Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Eur J Med Chem. 2017 Jul 28;135:196-203. doi: 10.1016/j.ejmech.2017.04.055.
Epub  2017 Apr 22.

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase.

Mostert S(1), Petzer A(1), Petzer JP(2).

Author information:
(1)Pharmaceutical Chemistry, School of Pharmacy, Centre of Excellence for 
Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 
2520, South Africa.
(2)Pharmaceutical Chemistry, School of Pharmacy, Centre of Excellence for 
Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 
2520, South Africa. Electronic address: jacques.petzer@nwu.ac.za.

The monoamine oxidase (MAO) enzymes are of considerable pharmacological interest 
and inhibitors are used in the clinic for the treatment of major depressive 
disorder and Parkinson's disease. A limited number of studies have shown that 
the quinone class of compounds possesses MAO inhibition properties. Most notable 
among these is a report that 2,3,6-trimethyl-1,4-naphthoquinone (TMN), present 
in extracts of cured tobacco leafs, is a non-selective inhibitor of both MAO 
isoforms. An older study reports that 1,4-benzoquinone inhibits MAO-A and MAO-B 
from human synaptosomes. Both 1,4-naphthoquinones and 1,4-benzoquinone are 
reported to inhibit the MAOs with a reversible mode of action. Since the MAO 
inhibition properties of additional members of the 1,4-benzoquinone class of 
compounds have not yet been explored, the present study investigates a small 
series of four 1,4-benzoquinones which incorporate phenyl, benzyl, benzyloxy and 
cyclopentyl monosubstitution on C2. The 1,4-benzoquinones were found to be 
moderately potent MAO inhibitors with IC50 values of 5.03-13.2 μM (MAO-A) and 
3.69-23.2 μM (MAO-B). These values are comparable to those recorded for 
1,4-benzoquinone of 4.82 μM (MAO-A) and 10.2 μM (MAO-B). Of interest however, is 
the finding that the 1,4-benzoquinones are irreversible inhibitors of MAO-A 
since prolonged incubation results in near complete inhibition, and enzyme 
activity is not recovered by dialysis. MAO-B is much less sensitive to 
inactivation by the 1,4-benzoquinones. These findings are discussed with 
reference to a possible mechanism by which irreversible inhibition occurs. It 
may be concluded that irreversible 1,4-benzoquinone-derived inhibitors may act 
as probes for investigating quinone reactive sites in the MAOs.

Copyright © 2017 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.ejmech.2017.04.055
PMID: 28456030 [Indexed for MEDLINE]


2. Chem Biol Drug Des. 2016 May;87(5):737-46. doi: 10.1111/cbdd.12708. Epub 2016 
Jan 12.

Evaluation of Natural and Synthetic 1,4-naphthoquinones as Inhibitors of 
Monoamine Oxidase.

Mostert S(1)(2), Petzer A(2), Petzer JP(1)(2).

Author information:
(1)Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private 
Bag X6001, Potchefstroom, 2520, South Africa.
(2)Centre of Excellence for Pharmaceutical Sciences, North-West University, 
Private Bag X6001, Potchefstroom, 2520, South Africa.

Previous reports have documented that 1,4-naphthoquinones act as inhibitors of 
the monoamine oxidase (MAO) enzymes. In particular, fractionation of the 
extracts of cured tobacco leafs has led to the characterization of 
2,3,6-trimethyl-1,4-naphthoquinone, a non-selective MAO inhibitor. To derive 
structure-activity relationships for MAO inhibition by the 1,4-naphthoquinone 
class of compounds, this study investigates the human MAO inhibitory activities 
of fourteen structurally diverse 1,4-naphthoquinones of natural and synthetic 
origin. Of these, 5,8-dihydroxy-1,4-naphthoquinone was found to be the most 
potent inhibitor with an IC50 value of 0.860 μm for the inhibition of MAO-B. A 
related compound, shikonin, inhibits both the MAO-A and MAO-B isoforms with IC50 
values of 1.50 and 1.01 μm, respectively. It is further shown that MAO-A and 
MAO-B inhibition by these compounds is reversible by dialysis. In this respect, 
kinetic analysis suggests that the modes of MAO inhibition are competitive. This 
study contributes to the discovery of novel MAO inhibitors, which may be useful 
in the treatment for disorders such as Parkinson's disease, depressive illness, 
congestive heart failure and cancer.

© 2015 John Wiley & Sons A/S.

DOI: 10.1111/cbdd.12708
PMID: 26684482 [Indexed for MEDLINE]


3. CNS Neurol Disord Drug Targets. 2015;14(6):777-85. doi: 
10.2174/1871527314666150325235608.

Monoamine Oxidase Inhibitors Extracted from Tobacco Smoke as Neuroprotective 
Factors for Potential Treatment of Parkinson's Disease.

Sari Y(1), Khalil A(2).

Author information:
(1)University of Toledo, College of Pharmacy and Pharmaceutical Sciences, 
Department of Pharmacology, Health Science Campus, 3000 Arlington Avenue, 
HEB282G, Toledo, OH 43614. USA. youssef.sari@utoledo.edu.
(2)Qatar University, College of Pharmacy, Pharmaceutical Sciences Section, Doha, 
Qatar. akhalil@qu.edu.qa.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the 
loss of mainly the nigrostriatal dopaminergic neurons, which leads to motor 
dysfunction. Although, most of the drugs are currently used for symptomatic 
treatment, there are at least three FDA-approved drugs for the treatment of PD 
that have been suggested preclinically to have neuroprotective effects. Among 
these drugs are monoamine oxidase (MAO) type B inhibitors such as selegiline and 
rasagiline, and non-ergot derivative dopamine agonist, pramipexole. In this 
review article, we focused on the potential uses of non-selective reversible MAO 
inhibitor, 2,3,6-trimethyl-1,4-naphthoquinone, from flue-cured tobacco leaves 
extract and two β- carboline alkaloids (harman and norharman) as potent, 
reversible and non-selective MAO inhibitors for the treatment of PD. In 
addition, we discussed the potential uses of farnesol as a potent inhibitor of 
MAO-B and farnesylacetone as a less potent selective MAO-B inhibitor. 
Furthermore, adducts of 1,2,3,4-tetrahydroisoquinoline have shown to have 
competitive inhibitory effects for both MAO-A and MAO-B. These inhibitors have 
potential neuroprotective effects, which might be mediated at least through 
nerve growth factor, neurotrophin 3, brain derived neurotrophic factor, and 
glial-cell-line-derived neurotrophic factor. We suggest here the neuroprotective 
implication of extracted MAO inhibitors from smoke tobacco; however, it is 
important to note that there are several existing compounds in tobacco smoke 
that have toxic effects in the brain, these include and not limited to the 
induction of neuropathological features observed in individuals suffering from 
Alzheimer's disease and dementia.

DOI: 10.2174/1871527314666150325235608
PMID: 25808895 [Indexed for MEDLINE]


4. Przegl Lek. 2013;70(10):865-8.

[Tobacco--once a medicinal plant. Does it contain substances with medicinal 
properties?].

[Article in Polish]

Budzianowski J(1).

Author information:
(1)Zaklad Botaniki Farmaceutycznej i Biotechnologii Roślin, Uniwersytet Medyczny 
im. Karola Marcinkowskiego w Poznaniu. jbudzian@ump.edu.pl

Tobacco and its use was discovered by Christopher Columbus in parallel with the 
discovery of America. Soon after, tobacco became a known medicinal plant in 
Europe. Its harmful effects were gradually discovered, especially those of 
tobacco smoke, and now it is considered a toxic plant. Tobacco leaf has a 
monograph in German "Hagers Enzyklopädie derArzneistoffe und Drogen", which 
describes its old, already not valid, medicinal use and clearly shows the toxic 
effects. Epidemiological studies indicate about 50% lower incidence of 
Parkinson's disease in smokers than in non-smokers. In turn, studies of the 
brains of smokers using positron emission tomography showed significantly 
decreased level of monoamine oxidase B--an enzyme which degrades dopamine--the 
neurotransmitter which the significant insufficiency of about 80-85%, is 
responsible for the symptoms of Parkinson's disease. From the tobacco leaves 
there were isolated MAO-B 
inhibitors--naphthoquinone--2,3,6-trimethyl-1,4-naphthoquinone and diterpenoid 
-trans,trans-farnesol, which occur also in tobacco smoke. In the last decade 
many papers have appeared on the neuroprotective activity of nicotine, the best 
known component of tobacco. through the effect of this compound on specific 
nicotinic cholinergic receptors (nAChRs), which interacts with nigrostriatal 
dopaminergic system as well as the possibility of using nicotine for the 
treatment of Parkinson's disease and other neurodegenerative diseases. Moreover, 
tobacco was also found to contain inhibitors of neuronal nitric oxide synthase 
(nNOS). Tobacco cannot be considered a medicinal plant, but some compounds 
occurring in that plant may find therapeutic use.

PMID: 24501813 [Indexed for MEDLINE]


5. Bioorg Med Chem. 2011 Dec 15;19(24):7416-24. doi: 10.1016/j.bmc.2011.10.049. 
Epub 2011 Oct 20.

Molecular insights into human monoamine oxidase (MAO) inhibition by 
1,4-naphthoquinone: evidences for menadione (vitamin K3) acting as a competitive 
and reversible inhibitor of MAO.

Coelho Cerqueira E(1), Netz PA, Diniz C, Petry do Canto V, Follmer C.

Author information:
(1)Department of Physical Chemistry, Institute of Chemistry, Federal University 
of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of biogenic and 
exogenous amines and its inhibitors have therapeutic value for several 
conditions including affective disorders, stroke, neurodegenerative diseases and 
aging. The discovery of 2,3,6-trimethyl-1,4-naphthoquinone (TMN) as a 
nonselective and reversible inhibitor of MAO, has suggested 1,4-naphthoquinone 
(1,4-NQ) as a potential scaffold for designing new MAO inhibitors. Combining 
molecular modeling tools and biochemical assays we evaluate the kinetic and 
molecular details of the inhibition of human MAO by 1,4-NQ, comparing it with 
TMN and menadione. Menadione (2-methyl-1,4-naphthoquinone) is a multitarget drug 
that acts as a precursor of vitamin K and an inducer of mitochondrial 
permeability transition. Herein we show that MAO-B was inhibited competitively 
by 1,4-NQ (K(i)=1.4 μM) whereas MAO-A was inhibited by non-competitive mechanism 
(K(i)=7.7 μM). Contrasting with TMN and 1,4-NQ, menadione exhibited a 60-fold 
selectivity for MAO-B (K(i)=0.4 μM) in comparison with MAO-A (K(i)=26 μM), which 
makes it as selective as rasagiline. Fluorescence and molecular modeling data 
indicated that these inhibitors interact with the flavin moiety at the active 
site of the enzyme. Additionally, docking studies suggest the phenyl side groups 
of Tyr407 and Tyr444 (for MAO-A) or Tyr398 and Tyr435 (for MAO-B) play an 
important role in the interaction of the enzyme with 1,4-NQ scaffold through 
forces of dispersion as verified for menadione, TMN and 1,4-NQ. Taken together, 
our findings reveal the molecular details of MAO inhibition by 1,4-NQ scaffold 
and show for the first time that menadione acts as a competitive and reversible 
inhibitor of human MAO.

Copyright © 2011 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.bmc.2011.10.049
PMID: 22071524 [Indexed for MEDLINE]