Antiparkinson potential of khellin on rotenone-induced Parkinson's disease in a zebrafish model: targeting MAO, inflammatory, and oxidative stress markers with molecular docking, MD simulations, and histopathology evidence.

In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of -6.5 and -10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of -36.04 ± 55.21 and -56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC50 value of 22.68 ± 0.5 µg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.

Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease.

A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.

Synthesis and biological evaluation of O4'-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents.

Design, synthesis, and biological evaluation of two series of O4'-benzyl-hispidol derivatives and the analogous corresponding O3'-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4'-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3'-benzyl derivatives series. The most potential compound 2e of O4'-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3'-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Identification of Sarmentosin as a Key Bioactive from Blackcurrants (Ribes nigrum) for Inhibiting Platelet Monoamine Oxidase in Humans.

Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro, and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo. These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives.

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 µM, followed by S16 (IC50 = 0.979 µM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 µM, followed by S5 (IC50 = 3.857 µM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 µM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

A Comparison of Phenolic, Flavonoid, and Amino Acid Compositions and In Vitro Antioxidant and Neuroprotective Activities in Thai Plant Protein Extracts.

The leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean are considered rich sources of plant protein with high levels of branched-chain amino acids. Furthermore, they contain beneficial phytochemicals such as antioxidants and anti-inflammatory agents. Additionally, there are reports suggesting that an adequate consumption of amino acids can reduce nerve cell damage, delay the onset of memory impairment, and improve sleep quality. In this study, protein isolates were prepared from the leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean. The amino acid profile, dietary fiber content, phenolic content, and flavonoid content were evaluated. Pharmacological properties, such as antioxidant, anticholinesterase, monoamine oxidase, and γ-aminobutyric acid transaminase (GABA-T) activities, were also assessed. This study found that concentrated protein from mung beans has a higher quantity of essential amino acids (52,161 mg/100 g protein) compared to concentrated protein from sunflower sprouts (47,386 mg/100 g protein), Azolla spp. (42,097 mg/100 g protein), cashew nut (26,710 mg/100 g protein), and mulberry leaves (8931 mg/100 g protein). The dietary fiber content ranged from 0.90% to 3.24%, while the phenolic content and flavonoid content ranged from 0.25 to 2.29 mg/g and 0.01 to 2.01 mg/g of sample, respectively. Sunflower sprout protein isolates exhibited the highest levels of dietary fiber (3.24%), phenolic content (2.292 ± 0.082 mg of GAE/g), and flavonoids (2.014 mg quercetin/g of sample). The biological efficacy evaluation found that concentrated protein extract from sunflower sprouts has the highest antioxidant activity; the percentages of inhibition of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical were 20.503 ± 0.288% and 18.496 ± 0.105%, respectively. Five plant-based proteins exhibited a potent inhibition of acetylcholinesterase (AChE) enzyme activity, monoamine oxidase (MAO) inhibition, and GABA-T ranging from 3.42% to 24.62%, 6.14% to 20.16%, and 2.03% to 21.99%, respectively. These findings suggest that these plant protein extracts can be used as natural resources for developing food supplements with neuroprotective activity.

Preliminary study on cytotoxicity of selegiline on different cancer cell lines: exploration of the induction of ROS-independent apoptosis in breast cancer cells.

The concept of drug repurposing is now widely utilized by biomedical scientists for drug discovery. An example of this is the use of selegiline (SEL), a monoamine oxidase inhibitor that was initially used for the management of depression but is now being considered for another purpose. This study compares the cytotoxic effects of SEL on different cancer cells. Further, the study explores the molecular mechanism of cell death, validating the possibility of its repurposing for cancer. Preliminary analysis of network pharmacological data was conducted in silico, followed by in vitro cytotoxicity tests on PC12, G361, MDA-MB231, MCF7, THP-1, and Hela cells under normoxic and hypoxic conditions, using the MTT assay. The mechanism of cell death was then confirmed by performing DAPI and FITC-conjugated Annexin V and Propidium Iodide (PI) staining assays. Additionally, ROS levels and PKC phosphorylation were also evaluated. In silico analysis has revealed that SEL is associated with ten genes linked to different cancer types. Specifically, SEL was most cytotoxic to neuronal pheochromocytoma, triple-negative human epithelial breast cancer cells, and ER+ and PR+ breast cancer cells. Furthermore, it was observed that this cell death occurred through ROS-independent apoptosis pathways. In addition, SEL was found to inhibit the phosphorylation of PKC, which may contribute to cell death. SEL induces apoptosis in breast cancer cells independently of reactive oxygen species and inhibits the phosphorylation of protein kinase C, which merits further exploration.

Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed.

A versatile family of quaternary propargylamines was synthesized employing the KA2 multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC50 values for hMAO-B range from 152.1 to 164.7 nM while the IC50 values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.

Antidepressant-like Effects of Chinese Quince (Chaenomeles sinensis) Fruit Based on In Vivo and Molecular Docking Studies.

In this study, we examined the potential antidepressant-like effects of Chinese quince fruit extract (Chaenomeles sinensis fruit extract, CSFE) in an in vivo model induced by repeated injection of corticosterone (CORT)-induced depression. HPLC analysis determined that chlorogenic acid (CGA), neo-chlorogenic acid (neo-CGA), and rutin (RT) compounds were major constituents in CSFE. Male ICR mice (5 weeks old) were orally administered various doses (30, 100, and 300 mg/kg) of CSFE and selegiline (10 mg/kg), a monoamine oxidase B (MAO-B) inhibitor, as a positive control following daily intraperitoneal injections of CORT (40 mg/kg) for 21 days. In our results, mice treated with CSFE exhibited significant improvements in depressive-like behaviors induced by CORT. This was evidenced by reduced immobility times in the tail suspension test and forced swim test, as well as increased step-through latency times in the passive avoidance test. Indeed, mice treated with CSFE also exhibited a significant decrease in anxiety-like behaviors as measured by the elevated plus maze test. Moreover, molecular docking analysis indicated that CGA and neo-CGA from CSFE had stronger binding to the active site of MAO-B. Our results indicate that CSFE has potential antidepressant effects in a mouse model of repeated injections of CORT-induced depression.

AMPK activation reduces cancer cell aggressiveness via inhibition of monoamine oxidase A (MAO-A) expression/activity.

AIM: AMPK can be considered as an important target molecule for cancer for its unique ability to directly recognize cellular energy status. The main aim of this study is to explore the role of different AMPK activators in managing cancer cell aggressiveness and to understand the mechanistic details behind the process. MAIN METHODS: First, we explored the AMPK expression pattern and its significance in different subtypes of lung cancer by accessing the TCGA data sets for LUNG, LUAD and LUSC patients and then established the correlation between AMPK expression pattern and overall survival of lung cancer patients using Kaplan-Meire plot. We further carried out several cell-based assays by employing different wet lab techniques including RT-PCR, Western Blot, proliferation, migration and invasion assays to fulfil the aim of the study. KEY FINDINGS: SIGNIFICANCE: This study identifies the importance of AMPK activators as a repurposing agent for combating lung and colon cancer cell aggressiveness. It also suggests SRT-1720 as a potent repurposing agent for cancer treatment especially in NSCLC patients where a point mutation is present in LKB1.

Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.

Indanone: a promising scaffold for new drug discovery against neurodegenerative disorders.

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.

Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin-Sulfonamide-Nitroindazolyl-Triazole Hybrids as Monoamine Oxidase Inhibitors.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

Anti-Depressant Like Effects of Aethoscytus Foveolus Oil by Improving Stress-mediated Alterations of Monoamine Oxidase, Oxidative Stress, and Neuroinflammation In-vivo.

Depression is a neuropsychological disorder with a complex pathophysiology and its pharmacotherapy is compromised by adverse side effects. Addressing the need for effective treatment for depression, the current study aims to characterize the antidepressant activity of oil extract derived from Aethoscytus foveolus, bugs that are widely available in India, in a mice model of stress-induced depression. Chemical moieties characterized by GC-MS of A. foveolus oil extract have shown good affinity for monoamine oxidase A (MAO-A) in-silico. In-vitro MAO-inhibitory assay using mouse brain homogenates also showed similar results at IC50 1.363 nM (R2 = 0.981, SD ± 0.05, n = 3) of it. These results encouraged us to investigate the antidepressant potential of this oil extract in vivo. Stress-exposed mice (Swiss Albino, either sex, 25-30 gm) were administered 5 and 10 mg/kg doses of oil extract and classified as separate groups (N = 6 per group). Behavioral tests like the forced-swim test, tail-suspension test, and open-field test demonstrated significant attenuation of stress-induced depressive-like behavior of mice by both doses (p < 0.0001 with positive control group i.e., stress group), while biochemical tests on mice brain tissues showed amelioration of stress-induced hyperactivation of MAO (p < 0.0001) and oxidative stress (by increasing Superoxide dismutase and catalase, while reducing lipid peroxidase and nitric oxide) (p < 0.0001). The altered mRNA expression of proinflammatory cytokines (NF-κB, IL-6, IL-12, and TNF-α) (p < 0.015) was also improved by this oil extract. In addition, histopathology of hippocampus tissues of mice supports that this oil recovers stress-mediated structural changes of the brain. In conclusion our findings suggest that oil derived from A. foveolus could be beneficial in the alleviation of stress-mediated depressive-like behavior of mice, and in our knowledge, this is the first report identifying anti-neurodegenerative potential of A. foveolus.

Effects of selegiline on neuronal autophagy involving α-synuclein secretion.

Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson's disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca2+ levels.

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

Comprehensive safety evaluation of a novel multitargeting compound XYY-CP1106: A candidate for Alzheimer's disease.

Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD pathology. In most pre-clinical studies, the effectiveness of these multi-targeted anti-AD drugs has been demonstrated but comprehensive safety assessments are lacking. Here, the safety evaluation of a novel multi-targeted candidate in AD (XYY-CP1106), characterized by its dual-property of iron chelation and monoamine oxidase B inhibition, was conducted by multifaceted analysis. Acute toxicity in mice was conducted to investigate the safety of oral administration and the maximum tolerated dose of the agent. In vitro Ames analysis, CHL chromosomal aberration analysis, and bone marrow micronucleus analysis were executed to evaluate the genotoxicity. A teratogenesis investigation in pregnant mice were meticulously performed to evaluate the teratogenesis of XYY-CP1106. Furthermore, a 90-day long-term toxicity analysis in rats was investigated to evaluate the cumulative toxicity after long-term administration. Strikingly, no toxic phenomena were found in all investigations, demonstrating relatively high safety profile of the candidate compound. The securing of safety heightened the translational significance of XYY-CP1106 as a novel multi-targeted anti-AD candidate, supporting the rationality of multitargeting strategy in the designs of smart anti-AD drugs.

Ferulago Angulata methanolic extract ameliorates scopolamine-induced memory impairment through the inhibition of hippocampal monoamine oxidase activity.

Ferulago angulata is a medicinal herb from the Apiaceae family known for its antioxidant, anti-apoptotic, and neuroprotective properties. This study aimed to assess the effects of F. angulata extract on neurobehavioral and biochemical parameters in scopolamine-induced amnesic rats. Fifty-six male Wistar rats were divided into seven groups and orally treated with F. angulata extract (100, 200, 400 mg/kg) and Rivastigmine (1.5 mg/kg) for 10 days. Starting on the sixth day of treatment, the Morris water maze behavioral study was conducted to evaluate cognitive function, with scopolamine administered 30 min before training. Biochemical assays, including monoamine oxidase and oxidative stress measures, were performed on hippocampal tissue. Results showed that extract treatment significantly attenuated scopolamine-induced memory impairment in a dose-dependent manner. Following scopolamine administration, malondialdehyde levels and monoamine oxidase A/B activity increased, while total thiol content and catalase activity decreased compared to the control group. Pretreatment with F. angulata extracts ameliorated the scopolamine-induced impairment in all factors. Toxicological evaluation of liver, lung, heart, and kidney tissues did not indicate any side effects at high doses. The total extract of F. angulata prevents scopolamine-induced learning and memory impairment through antioxidant mechanisms and inhibition of monoamine oxidase. These results suggest that F. angulata extract is effective in the scopolamine model and could be a promising agent for preventing dementia, especially Alzheimer's disease.

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid ß aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 µM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 µM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aß1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 µM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 µM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aß1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.