scholarly journals Enantioselective Interactions of Anti-Infective 8-Aminoquinoline Therapeutics with Human Monoamine Oxidases A and B

2021 ◽  
Vol 14 (5) ◽  
pp. 398
Author(s):  
Narayan D. Chaurasiya ◽  
Haining Liu ◽  
Robert J. Doerksen ◽  
N. P. Dhammika Nanayakkara ◽  
Larry A. Walker ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Pneumocystis Pneumonia ◽  
Clinical Development ◽  
Radical Cure ◽  
Inhibitor Binding ◽  
Strong Inhibitor ◽  
Computational Docking ◽  
Monoamine Oxidases ◽  
Mao B ◽  
Mao A

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and -B. NPC1161B, the (R)-(−) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and -B. Racemic PQ and (R)-(−)-PQ both showed marginally greater (1.2- and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, (S)-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The (S)-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and -B compared to the (R)-(−) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics.

scholarly journals Multifunctional Monoamine Oxidases and Cholinesterases Inhibitory Effects, as well as UPLC-DAD-MS Chemical Profile of Alkaloid Fractions Obtained from Species of the Palicoureeae Tribe

2016 ◽  
Vol 11 (9) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Luiz Carlos Klein-Júnior ◽  
Carolina dos Santos Passos ◽  
Juliana Salton ◽  
Fernanda Gobbi Bitencourt de ◽  
Luís Funez ◽  
...  
Keyword(s):  
Indole Alkaloids ◽  
The Other ◽  
Chemical Profile ◽  
Inhibitory Effects ◽  
Pharmacological Activities ◽  
Monoamine Oxidases ◽  
Mao B ◽  
Bche Activity ◽  
Neuropsychiatric Diseases ◽  
Mao A

In the present study, the effects were evaluated of alkaloid fractions (AFs) from Psychotria species and correlated genera, Palicourea and Rudgea, on monoamine oxidases (MAOs) and cholinesterases (ChEs). By HPLC-DAD and UPLC-DAD-MS analyses, indole alkaloids (IA) were detected in all AFs. For the Psychotria and Palicourea species, these IA corresponded to tetrahydro-β-carboline alkaloids (THβCA). On the other hand, pyrrolidinoindoline core compounds were observed for Rudgea species. Regarding their pharmacological activities, none of the AFs was able to inhibit AChE. However, the BChE activity was impaired by the Psychotria and Palicourea AFs. In addition, MAO-A was inhibited by both AFs, but only Psychotria nemorosa AF was able to inhibit significantly MAO-B. Rudgea AFs demonstrated a poor inhibitory profile on MAO-A. Taken together, our results highlighted the Psychotria and Palicourea genera as important sources of scaffolds for the development of MAO-A and BChE inhibitors aiming at the treatment of neurodegenerative and neuropsychiatric diseases.

scholarly journals Monoamine Oxidases, Oxidative Stress, and Altered Mitochondrial Dynamics in Cardiac Ageing

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Damien Maggiorani ◽  
Nicola Manzella ◽  
Dale E. Edmondson ◽  
Andrea Mattevi ◽  
Angelo Parini ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Scientific Evidence ◽  
Mitochondrial Enzymes ◽  
Oxidative Deamination ◽  
Monoamine Oxidases ◽  
Mao B ◽  
The Past ◽  
Age Dependent ◽  
Mao A

The advances in healthcare over the past several decades have resulted in populations now living longer. With this increase in longevity, a wider prevalence of cardiovascular diseases is more common and known to be a major factor in rising healthcare costs. A wealth of scientific evidence has implicated cell senescence as an important component in the etiology of these age-dependent pathologies. A number of studies indicate that an excess of reactive oxygen species (ROS) contributes to trigger and accelerate the cardiac senescence processes, and a new role of monoamine oxidases, MAO-A and MAO-B, is emerging in this context. These mitochondrial enzymes regulate the level of catecholamines and serotonin by catalyzing their oxidative deamination in the heart. MAOs’ expression substantially increases with ageing (6-fold MAO-A in the heart and 4-fold MAO-B in neuronal tissue), and their involvement in cardiac diseases is supposedly related to the formation of ROS, via the hydrogen peroxide produced during the substrate degradation. Here, we will review the most recent advances in this field and describe why MAOs could be effective targets in order to prevent age-associated cardiovascular disease.

scholarly journals Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)

Planta Medica ◽  
2019 ◽  
Vol 85 (14/15) ◽  
pp. 1136-1142
Author(s):  
Denise Prinsloo ◽  
Sandra van Dyk ◽  
Anél Petzer ◽  
Jacobus P. Petzer
Keyword(s):  
Enzyme Inhibitor ◽  
Dissociation Constants ◽  
Piper Methysticum ◽  
Experimental Conditions ◽  
Mao Inhibitor ◽  
Mao B ◽  
Mao Inhibition ◽  
Mao A ◽  
Ic50 Values

AbstractMonoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.

scholarly journals Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme

Metabolites ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 258
Author(s):  
Rajbir Singh ◽  
Sandeep Chandrashekharappa ◽  
Praveen Kumar Vemula ◽  
Bodduluri Haribabu ◽  
Venkatakrishna Rao Jala
Keyword(s):  
Monoamine Oxidase ◽  
Enzyme Inhibitor ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Functional Activities ◽  
Mao A ◽  
Mao Activity ◽  
Anti Oxidant ◽  
Urolithin B

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson’s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC50 value of 0.88 µM, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC50 (>100 µM) for MAO-B enzyme.

scholarly journals Synthesis of N′-(4-/3-/2-/Non-substituted benzylidene)-4-[(4-methylphenyl)sulfonyloxy] Benzohydrazides and Evaluation of Their Inhibitory Activities against Monoamine Oxidases and β-Secretase

2021 ◽  
Vol 11 (13) ◽  
pp. 5830
Author(s):  
Hasan Erdinç Sellitepe ◽  
Jong Min Oh ◽  
İnci Selin Doğan ◽  
Sercan Yildirim ◽  
Ahmet Buğra Aksel ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
Residual Activity ◽  
Docking Studies ◽  
Monoamine Oxidases ◽  
Mao B ◽  
Ic50 Value ◽  
Mao A ◽  
Inhibitory Activities ◽  
Bace 1

Nineteen tosylated acyl hydrazone derivatives were synthesized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) were evaluated. Compound 3o was the most potent inhibitor of MAO-A, with an IC50 value of 1.54 µM, followed by 3a (IC50 = 3.35 µM). A structural comparison with 3a indicated that the 3-F group in 3o increased its inhibitory activity against MAO-A. Compound 3s was the most potent inhibitor of MAO-B, with an IC50 value of 3.64 µM, followed by 3t (IC50 = 5.69 µM). The MAO-B inhibitory activity increased in the order of 3- > 4- > 2-NO2 groups in 3s, 3t, and 3r, respectively. All the compounds weakly inhibited AChE and BChE, which retained >50% residual activity at 10 µM, except for 3a, which inhibited BChE with an IC50 value of 16.1 µM. Interestingly, 3e, 3f, and 3n inhibited BACE-1 with IC50 values of 8.63, 9.92, and 8.47 µM, respectively, which were lower than the IC50 of the quercetin reference. Compounds 3o and 3s were found to be reversible competitive inhibitors of MAO-A and MAO-B, respectively, with Ki values of 0.35 ± 0.074 and 1.97 ± 0.65 µM, respectively. Moreover, compounds 3e, 3f, and 3n were effective BACE-1 inhibitors. The lead molecules were further investigated by molecular docking studies to elucidate the binding interactions with the target enzymes.

scholarly journals Interactions of Desmethoxyyangonin, a Secondary Metabolite fromRenealmia alpinia, with Human Monoamine Oxidase-A and Oxidase-B

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Narayan D. Chaurasiya ◽  
Francisco León ◽  
Yuanqing Ding ◽  
Isabel Gómez-Betancur ◽  
Dora Benjumea ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Equilibrium Dialysis ◽  
Monoamine Oxidase A ◽  
Tropical Rainforests ◽  
Reversible Binding ◽  
Mao B ◽  
Potent Inhibition ◽  
Mao A ◽  
Preferential Binding ◽  
Phytochemical Studies

Renealmia alpinia(Zingiberaceae), a medicinal plant of tropical rainforests, is used to treat snakebites and other injuries and also as a febrifuge, analgesic, antiemetic, antiulcer, and anticonvulsant. The dichloromethane extract ofR. alpinialeaves showed potent inhibition of human monoamine oxidases- (MAOs-) A and B. Phytochemical studies yielded six known compounds, including pinostrobin1, 4′-methyl ether sakuranetin2, sakuranetin3, pinostrobin chalcone4, yashabushidiol A5, and desmethoxyyangonin6. Compound6displayed about 30-fold higher affinity for MAO-B than MAO-A, with Ki values of 31 and 922 nM, respectively. Kinetic analysis of inhibition and equilibrium-dialysis dissociation assay of the enzyme-inhibitor complex showed reversible binding of desmethoxyyangonin6with MAO-A and MAO-B. The binding interactions of compound6in the active site of the MAO-A and MAO-B isoenzymes, investigated through molecular modeling algorithms, confirmed preferential binding of desmethoxyyangonin6with MAO-B compared to MAO-A. Selective reversible inhibitors of MAO-B, like desmethoxyyangonin6,may have important therapeutic significance for the treatment of neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease.

scholarly journals Immunocytochemical localization of monoamine oxidases A and B in human peripheral tissues and brain.

1987 ◽  
Vol 35 (1) ◽  
pp. 23-32 ◽  
Author(s):  
L W Thorpe ◽  
K N Westlund ◽  
L M Kochersperger ◽  
C W Abell ◽  
R M Denney
Keyword(s):  
Hepatoma Cell ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Peripheral Tissues ◽  
Monoamine Oxidases ◽  
Mao B ◽  
Mao A ◽  
Immunocytochemical Techniques ◽  
High Degree ◽  
The Brain

Monoamine oxidases (MAO; EC 1.4.3.4.) A and B occur in the outer mitochondrial membrane and oxidize a number of important biogenic and xenobiotic amines. Monoclonal antibodies specific for human MAO A or B and immunocytochemical techniques were used to visualize the respective enzymes in human placenta, platelets, lymphocytes, liver, brain, and a human hepatoma cell line. MAO A was observed in the syncytiotrophoblast layer of term placenta, liver, and a subset of neurons in brain, but was not observed in platelets or lymphocytes, which are known to lack type A enzyme. MAO B was observed in platelets, lymphocytes, and liver, but not in placenta, which contains little or no MAO B. MAO B was also observed in a subset of neurons in the brain that was distinct from that which contained MAO A. MAO A and MAO B were also observed in some glia. Unlike most tissues examined, liver cells appeared to contain both forms of the enzyme. These studies show that MAO A and MAO B can be specifically visualized by immunocytochemical means in a variety of human cells and tissues and can provide a graphic demonstration of the high degree of cell specificity of expression of the two forms of the enzyme.

scholarly journals Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 810 ◽  
Author(s):  
Narayan Chaurasiya ◽  
Jianping Zhao ◽  
Pankaj Pandey ◽  
Robert Doerksen ◽  
Ilias Muhammad ◽  
...  
Keyword(s):  
Methyl Ether ◽  
Enzyme Inhibitor ◽  
Equilibrium Dialysis ◽  
Selective Inhibition ◽  
Standard Drug ◽  
Mao B ◽  
Turnera Diffusa ◽  
Mechanism Of Inhibition ◽  
Mao A

The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4′, 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether’s selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson’s disease.

Sign in / Sign up

Export Citation Format

Share Document