Lung cancer, globally recognized as the leading cause of cancer-related mortality, presents a pressing need for innovative treatment strategies. Increasing evidence points towards the potential of monoamine oxidase (MAO) inhibitors in modulating cancer progression, primarily due to their role in regulating cellular metabolism and apoptotic pathways. This extraordinary study delves into the multifaceted therapeutic implications of MAO inhibitors in lung cancer management, elucidating their ability to pave the way for clinical advancement via novel targets and pathways. Capitalizing on recent advances in molecular biology, this research explores the molecular mechanisms underlying the anticancer actions of MAO inhibitors. By examining their impact on cell proliferation, migration, invasion, and apoptosis in lung cancer cell lines, we provide insight into the intricate signaling pathways and biochemical processes modulated by these compounds. The study also investigates the synergistic effects of MAO inhibitors in combination with established chemotherapeutic agents, elucidating their potential to enhance treatment efficacy and reduce cytotoxicity. Furthermore, we delve into the implications of MAO inhibitors on the tumor microenvironment, evaluating their influence on angiogenesis, immune regulation, and the epithelial-mesenchymal transition. This comprehensive analysis enables the identification of novel molecular targets, which hold promise for the development of advanced therapeutics tailored for specific lung cancer subtypes. To substantiate our findings, in this review, we thoroughly analyze the existing literature using state-of-the-art bioinformatics tools." in vivo orthotopic lung cancer models, and clinical patient cohorts. This robust and multidisciplinary approach permits the generation of clinical evidence supporting the integration of MAO inhibitors in lung cancer management. Conclusion: This ground-breaking study establishes the therapeutic potential of monoamine oxidase inhibitors in lung cancer management by unearthing novel pathways and targets for clinical advancement. The outcomes open doors for the development of innovative treatment strategies and inspire continued research efforts to combat the global burden of lung cancer.

We have recently reported that a series of 1,3,4-oxadiazol-2-ylbenzenesulfonamides acts as potent and specific monoamine oxidase B (MAO-B) inhibitors with some compounds possessing potencies in the nanomolar range. While sulfonamide compounds (e.g., zonisamide) have been reported to inhibit the MAO enzymes, nanomolar MAO inhibition potencies for this class are not frequently observed. The present study expanded on these findings by replacing the 1,3,4-oxazole moiety with a 1,3-thiazole heterocycle. A series of 23 primary sulfonamides were synthesized by reaction of an α-haloketone with a substituted carbothioamide. The results of the MAO inhibition studies showed that the 1,3-thiazolylbenzenesulfonamides were specific inhibitors of human MAO-B. The most potent MAO-B inhibitor exhibited an in vitro IC50 value of 0.103 µM (3j). The derivatives were, however, weaker inhibitors of human MAO-A with the most potent compound exhibiting an IC50 value of 11.9 µM (3a). Examination of the structure-activity relationships (SARs) showed that the most potent MAO-B inhibition was obtained with substitution of the sulfonamide on the meta position of the phenyl rather than the para position. This study concludes that 1,3-thiazolylbenzenesulfonamides represent a class of potent and specific MAO-B inhibitors, which may serve as leads for the development of new treatments for disease states such as Parkinson’s disease.

3,4-dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (S), a major component of Lewy bodies. DOPAL potently oligomerizes S, and S oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intra-neuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with S, and vice versa, are poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intra-neuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

The brain of Drosophila melanogaster is comprised of some 100,00 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g. motor activity, reward and aversion, memory formation, feeding, sexual appetite etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference etc. Flies harboring mutated human orthologs provide models, which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput.

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The obtained compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 3.47 μM for MAO-B and 43.3 μM for MAO-A. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for development anti-Parkinson’s disease agents.

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. Glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (> 40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (-7.8 kcal/mol) was greater than its affinity for AChE (-7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (-8.8 kcal/mol) was greater than its affinity for MAO-A (-7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer, such as glioblastoma and prostate cancer, where they have been found overexpressed. This finding is opening new frontiers for MAOs inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAOs inhibitor, our aim was to search for novel analogues with even greater inhibitory potency for human MAOs and, possibly, endowed with antiproliferative activity. A small in house library of polyamine analogs (2-7) was selected to investigate the effect of a constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compound 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety emerged as the most potent, reversible and mainly competitive MAO inhibitors (Ki < 1uM). Additionally, they exhibited a high antiproliferative activity in three tumor cell lines, in particular in the LN-229 line, a glioblastoma model (GI50 < 1uM). The scaffold of compound 5, in particular, could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

Oxidative stress is defined as an imbalance between the production of free radicals and reactive oxygen species (ROS) and the ability of the body to neutralize them by antioxidant defense systems. Cells produce ROS as a control of physiological processes, but increasing ROS becomes pathological leading to non-specific and irreversible damage to biological molecules, such as DNA, lipid, and protein. Endogenous ROS are mainly produced by mitochondria during both physiological and pathological conditions, and enzymes, such as nicotinamide adenine dinucleotide phosphate oxidase (NOX), xanthine oxidase (XO), lipoxygenase (LOX), myeloperoxidase (MPO) and monoamine oxidase (MAO). To neutralize ROS, the body employs enzymatic and non-enzymatic defense systems. The dietary intake of bioactive phenols, such as quercetin (Que), is a non-enzymatic system that can quench ROS and protect from pro-oxidative damage. In this review, we evaluate the ability of Que to target endogenous oxidant enzymes involved in ROS production and explore the mechanisms of action underlying its antioxidant properties. Que not only acts as a free radical scavenger by donating electrons through the negative charges in its phenolic and ketone groups, but it can effectively inhibit the activity of several endogenous oxidative enzymes, binding them with high affinity and specificity. Among all targets, Que showed the best results in molecular docking simulations with XO, followed by MAO-A, 5-LOX, NOX, and MPO. Taken together, these findings highlight the potential of Que as a natural antioxidant therapy for oxidative stress-related diseases.

3-(3,4-Dichlorophenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole was synthesized via the condensation of 3,4-dichlorobenzamidoxime and methyl 1H-indole-5-carboxylate using superbasic medium (NaOH/DMSO). The compound was tested as a potential inhibitor of human monoamine oxidase (MAO) A and B. It demonstrated notable inhibition with an IC50 value of 0.036 μM for MAO-B and isoform specificity. The product was characterized by 1H NMR, 13C NMR, and HRMS. In conclusion, the new active MAO-B inhibitor may serve as a candidate for the future discovery of therapeutic agents for neurodegenerative disorders such as Parkinson’s disease.

This study explores the potential of natural compounds, including Daidzin, Luteolin, and Silibinin, as inhibitors of human monoamine oxidase B (MAO-B) for the treatment of Parkinson's disease. Docking simulations were performed using Autodock Vina with Pyrx program to evaluate the binding affinities of these compounds with MAO-B. Results indicate that Daidzin, Luteolin, and Silibinin exhibit promising binding affinities with MAO-B, with Daidzin demonstrating the highest affinity. Toxicity parameters were further predicted using the PkCSM Server, confirming the low toxicity of these compounds. Overall, the findings suggest that Daidzin, Luteolin, and Silibinin have the potential to be effective and safe treatments for Parkinson's disease through their inhibition of MAO-B. Further experimental validation is warranted to support their therapeutic efficacy in clinical settings.

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 µM concentration. This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC₉₉ values of 8.31 – 29.70 µM and 44.15 – 57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively. These compounds were found to bind to albumin which may explain the variations in MIC between the two assays. Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria. Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect. Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria. Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.