A comprehensive review of monoamine oxidase-a inhibitors in their syntheses and potencies

Background: Monoamine oxidases (MAOs) play a crucial role during the development of various neurodegenerative disorders. There are two MAO isozymes, MAO-A and MAO-B. MAO-A is a flavoenzyme, which binds to the outer mitochondrial membrane and catalyzes the oxidative transformations of neurotransmitters like serotonin, norepinephrine, and dopamine. Materials and Methods: Focus on synthetic studies has culminated in the preparation of many MAO-A inhibitors, and advancements in combinatorial and parallel synthesis have accelerated the developments of synthetic schemes. Here, we provided an overview of the synthetic protocols employed to prepare different classes of MAO-A inhibitors. We classified these inhibitors according to their molecular scaffolds and the synthetic methods used. Results: Various synthetic and natural derivatives from a different class of MAO-A inhibitors were reported. Conclusion: The review provides a valuable tool for the development of a new class of various selective MAO-A inhibitors for the treatment of depression and other anxiety disorders

Halogenated Coumarin-Chalcones as Multifunctional Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors

A series of halogenated coumarin-chalcones were synthesized, characterized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were evaluated. Compound CC2 most potently inhibited MAO-B with an IC50 value of 0.51 μM, followed by CC1 (IC50 = 0.69 μM), with a selectivity index (SI) of >78.4 and >58.0, respectively, over MAO-A. However, none of the compounds effectively inhibited MAO-A, AChE, and BChE, except for CC2 and CC3 inhibiting BChE with IC50 values of 7.00 (SI > 5.73 over AChE) and 11.8 μM, respectively. CC1 and CC2 were found to be reversible and competitive inhibitors of MAO-B, with Ki values of 0.50 ± 0.06 and 0.53 ± 0.04 μM, respectively, and CC2 was also a reversible and competitive inhibitor of BChE, with a Ki value of 2.84 ± 0.09 μM. The parallel artificial membrane permeability assay (PAMPA) method showed that lead candidates can cross the blood-brain barrier (BBB). The in vitro toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both CC1 and CC2 were nontoxic up to 100 μg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, CC1 and CC2 attenuated H2O2-induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that CC1 and CC2 are selective and competitive inhibitors of MAO-B, and that CC2 is a selective and competitive inhibitor of BChE. Molecular docking studies of lead compounds provided the possible type of interactions in the targeted enzymes. Based on the findings, both compounds, CC1 and CC2, can be considered plausible drug candidates against neurodegenerative disorders

Current Progress in Quinazoline Derivatives as Acetylcholinesterase and Monoamine Oxidase Inhibitors

Among the N-containing heterocyclic compounds, quinazoline-4-(3H)-one derivatives have been the center of attraction of medicinal and synthetic chemists due to their excellent versatility in biological activities that are witnessed by many approved drugs available in the market which contains quinazoline as main pharmacophore unit. This review mainly focuses the recent and current progresses in quinazoline derivatives as an acetylcholinesterase (AChE) and monoamine oxidase (MAO)-B inhibitors. The review has leanings towards the molecular determinants and structure-activity relationships (SAR) of quinazoline derivatives on AChE and MAO inhibitory potencies

Development of Halogenated-Chalcones Bearing with Dimethoxy Phenyl Head as Monoamine Oxidase-B Inhibitors

Two series of dimethoxy-halogenated chalcones (DM1–DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 μM, followed by compound DM18 (IC50 = 0.118 μM), with selectivity index (SI) values of 93.88 and >338.98, respectively. However, none of the substances successfully inhibited MAO-A. The MAO-B inhibitors DM2 and DM18 were competitive and reversible, with Ki values of 0.032 ± 0.004 and 0.045 ± 0.001 μM, respectively. DM2 was non-toxic below 100 μg/mL in the cytotoxic test using the Vero epithelial cell line by the MTT method. According to molecular docking studies, DM2 and DM18 formed very similar conformations within the MAO-B binding pocket, with the ortho-chlorine and ortho-fluorine aromatic rings sandwiched between F168 and Y326. These conformations were predicted to show better interactions with the targeted MAO-B than MAO-A. In particular, the induced-fit docking of the dimethoxy phenyl ring of DM2 facing the hydrophobic pocket made up of FAD, Y398, and Y435 had an impact on F168 in the docking pocket. Taken together, DM2 and DM18 may be suitable candidates for treating neurodegenerative conditions such as Parkinson’s disease