DOI: 10.1002/cmdc.201600497
Communications
Monoamine Oxidase Inhibitory Activity: Methyl- versus
Chlorochalcone Derivatives
Bijo Mathew+,*[a] Gꢀlberk UÅar+,*[b] Githa Elizabeth Mathew,[c] Sincy Mathew,[d]
Praseedha Kalatharakkal Purapurath,[d] Fasil Moolayil,[d] Smrithy Mohan,[d] and
Sheeba Varghese Gupta[e]
Numerous studies have shown that chalcones are promising
scaffolds for the development of new monoamine oxidase-B
(MAO-B) inhibitors. As a continuation of our ongoing research
into the development of reversible human MAO-B (hMAO-B)
inhibitors, two series of twenty chalcones containing electron-
donating and electron-withdrawing substituents were synthe-
sized. All compounds were found to be competitive, selective,
and reversible inhibitors of hMAO-B except (2E)-1-(4-methyl-
phenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-
chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which
were found to be selective inhibitors of hMAO-A. The most
potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphe-
nyl)prop-2-en-1-one (P16), showed a Ki value of 0.11Æ0.01 mm.
Molecular docking simulations were carried out to identify the
hypothetical binding mode for the most potent compounds in
the active sites of hMAO-A and B. The ability of the com-
pounds to cross the blood–brain barrier was assessed by paral-
lel artificial membrane permeability assay (PAMPA). Additional-
ly, the most potent hMAO-B inhibitor P16 showed no toxicity
in cultured hepatic cells at concentrations of 5 and 25 mm.
a drug target to treat depression and anxiety disorders.[2] As
MAO-B appears to be the major dopamine-metabolizing
enzyme in the basal ganglia, selective MAO-B inhibitors are
used in the treatment of neurodegenerative disorders such as
idiopathic Parkinson’s disease (PD).[3,4] Irreversible MAO-B inhib-
itors in current use covalently bind their target, rendering the
enzyme functionless; MAO-B activity is therefore blocked until
the cell produces more enzyme. Reversible inhibitors have the
capacity to detach from their target enzyme, to facilitate
normal substrate catabolism.[5] There is an urgent need for re-
versible MAO-B inhibitors with safe side-effect profiles for use
as an adjunct to l-DOPA therapy for the treatment of PD.
Elevated central nervous system (CNS) levels of MAO-B in PD
patients leads to an increased production of hydrogen perox-
ide and reactive oxygen species.[6,7] These toxic metabolites are
responsible for neurodegeneration, leading to the death of
dopamine-containing neurons. Depletion of dopamine is re-
sponsible for the major motor symptoms associated with PD.[8]
Notable MAO-B-selective and irreversible inhibitors such as se-
legiline and rasagiline are approved for PD monotherapy, or as
adjunctive therapies to l-DOPA.[9] Safinamide, a reversible
MAO-B-selective inhibitor, has completed phase III trials for the
treatment of PD.[10] Clinical trials of another MAO-B inhibitor,
lazabemide, have been discontinued due to reports of liver
toxicity.[11,12] Some studies have suggested that MAO-B inhibi-
tors with neuroprotective properties can be used as an ancil-
lary treatment for Alzheimer’s disease (AD).[13] The design and
development of new multifunctional MAO-B inhibitors for the
treatment of PD and AD appears to be a promising course.
Chemically, chalcones are 1,3-diphenyl-2-propen-1-ones,
consisting of two aromatic rings (rings A and B) with a double
bond in conjugation with a carbonyl group.[14] Many studies
have shown that these scaffolds have selective and reversible/
irreversible MAO-B inhibitory activity in the nanomolar
range.[15–21] Prior studies revealed that the removal of the
double bond system in chalcone leads to decreased activity in
MAO inhibition.[22,23] Additionally, heterocyclic substituents
such as furan, chromene, thiophene, piperidine, quinoline, and
indole in the chalcone scaffold lead to improved MAO inhibi-
tion.[24–32] Recent reports have shown that chalcones are more
potent inhibitors of MAO-A than of MAO-B. This selectivity
may be due to steric hindrance and the nature and orientation
of functional groups on the phenyl ring of chalcones.[33,34] The
presence of lipophilic groups such as ethyl, methyl, dimethyla-
mino, bromo, chloro, fluoro, and trifluoromethyl groups at the
para position of ring B increases MAO-B inhibitory activity. Lip-
Monoamine oxidase inhibitors (MAOIs) have been extensively
studied because of their role in the treatment of psychiatric
and neurological disorders. The first generation of MAOIs were
nonselective and irreversible, with serious side effects such as
liver toxicity and hypertensive crisis. This led to their withdraw-
al from clinical use.[1] Based on the catalytic activities of the
MAO-A and MAO-B isoforms, MAO-A has been considered
[a] Dr. B. Mathew+
Division of Drug Design and Medicinal Chemistry Research, Department of
Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557
Kerala (India)
[b] Prof. Dr. G. UÅar+
Department of Biochemistry, Faculty of Pharmacy, Hacettepe University,
Sıhhiye, 06100 Ankara (Turkey)
[c] G. E. Mathew
Department of Pharmacology, Grace College of Pharmacy, Palakkad
678004, Kerala (India)
[d] S. Mathew, P. Kalatharakkal Purapurath, F. Moolayil, S. Mohan
Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Pal-
akkad 678004, Kerala (India)
[e] Dr. S. Varghese Gupta
Department of Pharmaceutical Sciences, College of Pharmacy, University of
South Florida, Tampa, FL 33612 (USA)
[+] These authors contributed equally to this work.
ChemMedChem 2016, 11, 1 – 8
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