Search Results (147)

Some studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cyclization approach is applied to synthesize the basic hydrazine used for the formation of the designed series of hydrazones (15a–15g). The potential neurotoxic and neuroprotective effects of the newly synthesized derivatives were investigated in vitro using different models of induced oxidative stress at three subcellular levels (rat brain synaptosomes, mitochondria, and microsomes). The results identified as the least neurotoxic molecules, 15a, 15d, and 15f applied at a concentration of 100 µM to the isolated fractions. In addition, the highest statistically significant neuroprotection was observed for 15a and 15d at a concentration of 100 µM using three different injury models on subcellular fractions, including 6-hydroxydopamine in rat brain synaptosomes, tert-butyl hydroperoxide in brain mitochondria, and non-enzyme-induced lipid peroxidation in brain microsomes. The hMAOA/MAOB inhibitory activity of the new compounds was studied at a concentration of 1 µM. The lack of a statistically significant hMAOA inhibitory effect was observed for all tested compounds, except for 15f, which showed 40% inhibitory activity. The most prominent statistically significant hMAOB inhibitory effect was determined for 15a, 15d, and 15f, comparable to that of selegiline. The corresponding selectivity index defined 15f as a non-selective MAO inhibitor and all other new hydrazones as selective hMAOB inhibitors, with 15d indicating the highest selectivity index of >471. The most active and least toxic representative (15d) was evaluated in vivo on Rotenone based model of Parkinson’s disease. The results revealed no microscopically visible alterations in the ganglion and glial cells in the animals treated with rotenone in combination with 15d. Full article

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder with a pressing need for novel therapeutics. However, current medications only offer symptomatic relief, without tackling the underlying pathology. To explore the bioactive potential of marine-derived fungi, this study focused on Aspergillus terreus C23-3, a strain isolated from the coral Pavona cactus in Xuwen County, China, which showed a richer metabolite fingerprint among the three deposited A. terreus strains. AntiSMASH analysis based on complete genome sequencing predicted 68 biosynthetic gene clusters (BGCs) with 7 BGCs synthesizing compounds reported to have anti-AD potential, including benzodiazepines, benzaldehydes, butenolides, and lovastatin. Liquid chromatography coupled with mass spectrometry (LC-MS)-based combinational metabolomic annotation verified most of the compounds predicted by BGCs with the acetylcholinesterase (AChE) inhibitor territrem B characterized from its fermentation extract. Subsequently, molecular docking showed that these compounds, especially aspulvione B1, possessed strong interactions with AD-related targets including AChE, cyclin-dependent kinase 5-p25 complex (CDK5/p25), glycogen synthase kinase-3β (GSK-3β), and monoamine oxidase-B (MAO-B). In conclusion, the genomic–metabolomic analyses and molecular docking indicated that C23-3 is a high-value source strain for anti-AD natural compounds. Full article

Alzheimer’s disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure–activity relationships, and their interactions with the molecular targets at the molecular level. Full article

Coumarin represents a privileged structural motif that is quite common in nature-derived and synthetic bioactive molecules. Some of us have recently described the straightforward preparation of complex furo[3,2-c]coumarins through a sequential double coupling protocol. Aiming at finding novel chemical probes for the modulation of key anti-Alzheimer’s targets, a small subset of furo[3,2-c]coumarin prototypes and their non-aromatic synthetic precursors were tested in vitro as inhibitors of ChEs (acetyl- and butyrylcholinesterase, AChE and BChE) and MAOs (monoamine oxidases A and B, MAO A and MAO B). All compounds were low-micromolar AChE inhibitors devoid of toxic effects against SH-SY5Y cells. Lineweaver-Burk plots and docking simulations suggested mixed-type kinetics for inhibitor 3d (IC₅₀ = 4.1 μM toward AChE). Its promising inhibitory profile encompasses additional, highly selective, activity against monoamine oxidase B, with a submicromolar IC₅₀ value (561 nM). Full article

There is an urgent need to identify interventions that broadly target aging-related cognitive decline and progression to Alzheimer’s disease (AD). Bottlenose dolphins (Tursiops truncatus) have histologic changes similar to AD in humans, and they also develop shared age-associated co-morbidities identified as risk factors for AD in humans, including type 2 diabetes, ferroptosis, and iron overload, which can be driven by nutritional C15:0 deficiency. We hypothesized that (1) dolphins would have amyloid beta (Aβ) plaques and neuroinflammation that paralleled that of humans in relation to age-related progression, quantitative concentration, and brain region; and (2) C15:0 would have dose-dependent activities relevant to protecting cognitive health. Quantitative immunohistochemistry staining was used to assess 68 tissues from archived brains of 19 Navy dolphins to evaluate associations among amyloid beta (Aβ) plaques and neuroinflammation by brain region, sex, and age group. Further, dose-dependent C15:0 activities, using a third-party panel intended to screen for potential AD therapeutics, were evaluated. Similar to humans, dolphins had the highest Aβ plaque density variation in the hippocampus (90th percentile of 4.95 plaques/mm²), where plaque density increased with age (p = 0.05). All measured markers of neuroinflammation were detected, including the highest concentrations of activated microglia (CD68⁺) in the hippocampus (0.46 ± 0.38 cells/mm²). C15:0 was a dose-dependent inhibitor of two targets, fatty acid amide hydrolase (FAAH) (IC₅₀ 2.5 µM, 89% maximum inhibition at 50 µM relative to URB597) and monoamine oxidase B (MAO-B) (IC₅₀ 19.4 µM, 70% maximum inhibition at 50 µM relative to R(-)-Deprenyl). These activities have demonstrated efficacy against Aβ formation and neuroinflammation, including protection of cognitive function in the hippocampus. These findings suggest that, in addition to protecting against AD co-morbidities, C15:0 may play a distinct role in supporting cognitive health, especially at higher concentrations. Full article

Background: Fatigue is a common and debilitating non-motor symptom (NMS) in Parkinson’s disease (PD), significantly affecting patients’ quality of life. MAO-B inhibitors are effective therapy for motor symptoms and fluctuations and may also play a role in fatigue management. Methods: We searched PubMed for English-language articles (January 1978–August 2024) using keywords including “selegiline”, “rasagiline”, “safinamide”, “MAO-B”, “fatigue”, and “Parkinson’s disease”. Clinical trials, observational, and preclinical studies were included. Results: While the role of MAO-B inhibitors in fatigue remains unclear, evidence suggests potential benefits. Selegiline has shown effectiveness in improving fatigue in animal models, supporting its potential utility in treating fatigue and motivational impairments in PD patients. Rasagiline has been associated with reduced fatigue progression in early PD, with some studies showing significant improvements compared to placebo. Safinamide, with its dual action as an MAO-B inhibitor and glutamate modulator, may further enhance fatigue management. Its ability to reduce glutamate release is particularly relevant, given the role of glutamate overactivity in PD-related fatigue. Studies indicate safinamide can significantly reduce fatigue levels. Conclusions: Fatigue in PD is a complex symptom with multiple contributing factors. While MAO-B inhibitors may support fatigue management, their precise role and optimal use require further investigation. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neuro-degenerative disorder characterized by α-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce α-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), a monoamine oxidase-B (MAO-B) inhibitor, has low bioavailability, restricting its effectiveness. This study aims to develop an intranasal (IN) albumin-coated liposomal system (C-Lip_Sel-siSNCA2) for the co-delivery of Sel and α-synuclein-targeting siRNA (siSNCA2) to enhance brain targeting and therapeutic efficacy. Methods: Liposomes were prepared using the ethanol injection method and optimized via D-optimal design for size, charge, and encapsulation efficiency (EE%). The optimized formulation was coated with human serum albumin (HSA) and characterized for stability, cellular uptake, and gene silencing. In vivo pharmacokinetics and pharmacodynamics were assessed in a rotenone-induced PD rat model to evaluate the motor function, biochemical markers, and brain-targeting efficiency. Results: Optimized liposomes had a particle size of 113.5 ± 6.8 nm, zeta potential of 6.2 ± 0.8 mV, and high EE% (Sel: 92.35%; siRNA: 78.66%). Albumin coating increased size to 136.5 ± 10.3 nm and shifted zeta potential to −13.5 ± 1.4 mV, enhancing stability and targeting. IN administration achieved a 3-fold increase in brain area under the concentration-time curve (AUC) versus intravenous delivery. In PD rats, C-Lip_Sel-siSNCA2 improved motor and non-motor functions, restored dopamine levels, enhanced catalase activity, and reduced MAO-B levels, mitigating dopamine degradation and α-synuclein aggregation. Conclusions: This non-invasive, dual-action nanoplatform offers a targeted therapy for PD, combining siRNA gene silencing and MAO-B inhibition, with the potential for clinical translation in neurodegenerative diseases. Full article

Monoamine oxidase B (MAO-B) is a key enzyme in the mitochondrial outer membrane, pivotal for the oxidative deamination of biogenic amines. Its overexpression has been implicated in the pathogenesis of several cancers, including glioblastoma and colorectal, lung, renal, and bladder cancers, primarily through the increased production of reactive oxygen species (ROS). Inhibition of MAO-B impedes cell proliferation, making it a potential therapeutic target. Various monoamine oxidase B inhibitors have shown promise in inhibiting tumor growth and inducing apoptosis across different cancer types. In this review, we investigate MAO-B network biology, which highlighted glycolysis pathways as notable links between MAO-B and cancer. Further molecular modeling analysis illustrated the basis of MAO-B ligand binding, revealing a hydrophobic binding pocket, with key residues such as Tyr398 and Tyr435 playing crucial roles in substrate oxidation. MAO-B inhibitors that were reportsed in the literature (2012–2024) and their potential application in cancer therapy were discussed, highlighting key molecular scaffolds, such as propargyl analogs of phenyl alkyl amines, hydrazine derivatives, cyclopropylamine derivatives, MAO-B activated pro-drugs, and natural phenylpropanoid derivatives. The reported literature underscores the therapeutic potential of MAO-B inhibitors as versatile anticancer agents, warranting further investigation to optimize their efficacy and specificity across various malignancies. Full article

Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the inhibitory activity of Prottremine and its derivatives (including 14 new 9-N- and S-derivatives) against MAO-A and MAO-B enzymes has been investigated for the first time. Compounds containing fragments of substituted anilines have demonstrated the highest activity against MAO-A; for example, compound 28 had an IC₅₀ of 178 ± 44 μM. A significant proportion of the compounds tested, including Prottremine, exhibited moderate inhibitory activity towards MAO-B, with the most active being the o-aminoacetophenone derivative, which had an IC₅₀ of 95 ± 5 μM. A molecular docking method for studying murine MAO-A and -B enzymes was developed using AlphaFold2 (v2.3.2), with further improvements. For the MAO-B enzyme, a strong correlation was observed between the molecular docking data and the measured activity of the compounds, with the maximum binding affinity registered for the most active compound. It is conceivable that the antiparkinsonian activity of Prottremine and some of its derivatives may be partially mediated, among other mechanisms, by MAO-B enzyme inhibition. Full article

Introduction: Randomized clinical trials should be complemented with data from real-world studies. We report our long-term experience with safinamide in a movement disorders unit. Methods: This retrospective study included patients with Parkinson’s disease (PD) treated with safinamide in our unit from February 2016 to May 2022 under routine clinical practice. Assessments included the Hoehn and Yahr (HY) stage, unified Parkinson’s disease rating scale (UPDRS) part III score, levodopa equivalent daily dose (LEDD), LEDD for dopamine agonists, and safinamide treatment discontinuation. Results: We included 180 patients with a median age of 74 years (IQR 11), and the majority (90.6%) had an HY stage of ≤2. After a median follow-up of 40 months (IQR 34), 14 patients discontinued treatment with safinamide (7.8%, 95% CI 4.7 to 12.6). Among the 166 patients who remained on safinamide, the UPDRS III score was stable (10 (IQR 9) vs. 9 (IQR 13), p = 0.455). The LEDD significantly increased from a median of 300 mg to 500 mg (p < 0.001), whereas the LEDD for dopamine agonists did not significantly increase. A subgroup of 89 patients who did not require dopamine agonists during follow-up showed stable UPDRS III score (10 (IQR 7) vs. 9 (IQR 14); p = 0.923), with a significant LEDD increase (300 mg to 400 mg, p < 0.001). Conclusions: Our results support the long-term effectiveness and tolerability of safinamide in patients with PD in clinical practice. Full article

Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer’s disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with O-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔG_bind estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC₅₀: 1.52–4.95 μM for hAChE, 6.97–7.65 μM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC₅₀: 1.88–4.76 μM for hMAO-B). They displayed binding free energy (ΔG_bind) of −76.32 kcal/mol (11) and −70.12 kcal/mol (12) against AChE and −66.27 kcal/mol (11) and −62.89 kcal/mol (12) against MAO-A. It is noteworthy that compounds 11 and 12 demonstrated efficient binding to both AChE and MAO-A, while compounds 3 and 10 significantly reduced MAO-B and AChE aggregation in vitro. These findings provide structural templates for the development of dual MAO and AChE inhibitors for the treatment of neurodegenerative diseases. Full article

Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson’s disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6H)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6H)-ones. The results of the in vitro MAO inhibition studies showed that the 1,2,4-oxadiazin-5(6H)-ones were indeed inhibitors of human MAO with the most potent inhibition observed for 5f (IC₅₀ = 0.900 µM) and 7c (IC₅₀ = 0.371 µM). It was concluded that, with appropriate substitution, 1,2,4-oxadiazin-5(6H)-one derivatives would act as good potency MAO-B inhibitors and lead compounds for the development of antiparkinsonian drugs. In Parkinson’s disease, MAO-B inhibitors enhance central dopamine levels and reduce MAO-mediated production of hydrogen peroxide and resultant oxidative injury. This study represents one of few works to investigate synthetic approaches and biological activities of the 1,2,4-oxadiazin-5(6H)-one class of heterocycles. Full article

Background/Objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson’s disease (DwP) have impaired driving ability, but little is known about the impact of “wearing-off” and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities. Methods: DwP (n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A (n = 12) or opicapone for DwP-B (n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their “best-on” time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes. Results: DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS (p < 0.01) and LC (p = 0.021) than CON. Lower VDRS was associated with wearing-off (p < 0.01), but DwP-B had better driving performance while in their “best-on” time (p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A. Conclusions: DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities. Full article

Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG^‡ = −2.5 kcal mol⁻¹) and an improved reaction exergonicity (ΔΔG_R = −4.3 kcal mol⁻¹), together with its higher binding affinity, consistently determined by docking (ΔΔG_BIND = −0.1 kcal mol⁻¹) and MM-PBSA analysis (ΔΔG_BIND = −1.5 kcal mol⁻¹). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases. Full article

Monoamine oxidases (MAOs), mitochondrial enzymes that constantly produce hydrogen peroxide (H₂O₂) as a byproduct of their activity, have been recently acknowledged as contributors to oxidative stress in cardiometabolic pathologies. The present study aimed to assess whether MAOs are mediators of valvular oxidative stress and interact in vitro with angiotensin 2 (ANG2) to mimic the activation of the renin–angiotensin system. To this aim, valvular tissue samples were harvested from 30 patients diagnosed with severe primary mitral regurgitation and indication for surgical repair. Their reactive oxygen species (ROS) levels were assessed by means of a ferrous oxidation xylenol orange (FOX) assay, while MAO expression was assessed by immune fluorescence (protein) and qRT-PCR (mRNA). The experiments were performed using native valvular tissue acutely incubated or not with angiotensin 2 (ANG2), MAO inhibitors (MAOI) and the angiotensin receptor blocker, irbesartan (Irb). Correlations between oxidative stress and echocardiographic parameters were also analyzed. Ex vivo incubation with ANG2 increased MAO-A and -B expression and ROS generation. The level of valvular oxidative stress was negatively correlated with the left ventricular ejection fraction. MAOI and Irb reduced valvular H₂O_2. production. In conclusion, both MAO isoforms are expressed in pathological human mitral valves and contribute to local oxidative stress and ventricular functional impairment and can be modulated by the local renin–angiotensin system_. Full article