditions for ligand fishing were further optimized. Finally, the optimized immobilized AChE was combined with UPLC-MS to screen for AChE inhibitors in Selaginella doederleinii Hieron extracts. Four compounds were confirmed to be potent AChE inhibitors. Among the four compounds, amentoflavone had a stronger AChE inhibitory effect than tacrine (positive control) with an IC50 of 0.73 ± 0.009 μmol/L. The results showed that AChE-functionalized magnetic nanoparticles can be used in the discovery of target drugs from complex matrices.
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•A screening method using magnetic nanoparticles-based acetylcholinesterase microreactor (immobilized AChE) was established.•Immobilized AChE was firstly applied for the AChE ligand fishing from Selaginella doederleinii Hieron.•The immobilized AChE based assay offers a novel anti-acetylcholinesterase drug discovery tool.•The method may be used to other enzymes to screen bioactive ligands.
-Synthesis of pyrazole and pyrazolone derivatives (1), (3) and (4).-In silico study of pyrazole and pyrazolone derivatives as (AChE) inhibitors.-In vitro (AChE) inhibition study of pyrazole and ...pyrazolone (1), (3) and (4).-pyrazolone derivative (1) exhibited good inhibitory activity against AchE.-pyrazolone derivative (1) has potential for in vivo anti-Alzheimer evaluations.
Pyrazole and pyrazolone derivatives have attracted growing interest over the years because of their versatile applications in various fields. In this work, we describe the condensation of thiosemicarbazide and tosylhydrazine with ethyl acetoacetate using different catalysis. Docking study was performed for the reference compound rivastigmine and the prepared pyrazole and pyrazolones against human acetylcholinesterase (AChE). Based on the binding pose, compound (1) and (3) were occupying the site located in the deep cavity of AChE and rivastigmine was occupied the central active site cavity of AChE. While, the compound (4) was occupied the exterior active site cavity of the enzyme. The detailed interactions between the rivastigmine and the synthesized compounds and human acetylcholinesterase were determined and showed that the AChE- compound (1) complex was established several interactions with catalytic residues (His 447 and Ser 203) and the critical residue for the inhibition of the human enzyme (Tyr 337). Thus, this compound was predicted to be the most potent compound. The in vitro Acetylcholinesterase (AChE) inhibition studies showed that compound (1) has a good inhibitory activity against AChE and this activity is similar to that of rivastagmine with an IC50 value of 0.38 ± 0.019 mg/mL (p < 0.05) and 0.36 ± 0.018 mg/mL (p < 0.05), respectively. These findings confirmed the in silico results and suggest the possibility of using compound (1) as anti-Alzheimer drug.
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The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine ...analogs (17–31 and 32–46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ1-42-induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies.
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•Design and synthesis of a series of N-benzylpiperidine analogs (17–46).•Compounds 25, 26, 40, and 41 exhibited balanced inhibition of AChE and BACE-1.•Propidium iodide displacement and inhibition of Aβ aggregation by 40 and 41.•Biochemical analysis of rat brain homogenates suggested antioxidant potential.•Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models.
The present study investigated the synthesis of mesoporous hollow carbon spheres (MHCS) and magnetic mesoporous hollow carbon spheres with core-shell structures (Fe₃O₄@MHCS). Two acetylcholinesterase ...sensors (acetylcholinesterase/mesoporous hollow carbon spheres/glassy carbon electrode (AChE/MHCS/GCE) and acetylcholinesterase/core-shell magnetic mesoporous hollow carbon spheres/glassy carbon electrode (AChE/Fe₃O₄@MHCS/GCE) based on mesoporous carbon materials were prepared. Under the optimum conditions, using Malathion as the model compound, the developed biosensors showed a wide detection range, low detection limit, good reproducibility, and high stability. The AChE/MHCS/GCE electrochemical sensor response exhibited two good linear ranges at the incubation time of 10 min at the Malathion concentration ranges of 0.01 to 100 ppb and 100 to 600 ppb, with a detection limit of 0.0148 ppb (S/N = 3). The AChE/Fe₃O₄@MHCS/GCE electrochemical sensor that was operated with an incubation time of 12 min at the malathion concentration ranges between 0.01⁻50 ppb and 50⁻600 ppb had a detection limit of 0.0182 ppb (S/N = 3). Moreover, the AChE/MHCS/GCE and AChE/Fe₃O₄@MHCS/GCE biosensors were effective for the detection of real samples, and were demonstrated to be suitable for the field-testing of organophosphorus pesticide (OP) residues.
Carbaryl is a widely-used carbamate pesticide and the detection of its residues in environmental, food and clinical samples is of great importance. In this sturdy, we developed a green ...photocatalytic-biosensor based on double strand DNA-SYBR green I complex for sensitively colorimetric detection of carbaryl. This green photocatalytic-biosensor can oxidize 3,3′,5,5′-tetramethylbenzidine (TMB) into blue ox-TMB. Meanwhile thiocholine is catalytically produced by acetylcholinesterase (AChE) to directly reduce blue ox-TMB into colorless TMB. But the activity of AChE will be suppressed by carbaryl, thus generating less thiocholine and resulting in more ox-TMB for colorimetric analysis. After the careful optimization of sensing conditions (2 μM for DNA concentration, 50 × concentration for SYBR Green I, 10 min for illumination time), the lowest detectable concentration for carbaryl is 0.008 ng/mL with a linear response in the range of 0.01–0.25 ng/mL. In addition, this photocatalytic-biosensor has good selectivity over non-target chemicals (acetamiprid, atrazine, carbendazim, melamine, bisphenol A, estradiol). It also allows detection of pesticides in real samples verified by a standard HPLC method.
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•A novel photocatalytic-biosensor for colorimetric detection of pesticide (carbaryl).•The photo-catalyst is green without using any unstable H2O2, or noxious metal ions/nanoparticles.•The biosensor has low detection limit, good specificity, ability for real samples detection.
•A new series of chalcones based pyrazole were designed and synthesized.•Compounds 5a, 5l and 5w were assigned their chemical structures by X-ray diffraction analysis.•Some compounds exhibited in ...vitro anti-acetylcholinesterase potential, antidiabetic potential against α-glucosidase and α-amylase, and antioxidant potentials against DPPH free radicals.
About 25 chalcones engrafted pyrazole scaffold combined with benzothiophene and indole moieties 5a-y were designed and constructed in two steps using readily available acetyl acetone, phenyl hydrazine and DMF-DMA as starting material. The synthesized chalcone analogs were screened for in vitro anti-acetylcholinesterase potential, antidiabetic potential against α-glucosidase and α-amylase, and antioxidant potentials against DPPH free radicals. The compounds 5a, 5r, 5m, 5o and 5p showed strongest acetylcholine esterase inhibition (AChEI) with IC50 values of 5 ± 1.16 μg/mL (5p), 8 ± 0.14 μg/mL (5a), 8 ± 0.57 μg/mL (5r), 10 ± 1.73 μg/mL (5m) and 10 ± 0.60 μg/mL (5o). The highest inhibition against α-glucosidase was demonstrated by compounds 5f, 5o, 5j, 5e, 5c, and 5a with IC50 values of 4 ± 0.14, 6 ± 0.43, 8 ± 0.43, 10 ± 0.11, 11 ± 0.28 and 12 ± 0.57 μg/mL respectively, whereas, the compounds 5x, 5d, 5w, 5y and 5u showed prominent α-amylase inhibition with IC50 values of 20 ± 1.15 μg/mL (5x), 30 ± 0.60 μg/mL (5d), 40 ± 0.72 μg/mL (5w), 40 ± 0.50 μg/mL (5y), and 60 ± 2.19 μg/mL (5u). The highest anti-oxidant potential against DPPH free radicals was demonstrated by compounds 5w, 5v and 5y with IC50 values of 160 ± 5.77, 260 ± 4.63, and 360 ± 4.04 μg/mL respectively. Molecular docking was used to study their interaction with the active site of enzymes.
Chemical insecticides are effective at controlling mosquito populations, but their excessive use can pollute the environment and harm non-target organisms. Mosquitoes can also develop resistance to ...these chemicals over time, which makes long-term mosquito control efforts challenging. In this study, we assessed the phytochemical, biochemical, and insecticidal properties of the chemical constituents of cajeput oil. Results show that
essential oil may exhibit mosquito larvicidal properties against
larvae (second-fourth instar) at 24 h post-treatment. At 24 h post-exposure, the essential oil resulted in a significant decrease in detoxifying enzymes. All of these findings indicate that cajeput oil infects
larvae directly affect the immune system, leading to decreased immune function. Cajeput oil significantly affects the second, third, and fourth instar larvae of
, according to the bioassay results. Cajeput oil does not induce toxicity in non-target
earthworm species, as indicated by a histological study of earthworms. Phytochemical screening and GC-MS analysis of the essential oil revealed the presence of several major phytochemicals that contribute to mosquito larvicidal activity. The importance of cajeput oil as an effective candidate for biological control of the malarial vector
is supported by this study.
Organophosphorus flame retardants (OPFRs) have been implicated as neurotoxicants, but their potential neurotoxicity and mechanisms remain poorly understood. Herein, we investigated the neurotoxicity ...of selected OPFRs using zebrafish as a model organism. Environmentally relevant concentrations (3–1500 nM) of three classes of OPFRs (aryl-OPFRs, chlorinated-OPFRs, and alkyl-OPFRs) were tested in zebrafish larvae (2–144 h post-fertilisation) alongside the neurotoxic chemical chlorpyrifos (CPF) that inhibits acetylcholinesterase (AChE). Exposure to aryl-OPFRs and CPF inhibited AChE activities, while chlorinated- and alkyl-OPFRs did not inhibit these enzymes. Biolayer interferometry (BLI) was used to probe interactions between OPFRs and AChE. The association and dissociation response curves showed that, like CPF, all three selected aryl-OPFRs, triphenyl phosphate (TPHP), tricresyl phosphate (TCP) and cresyl diphenyl phosphate (CDP), bound directly to AChE. The affinity constant (KD) for TPHP, TCP, CDP and CPF was 2.18 × 10−4, 5.47 × 10−5, 1.05 × 10−4 and 1.70 × 10−5 M, respectively. In addition, molecular docking revealed that TPHP, TCP, CDP and CPF bound to AChE with glide scores of − 7.8, − 8.3, − 8.1 and − 7.3, respectively. Furthermore, the calculated binding affinity between OPFRs and AChE correlated well with the KD values measured by BLI. The present study revealed that aryl-OPFRs can act as potent AChE inhibitors, and may therefore present a significant ecological risk to aquatic organisms.
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•Inhibition of AChE by OPFRs was evaluated in zebrafish larvae.•Aryl-OPFRs inhibited AChE activity, but chlorinated- and alkyl-OPFRs did not.•Biolayer interferometry showed that aryl-OPFRs bind AChE.•Molecular docking showed that aryl-OPFRs interact more strongly than other OPFRs.•Aryl-OPFRs are potent neurotoxicants that posing a risk to aquatic organisms.
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