Author: Mormino, Alessandro ; Binda, Claudia ; Gottinger, Andrea ; Reis, Joana ; Mattevi, Andrea ; Limatola, Cristina ; Valente, Sergio ; Castelôa, Mariana ; Lambona, Chiara ; Fioravanti, Rossella ; Marchese, Sara ; Noce, Beatrice ; Garofalo, Stefano ; Mai, Antonello ; Fiorentino, Francesco ; Massari, Marta ; Raucci, Alessia ; Basile, Lorenzo

NADPH oxidases (NOXs) are enzymes dedicated to reactive oxygen species (ROS) production and are implicated in cancer, neuroinflammation, and neurodegenerative diseases. VAS2870 is a covalent inhibitor of mainly NOX2 and NOX5. It alkylates a conserved active-site cysteine, blocking productive substrate binding. To enhance potency and selectivity toward NOXs, we conducted some chemical modifications, leading to the discovery of compound 9a that preferentially inhibits NOX2 with an IC₅₀ of 0.155 μM, and only upon its preactivation. We found that 9a, bearing a pargyline moiety, is also able to selectively inhibit MAOB over MAOA (465-fold) with an IC₅₀ of 0.182 μM, being the first-in-class dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation model, 9a decreased ROS production and downregulated proinflammatory cytokines as iNOS, IL-1β, and IL-6 expression more efficiently than the single target inhibitors (rasagiline for MAOB and VAS2870 for NOXs) but also, more importantly, than their combination.

19 Mar 2025·ACS Chemical Neuroscience

Monoamine Oxidase Inhibitors Present in Tobacco Modulate Dopamine Balance Via the Dopamine Transporter

Article

Author: Saro, Gabriella ; Moine, Fabian ; Latino, Diogo A.R.S. ; Veljkovic, Emilija ; Johne, Stephanie ; Mathis, Carole ; van der Toorn, Marco

It has been reported that nicotine affects brain dopamine homeostasis. By binding to nicotinic acetylcholine receptors, including those expressed by dopaminergic neurons of the ventral tegmental area, nicotine stimulates dopamine release and signaling. Dopamine is taken up from the synaptic cleft by the dopamine transporter (DAT) into presynaptic neurons, where it is degraded by monoamine oxidase (MAO). Besides nicotine, other tobacco compounds play a role in dopamine modulation. To better understand the biological effects of nicotine and other tobacco compounds on dopamine regulation, we selected a group of tobacco compounds based on their potential affinity to bind human MAO-A and MAO-B enzymes using an in silico approach. Subsequently, we tested the putative compounds in an enzymatic assay to verify their ability to inhibit human MAO-A or MAO-B. The positive hits were harman, norharman, harmaline, and 1-ethyl-β-carboline. While harman and norharman have been extensively studied, both harmaline and 1-ethyl-β-carboline have not been described in the context of tobacco and MAO inhibition before. We investigated DAT activity in an overexpressing cell line and dopamine release and uptake in rat striatal synaptosomes. We clearly demonstrate that tested MAO-A inhibitors (MAO-AIs) significantly attenuated human DAT activity and consequent dopamine uptake, establishing a functional connection between MAOIs and dopamine uptake via DAT. Interestingly, the tested MAO-AIs elicited pronounced dopamine release in crude synaptosomal preparations. In summary, this in vitro study demonstrates that tested MAO-AIs found in cigarette smoke not only reduce MAO activity but also strongly impact dopamine homeostatic mechanisms via DAT. Further in vivo investigations would advance our understanding of the underlying mechanisms of dopamine regulation and homeostasis.

01 Mar 2025·Results in Chemistry

Anti-diabetic, anti-inflammatory and molecular docking studies of benzofuran derivatives as potential α-glucosidase and lipoxygenase inhibitors

Author: Gumede, N. J. ; Segodi, Redolf. S. ; Poopedi, K. W. ; Agbo, E. N. ; Leboho, T. C. ; Nxumalo, W. ; Mampa, R. M.

Sonogashira cross-coupling of 5-bromo-2-hydroxy-3-iodoacetophenone and subsequent Suzuki-Miyaura cross-coupling of the 1-(5-bromo)-2-substituted furan-7-yl) ethanones afforded series of novel 1-(5-(4-aryl)-2-substituted furan-7-yl) ethanone derivativesThe potential anti-inflammatory and anti-diabetic properties of the prepared compounds were evaluated against lipoxygenase (LOX-15) and α-glucosidase enzymes, resp.Besides compounds 1-(5-bromo-2-(1-hydroxyethyl)benzofuran-7-yl)ethanone and 1-(5-bromo-2-(1-hydroxybutyl)benzofuran-7-yl)ethanone with IC₅₀ values of 8.8μM and 11.2μM against α-glucosidase and LOX-1, resp., the 1-(5-bromo)-2-substituted furan-7-yl)ethanones were found to be poorly inhibitors of both enzymes.On the other hand, compounds 1-(2-(1-hydroxybutyl)-5-(4-methoxyphenyl)benzofuran-7-yl)ethanone (IC₅₀ = 8.0μM) and 1-(2-(1-hydroxybutyl)-5-(thiophen-3-yl)benzofuran-7-yl)ethanone (IC₅₀ = 5.3μM) exhibited significant inhibitory activity against LOX-15 and α-glucosidase, resp.Cytotoxicity of the most active compound was evaluated against Raw 264.7 macrophages.Mol. docking and MDS studies of the most active compounds against α-glucosidase enzyme have revealed that the structure-activity relationship (SAR) of the 1-(5-(4-aryl)-2-substituted furan-7-yl)ethanone analogs indicates a water-mediated hydrogen bond between ASP232 and ARG552 influences the activity of these analogs.

100 Deals associated with Pargyline Hydrochloride

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KEGG	Wiki	ATC	Drug Bank
D02564	Pargyline Hydrochloride	C02KC01	DB01626

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