MAO-B Inhibitor Research Articles

Machine learning driven web-based app platform for the discovery of monoamine oxidase B inhibitors

Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred (https://mao-b-pred.streamlit.app/), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders.

Design, synthesis and in-vitro anti-depressant activity evaluation of some 2-styrylbenzimidazole derivatives

BackgroundExisting antidepressants possess various adverse effects and so they are not considered as the first line of drug in mild depression. The lack of proper drugs to treat the mild depression on the other hand alleviates severe depressive cases. To overcome this problem, the nucleus of benzimidazole and cinnamic acid having very less toxicity were fused and a small library of 40 compounds was prepared. The library was then screened for ADMET properties and probable toxicity. Those compounds which had not shown any toxicity as well as possessed better in-silico absorption, distribution and metabolism were selected for the first phase of the study. Synthesized compounds were characterized by FTIR, 1H-NMR and 13C-NMR and were screened for in-vitro antidepressant activity by DNPH spectrophotometry.ResultThe compounds MS-3 and MS-8 had shown good antidepressant activity with IC50 values of 367.19 μM/mL and 184.56 μM/mL against MAO-A and MAO-B, respectively.ConclusionFrom this study, it can be concluded that the structural requirements for the inhibition of MAO-A and MAO-B were totally different. MAO-A inhibitors required the presence of nitrogen and oxygen containing ring substitutions whereas MAO-B inhibitors required the presence of 4-halogen containing phenyl ring substitutions.Graphical abstract

Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases

We and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.

Development of morpholine ring-bearing halogenated α,β-unsaturated ketones as selective monoamine oxidase-B inhibitors

Nine morpholine-derived halogenated chalcone derivatives (MHC1-MHC9) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC50 value of 0.065 μM, followed by MHC7 (IC50 = 0.078 μM) and MHC6 (IC50 = 0.082 μM). The para-F substituent MHC4 was also potent (IC50 = 0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with Ki values of 0.024 ± 0.00062 and 0.041 ± 0.0028 μM, respectively. In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safinamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92 ± 0.08 and –10.64 ± 0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confirmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

KDS2010, a reversible MAO-B inhibitor, extends the lifetime of neural probes by preventing glial scar formation.

Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain-computer interface. However, the long-term functionality of these devices is hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO-B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long-term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO-B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long-term functionality of neural devices.

Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC50 = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC50 = 88.79 and 9.910 nM), MAO-A (IC50 = 0.763 and 629.1 nM) and MAO-B (IC50 = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics.

Exploration of oxadiazole clubbed benzhydrylpiperazine pharmacophoric features as structural feature for antidepressant activity: In vitro, in vivo and in silico analysis

Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.

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.

Enzyme Inhibition Assays for Monoamine Oxidase.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines with two isoforms, namely, MAO-A and MAO-B, in mitochondrial outer membranes. These two types of MAO-A and MAO-B participate in changes in levels of neurotransmitter such as serotonin (5-hydroxytryptamine) and dopamine. Selective MAO-A inhibitors have been targeted for anti-depression treatment, while selective MAO-B inhibitors are targets of therapeutic agents for Alzheimer's disease and Parkinson's disease. For this reason, study on the development of MAO inhibitors has recently become important. Here, we describe methods of MAO activity assay, especially continuous spectrophotometric methods, which give relatively high accuracy. MAO-A and MAO-B can be assayed using kynuramine and benzylamine as substrates, respectively, at 316nm and 250nm, respectively, to measure their respective products, 4-hydroxyquinoline and benzaldehyde. Inhibition degree and pattern can be analyzed by using the Lineweaver-Burk and secondary plots in the presence of inhibitor, and reversibility of inhibitor can be determined by using the dialysis method.

In-silico screening and ADMET evaluation of therapeutic MAO-B inhibitors against Parkinson disease

MAOs are flavoenzymes that aid in the oxidative deamination of neurotransmitters such as dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that act by inhibiting neurotransmitter breakdown in the brain and controlling mood. MAO inhibitors with the chlorophenyl-chromone-carboxamide structure have been shown in investigations to be extremely effective. The current study employs in-silico screening, MD simulation, and drug kinetics evaluation, all of which are evaluated using different criteria. The study comprised 37 ligands, and three stood out as the best, with greater binding scores above the threshold value. Docking analysis found that compound 34 had the highest docking score in the series (−13.60 ​kcal/mol) and interacted with the important amino acids TYR 435, CYS 397, CYS 172, PHE 343, TYR 398, and LYS 296 required for MAO inhibitory activity. The ADMET study revealed that the compounds had drug-like properties. The results of this study could be used to develop chromone drugs that target the MAO inhibitor. The top three ligands with the highest force and work were then simulated using molecular dynamics. The protein-ligand complexes had steady trajectories throughout the 100 ns simulation, according to the data. Furthermore, the drug likeliness predicted by ADMET analysis findings indicated that the top three lead compounds had strong inhibitory efficiency, superior pharmacokinetics, and were non-toxic under physiological settings. As a result, these compounds have the potential to be exploited as possible treatment medications for PD.

Indazole derivatives as novel inhibitors of monoamine oxidase and D-amino acid oxidase

The monoamine oxidase (MAO) enzymes metabolize neurotransmitter amines in the peripheral and central tissues, and inhibitors of these enzymes find application in the treatment of neuropsychiatric and neurodegenerative disorders. Based on reports that the neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole, inhibits the MAO-B isoform, the present study investigated the MAO inhibition potencies of a synthetic series of fifteen C5- and C6-substituted indazole derivatives. While only one derivative (5c) was a submicromolar inhibitor of human MAO-A (IC50 = 0.745 µM), all compounds inhibited human MAO-B with submicromolar IC50 values. Substitution on C5 of indazole yielded particularly potent MAO-B inhibition with IC50 values that ranged from 0.0025–0.024 µM. Further investigation of a selected indazole derivative showed a competitive mode of MAO inhibition. To further explore the pharmacological properties of the indazole derivatives, they were also evaluated as potential inhibitors of porcine D-amino acid oxidase (DAAO). None of the synthetic compounds were noteworthy DAAO inhibitors, however, 1H-indazol-5-ol, a synthetic precursor, was found to be a good potency inhibitor with an IC50 value of 2.03 µM.

Virtual Screening, Pharmacokinetic Prediction, Molecular Docking and Dynamics Approaches in the Search for Selective and Potent Natural Molecular Inhibitors of MAO-B for the Treatment of Neurodegenerative Diseases

This research aims to find natural product compounds that have the potential to act as MAO-B inhibitors that are useful in the treatment of neurodegenerative diseases, through the stages: a) Virtual Screening, b) Molecule Docking, c) Pharmacokinetic and toxicity prediction, and d) Simulation approach Molecular dynamics.The research steps include the following steps: a) searching for molecules in the ZINC15 data base that are similar to the natural ligand molecule (safinamide) obtained from the protein data bank (PDB code: 2v5z) and the control ligand L-DOPA. A total of 481 molecules were downloaded from the data base and then molecular docking was carried out using the autodock program on the MAO-B target in the 2v5z receptor. After carrying out the docking analysis, 48 ligand molecules were selected which had a binding affinity (DG/kcal/mol) that was smaller than the DG of the natural ligand and the control ligand and nine (9) ligand molecules were taken to be tested: (i) ligand-ligand interactions MAO-B with discovery studio, (ii) Absorption, Distribution, Metabolism and Excretion properties with SwissADME and (iii) toxicity using PROTOX-II. Molecular dynamics simulations were carried out to determine the stability of ligands in proteins. Ligand complex [CC(C)c1ccc(NC(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1]-2v5z was chosen to simulate for 100 ps. The results of the molecular docking study showed that there were 9 molecules that had binding affinity values that were smaller than the binding affinity of the natural ligand and the control ligand. Ligand and residue interactions are dominated by hydrogen bonds, donor-donor and pi-pi stacked interactions. Based on SwissADME, the Blood Brain Barrier (BBB) permeant on ligand number 1, 2, 3, 5, 6, and 9 shows that it is orally active and cannot pass through the BBB and will not cause any side effects, whereas ligand number 4, 7, 8, 10, and 11 can cross the BBB and may cause side effects. Based on the results of toxicity prediction (PROTOX-II), it is known that there are four (4) ligands in class V, five (5) ligands in class IV and the rest in class II. Hepatotoxicity, carcinogenicity, and Phosphoprotein (Tumor Suppressor) p53 in eleven ligands are predicted to be inactive and have a small probability. The stimulated [CC(C)c1ccc(NC(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1]-2v5z complex apparently still shows ligand-protein fluctuations so that its conformation is still unstable.

Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones.

A total of 14 acyl hydrazine derivatives (ACH1-ACH14) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 μM, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC50 = 0.15, 0.18, 0.20, and 0.22 μM, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with Ki values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.

Analysis of treatment methods for Parkinson's disease

This research mainly introduces the symptoms and harms of Parkinson's disease, as well as the mainstream treatment methods in the past five years and potential treatments for Parkinson's disease (PD) in the future. First of all, it talks about a biological treatment of PD. Levodopa and dopamine, which is currently the main drug used to relieve PD motor symptoms. It helps patients reduce motor symptoms as much as possible by supplementing the lack of dopamine in the brain. Secondly, it talks about MAO-B inhibitors, like medicine rasagiline and selegiline. These drugs increase dopamine availability by inhibiting dopamine metabolism, thereby reducing the symptoms of PD while reducing potential drug side effects. In addition, this research introduces two potential treatments for PD that are under development: nanomedicine and deep brain stimulation (DBS). The application of nanomedicine in PD treatment such as how it can improve the lives of PD patients through innovative methods in drug delivery, early diagnosis and nerve repair and some potential problems of nanomedicine during PD treatment, and how deep brain stimulation, a surgical treatment, can significantly reduce the symptoms of PD by implanting electrodes and stimulating specific brain areas, thereby improving patients' quality of life.

Management of OFF condition in Parkinson disease.

Parkinson disease (PD) impacts nearly 1 million individuals in the United States. Nearly every patient with PD will require therapy with dopamine in the form of levodopa as the disease progresses. In more advanced stages of the disease, patients will experience motor fluctuations and require adjustment to their medication regimens to maintain good control of their symptoms. During the last 10 years, several new therapeutic treatment options have come to the market to treat motor fluctuations and improve patient quality of life. Some of these agents represent additional options to previously available drug classes, such as the catechol-O-methyl transferase (COMT) inhibitor, opicapone, and monoamine-oxidase B-inhibitor (MAO-B inhibitor), safinamide, as well as new dosage forms for available therapeutics. One new agent, istradefylline, has a novel mechanism in the treatment of PD. The place in therapy for these newer therapeutic options will be explored through a series of patient cases. This article focuses on evidence-based recommendations for the use of these newer options in the management of patients experiencing OFF episodes.

Benzothiazole-Propanamide Linker Pyrrolidine (Morpholine) as Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors.

According to the fusion technique create effective multi-target-directed ligands, in this study, we designed and synthesized a series of benzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl) or 3-(morph- olino-1-yl)propanamide derivatives, and evaluated their inhibitory potency against MAOs, AChE, BuChE by in vitro enzyme effect assays. Based on activity results, we found that derivatives N-(5-methylbenzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2 c) and N-(6-bromobenzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2 h) showed good inhibitory potency against BuChE with IC50 values of 15.12 μM and 12.33 μM, respectively. Besides, 2 c and 2 h also exhibited selective MAO-B inhibitory effects with inhibition rates of 60.10 % and 66.30 % at 100 μM, respectively. In contrast, all designed derivatives were poor active against AChE and MAO-A at a concentration of 100 μM. The toxicity analysis in vitro by MTT and AO/EB fluorescence staining confirmed that 2 c and 2 h were nontoxic up to 100 μM. Molecular modeling studies showed that 2 c and 2 h could bind to the active site of BuChE. This research paves the way for further study aimed at designing MAO-B and BuChE inhibitors for the treatment of neurodegenerative disorders.

Green approach for the synthesis of chalcogenyl-2,3-dihydrobenzofuran derivatives through allyl-phenols/naphthols and their potential as MAO-B inhibitors.

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2/DMSO catalytic system. All compounds were fully structurally characterized using 1H and 13C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.

Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.

Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.

Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme. The results of repurposing revealed that Clotrimazole showed equipotent activity against the Mycobacterium tuberculosis (Mtb) H37Rv strain compared to Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 μM. Additionally, Clotrimazole exhibited reasonable MIC50 values of 0.17 μM, 1.72 μM, 1.53 μM, and 5.07 μM against the inhA promoter+, katG+, rpoB+, and MDR clinical Mtb isolates, respectively, compared to Linezolid. Clotrimazole also exhibited 3.90-fold less inhibition of MAO-A and 50.35-fold less inhibition of MAO-B compared to Linezolid, suggesting a reduced serotonergic toxicity burden.