Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents

Article abstract of DOI:10.3109/14756366.2016.1161621

In the present work, 12 new 2-(5-substituted-benzothiazol-2-ylsulfanyl)-N-(substitutedbenzyl)-N-(4-substitutedphenyl) acetamide derivatives (4a–l) was designed and synthesized. The structures of the synthesized compounds were clarified using Fourier trans

Full text of DOI:10.3109/14756366.2016.1161621

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Synthesis of some novel 2-substituted
benzothiazole derivatives containing benzylamine
moiety as monoamine oxidase inhibitory agents
Betül Kaya, Begüm Nurpelin Sağlık, Serkan Levent, Yusuf Özkay & Zafer
Asım Kaplancıklı
To cite this article: Betül Kaya, Begüm Nurpelin Sağlık, Serkan Levent, Yusuf Özkay & Zafer
Asım Kaplancıklı (2016): Synthesis of some novel 2-substituted benzothiazole derivatives
containing benzylamine moiety as monoamine oxidase inhibitory agents, Journal of Enzyme
Inhibition and Medicinal Chemistry, DOI: 10.3109/14756366.2016.1161621
To link to this article: http://dx.doi.org/10.3109/14756366.2016.1161621
Published online: 30 Mar 2016.
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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–8
2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.3109/14756366.2016.1161621
!
RESEARCH ARTICLE
Synthesis of some novel 2-substituted benzothiazole derivatives
containing benzylamine moiety as monoamine oxidase inhibitory
agents
1
Betu¨l Kaya , Begu¨m Nurpelin Saglık1,2, Serkan Levent1,2, Yusuf Ozkay1,2, and Zafer Asım Kaplancıklı1
¨
˘
2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey and Doping and Narcotic Compounds
Analysis Laboratory, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey
Abstract
Keywords
In the present work, 12 new 2-(5-substituted-benzothiazol-2-ylsulfanyl)-N-(substitutedbenzyl)-
N-(4-substitutedphenyl) acetamide derivatives (4a–l) was designed and synthesized. The
structures of the synthesized compounds were clarified using Fourier transform infrared
spectroscopy (FTIR), proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic
resonance (13C-NMR) and high-resolution mass spectrometry (HRMS) spectral data. Purity of
synthesized compounds was checked by high-performance liquid chromatography (HPLC)
analyses and purity ratio was found between 96.5–99.9%. The inhibitory activity of the
compounds against MAO-A and MAO-B enzymes was evaluated by using in vitro flurometric
method in which kynuramine was used as a substrate. Most of the compounds exhibited more
selective inhibitory activity towards monoamine oxidase B (MAO-B) than monoamine oxidase A
(MAO-A). Compound 4h was determined as the most potent compound against both enzyme
types. The MAO-B enzyme kinetic of the compound 4h was studied and nature of MAO-B
inhibition, caused by this compound, was investigated. The graphical analysis of steady-state
inhibition data indicated that compound 4h is a mixed type inhibitor. Theoretical calculation
of absorption, distribution, metabolism, excretion (ADME) properties for the synthesized
compounds was also carried out and observed data supported the potential of compound 4h.
Benzothiazole, kynuramine, MAO-A, MAO-B
History
Received 11 February 2016
Revised 1 March 2016
Accepted 1 March 2016
Published online 23 March 2016
Introduction
generally used in dealing with symptoms associated with
Parkinson’s and Alzheimer’s diseases13,14. Iproniazid is the first
drug used in the therapy of depressive disorder during 1950s15.
First-generation MAO inhibitors, such as iproniazid, imipramine
and tranylcipromine, are irreversible and nonselective against
MAO isoforms16. Despite their long clinical success, first-
generation MAO inhibitors have a number of problems including
interactions with other drugs and tyramine, which is a dietary
amine and may cause a fatal hypertensive crisis17,18. In view of
these adverse actions and restrictions, the clinical use of first
generation of MAO inhibitors have been decreased, whereas
second-generation MAO inhibitors, such as selegiline and
moclobemide, have come into prominence due to lack of above
problems19.
In view of information mentioned previously, researchers have
shown an increased interest in developing novel and potent MAO
inhibitors. Structural similarity with the current drugs is one of
the most used strategy for new MAO inhibitor development. The
presence of arylalkylamine or benzylamine functions commonly
in many MAO inhibitors may be suggested as a structural
requirement for the development of a new class of MAO
inhibitors (Figure 1). Resemblance in the chemical structures of
MAO inhibitors and neurotransmitters or intracellular amines also
cites to this requirement. Hence, it may conceivably be declared
that arylalkylamine or benzylamine moieties contest with endo-
genic amines. This consideration has been supported by some
In the regulation of different biological processes, the monoamine
oxidase (MAO) enzymes play a significant role, thereby crucial
targets in drug design for the treatment of psychiatric and
neurological disorders1,2. MAOs are in charge of catalysing the
oxidative deamination of neurotransmitters and intracellular
amines and thus control their concentrations in brain and
peripheral tissues3,4. MAOs include the covalently linked cofactor
flavinadenosine-dinucleotide (FAD) and exist in outer mitochon-
drial membrane5,6. Relying on their affinities to inhibitors and
specificities to substrates, two isoforms of MAO, namely MAO-A
and MAO-B, have been identified in mammals7,8. MAO-A
predominantly metabolizes serotonin, adrenaline and noradren-
aline, while MAO-B utilize phenylethylamine and benzylamine as
substrate8,9. On the other hand, tyramine and dopamine were
metabolized by both forms of the enzyme10.
By means of their regulatory effect on the metabolism of
neurotransmitters, MAOs are increasingly becoming an important
area in medicinal chemistry. MAO-A inhibitors are clinically used
mostly as antidepressants11,12, whereas MAO-B inhibitors are
¨
Address for correspondence: Yusuf Ozkay, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry, Anadolu University,
Yunusemre Campus, 26470 Tepebas¸ı/Eskis¸ehir, Turkey. Tel: +90-222-
3350580/3779. Fax: +90-222-3350750. E-mail: yozkay@anadolu.edu.tr

2
B. Kaya et al.
J Enzyme Inhib Med Chem, Early Online: 1–8
Cl
Figure 1. Structure of various MAO inhibi-
tors and synthesized compounds.
CH
CH
N
3
NH
N
N
CH
3
CH
H C
O
O
3
Pargyline
Moclobemide
Selegiline
CH
O
N
NH
2
CH
Cl
3
Clorgyline
Tranylcypromine
Cl
R
3
R
N
1
R
4
N
S
O
S
R
2
Synthesized Compounds 4a-4l
studies indicating that benzylamine moiety possesses MAO precipitated product was filtered and recrystallized from
inhibitory activity20–22. In addition to benzylamine, the com- ethanol25.
pounds containing benzothiazole moiety have been reported to
inhibit MAO enzymes23. Besides, it has been declared that Preparation of N-(3 or 4-nitrobenzyl)-4-substituted anilines
aromatic nitro compounds have an inhibition potency on MAO (2a–d)
enzymes24.
The compounds 1a–d (20 mmol) were dissolved in methanol
In the light of above information, herein, we report the
(100 ml). Sodium borohydride (40 mmol, 0.76 g) was divided in to
synthesis and monoamine oxidase inhibitory activity of some
four portion (4 ꢀ 0.38 g) and added to the methanolic solution
novel 2–(5-substituted-benzothiazol-2-ylsulfanyl)-N-(3 or 4-nitro
15 min intervals. After addition of last portion, reaction mixture
benzyl)-N-(4-substitutedphenyl) acetamide derivatives (4a–l).
was allowed to stir for 1 h at room temperature. The excess of
solvent was evaporated under reduced pressure, crude product
Materials and methods
was washed with water, dried and recrystallized from ethanol25.
All chemicals were purchased from Sigma-Aldrich Chemicals
(Sigma-Aldrich Corp., St. Louis, MO) and Merck Chemicals Preparation of 2-chloro-N-(3- or 4-nitrobenzyl)-N-(4-substitu-
(Merck KGaA, Darmstadt, Germany). All melting points (m.p.) tedphenyl) acetamides (3a–d)
were determined by MP90 digital melting point apparatus
The compounds 2a–d (10 mmol) were dissolved in tetrahydro-
(Mettler Toledo, OH) and were uncorrected. All reactions were
furan (50 ml) and triethylamine (11 mmol, 1.55 ml) was added.
monitored by thin-layer chromatography (TLC) using Silica Gel
The mixture was cooled in an ice bath and chloroacetyl chloride
60 F254 TLC plates (Merck KGaA, Darmstadt, Germany).
(11 mmol, 0.88 ml) was added dropwise with stirring. After
Spectroscopic data were recorded with the following instruments:
addition of chloroacetyl chloride, the reaction mixture was stirred
IR, Shimadzu Affinity 1S spectrophotometer (Shimadzu, Tokyo,
for additional 1 h at room temperature. The solvent was
Japan); NMR, Bruker DPX 500 NMR spectrometer (Bruker
evaporated under reduced pressure, product was washed with
Bioscience, Billerica, MA), in DMSO-d6, using TMS as internal
water, dried and recrystallized from ethanol26.
standard; M + 1 peaks were determined by Shimadzu LC/MS IT-
TOF system (Shimadzu, Tokyo, Japan). Purity of synthesized
compounds was checked by Shimadzu LC-20A prominence
HPLC system, equipped with a Shimadzu DGU-14A degasser,
Preparation of N-(3- or 4-nitrobenzyl)-N-(4-substitutedphenyl)-2-
((5-substitutedbenzo[d]thiazol-2-yl)thio)acetamides (4a–l)
LC-20 A dual piston pump, CTO-10 ASVP column oven and
SPD-MI20A PDA detector, reodyne 7725i injection valve and a
stainless steel GL Science Inertsil ODS-3 (4.6 ꢀ 250 mm)
column. Mobile phase was used as solvent A, acetonitrile
(95%); solvent B, water (5%) at a flow rate of 0.8 ml/min and a
sample injection volume of 20 ml.
The compounds 3a–d (2 mmol), appropriate 5-substituted ben-
zothiazole-2-thiol (2 mmol) and potassium carbonate (2 mmol,
0.276 g) in acetone (40 ml) was refluxed for 12 h. After TLC
screening, the solvent was evaporated under reduced pressure.
The product was washed with water, dried and recrystallized from
ethanol26.
General procedure for synthesis of the compounds
2-(Benzo[d]thiazol-2-yl-thio)-N-(4-chlorophenyl)-N-(4-nitroben-
zyl)acetamide (4a)
Preparation of N-(3 or 4-nitrobenzylidene)-4-substituted anilines
(1a–d)
Yield 65–67%, m.p. 119–121 ꢁC. HPLC: 99.7% purity. IR ꢀmax
(cmꢂ1): 3104.92–3032.06 (aromatic C–H), 2951.49–2928.99
(aliphatic C–H), 1666.50 (C¼O amide), 1605.98–1427.32
(C¼N, C¼C), 839.03 (1,4-disubstitutedbenzene). 1H-NMR
(500 Mhz, DMSO-d6, ppm) d 4.23 (2H, s, CO-CH2), 5.04
Corresponding nitrobenzaldehyde derivative (30 mmol) appropri-
ate four-substituted aniline (30 mmol) and catalytic amount of
glacial acetic acid (0.5 ml) were refluxed in ethanol (100 ml) for
2 h. After completion of reaction, the mixture was cooled,

DOI: 10.3109/14756366.2016.1161621
Synthesis of novel 2-substituted benzothiazole derivatives
3
(2H, s, N-CH2), 7.38 (1H, t, J ¼ 8.0 Hz, Ar-H), 7.47–7.54 (7H, m, (C¼N, C¼C), 840.96 (1,4-disubstitutedbenzene). 1H-NMR
Ar-H), 7.82 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.02 (1H, d, J ¼ 8.0 Hz, (500 Mhz, DMSO-d6, ppm) d 4.22 (2H, s, CO-CH2), 5.04 (2H,
Ar-H), 8.11 (2H, d, J ¼ 8.2 Hz, Ar-H). 13C-NMR (125 Mhz, s, N-CH2), 7.43–7.55 (7H, m, Ar-H), 7.87 (1H, s, Ar-H), 8.05 (1H,
DMSO-d6, ppm) d 37.08, 52.76, 121.54, 122.37, 123.95, 125.03, d, J ¼ 8.7 Hz, Ar-H), 8.13 (2H, d, J ¼ 8.2, Ar-H). 13C-NMR
126.82, 129.43, 130.30, 130.50, 133.46, 135.24, 140.66, 145.39, (125 Mhz, DMSO-d6, ppm) d 37.18, 52.72, 121.00, 123.79,
147.19, 152.84, 166.23, 167.17. HRMS (m/z): [M + H]+ calcd for 123.95, 125.00, 129.54, 130.35, 130.57, 131.71, 133.49, 134.04,
C22H16ClN3O3S2: 470.0394; found 470.0402.
140.61, 145.37, 147.21, 153.70, 166.97, 169.13. HRMS (m/z):
[M + H]+ calcd for C22H15Cl2N3O3S2: 504.0005; found 504.0003.
2-((Benzo[d]thiazol-2-yl-thio)-N-(4-fluorophenyl)-N-(4-nitroben-
zyl)acetamide (4b)
2-((5-Chlorobenzo[d]thiazol-2-yl)thio)-N-(4-fluorophenyl)-N-(4-
nitrobenzyl)acetamide (4f)
Yield 64–65%, m.p. 149–151 ꢁC. HPLC: 98.8% purity. IR ꢀmax
(cm ꢂ1): 3106.14–3056.02 (aromatic C–H), 2998.51–2939.04 Yield 66–68%, m.p. 192–194 ꢁC. HPLC: 98.2% purity. IR ꢀmax
(aliphatic C–H), 1662.64 (C¼O amide), 1616.05–1427.98 (cmꢂ1): 3171.89–3046.19 (aromatic C–H), 2982.18–2893.38
(C¼N, C¼C), 856.75 (1,4-disubstitutedbenzene). 1H-NMR (aliphatic C–H), 1664.57 (C¼O amide), 1617.98–1427.32
(500 Mhz, DMSO-d6, ppm) d 4.20 (2H, s, CO-CH2), 5.03 (2H, (C¼N, C¼C), 842.82 (1,4-disubstitutedbenzene). 1H-NMR
s, N-CH2), 7.32 (2H, m, Ar-H), 7.38 (1H, t, J ¼ 8.0 Hz, Ar-H), (500 Mhz, DMSO-d6, ppm) d 4.19 (2H, s, CO-CH2), 5.03 (2H,
7.47–7.54 (5H, m, Ar-H), 7.82 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.02 s, N-CH2), 7.32 (2H, t, J ¼ 8.6 Hz, Ar-H), 7.42 (1H, dd, J ¼
(2H, d, J ¼ 8.0 Hz, Ar-H), 8.11 (2H, d, J ¼ 8.4 Hz, Ar-H). 13C- 8.5 Hz–1.4 Hz, Ar-H), 7.50–7.54 (4H, m, Ar-H), 7.87 (1H, d, J ¼
NMR (125 Mhz, DMSO-d6, ppm) d 37.13, 52.88, 117.14 (d, J ¼ 1.4 Hz Ar-H), 8.05 (1H, d, J ¼ 8.5 Hz, Ar-H), 8.13 (2H, d, J ¼
22.6 Hz), 121.52, 122.37, 123.93, 125.02, 126.81, 129.47, 130.88 8.5 Hz, Ar-H). 13C-NMR (125 Mhz, DMSO-d6, ppm) d 37.27,
(d, J ¼ 8.9 Hz), 135.23, 138.07, 145.45, 147.19, 152.86, 161.93 52.86, 117.18 (d, J ¼ 22.6 Hz), 120.98, 123.79, 123.93, 124.99,
(d, J ¼ 244.4 Hz), 166.28, 167.27. HRMS (m/z): [M + H]+ calcd 129.58, 130.91 (d, J ¼ 8.8 Hz), 131.70, 134.03, 138.03 (d, J ¼
for C22H16FN3O3S2: 454.0690; found 454.0693.
2.9 Hz) 145.44, 147.20, 153.73, 162.01 (d, J ¼ 244.6 Hz), 167.06,
169.21. HRMS (m/z): [M + H]+ calcd for C22H15ClFN3O3S2:
2-((Benzo[d]thiazol-2-yl-thio)-N-(4-chlorophenyl)-N-(3-nitroben- 488.0300; found 488.0306.
zyl)acetamide (4c)
2-((5-Chlorobenzo[d]thiazol-2-yl)thio)-N-(4-chlorophenyl)-N-(3-
nitrobenzyl)acetamide (4 g)
Yield 66–68%, m.p. 116–118 ꢁC. HPLC: 99.8% purity. IR ꢀmax
(cmꢂ1): 3116.14–3008.52 (aromatic C–H), 2989.05–2902.29
(aliphatic C–H), 1664.57 (C¼O amide), 1620.48–1439.21 Yield 67–68%, m.p. 164–166 ꢁC. HPLC: 97.1% purity. IR ꢀmax
(C¼N, C¼C), 840.96 (1,4-disubstitutedbenzene), 783.10 (1,3- (cmꢂ1): 3104.51–3005.39 (aromatic C–H), 2993.03–2921.66
disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d (aliphatic C–H), 1672.28 (C¼O amide), 1629.55–1427.32
4.21 (2H, s, CO-CH2), 5.06 (2H, s, N-CH2), 7.37 (1H, t, J ¼ (C¼N, C¼C), 839.03 (1,4-disubstitutedbenzene), 785.03 (1,3-
8.0 Hz, Ar-H), 7.42–7.47 (3H, m, Ar-H), 7.53–7.57 (3H, m, Ar-H), disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d
7.70 (1H, d, J ¼ 7.0 Hz, Ar-H), 7.77 (1H, d, J ¼ 8.0 Hz, Ar-H), 4.20 (2H, s, CO-CH2), 5.05 (2H, s, N-CH2), 7.40–7.47 (3H, m,
8.00 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.10–8.12 (2H, m, Ar-H). 13C- Ar-H), 7.53–7.57 (3H, m, Ar-H), 7.69 (1H, d, J ¼ 7.4 Hz, Ar-H),
NMR (125 Mhz, DMSO-d6, ppm) d 37.12, 52.43, 121.48, 122.32, 7.78 (1H, s, Ar-H), 7.53 (1H, d, J ¼ 8.6 Hz, Ar-H), 8.09–8.13
122.81, 123.20, 124.97, 126.80, 130.29, 130.37, 130.60, 133.45, (2H, m, Ar-H). 13C-NMR (125 Mhz, DMSO-d6, ppm) d 37.21,
135.08, 135.20, 139.79, 140.53, 148.31, 152.86, 166.21, 167.21. 52.44, 120.94, 122.32, 122.81, 123.27, 124.95, 130.33, 130.63,
HRMS (m/z): [M + H]+ calcd for C22H16ClN3O3S2: 470.0394; 131.67, 133.50, 134.06, 135.18, 139.77, 140.49, 148.30, 153.71,
found 470.0402.
167.05,
C22H15Cl2N3O3S2: 504.0005; found 504.0008.
169.08.
HRMS
(m/z):
[M + H]+ calcd
for
2-((Benzo[d]thiazol-2-yl-thio)-N-(4-fluorophenyl)-N-(3-nitroben-
zyl)acetamide (4d)
2-((5-Chlorobenzo[d]thiazol-2-yl)thio)-N-(4-fluorophenyl)-N-(3-
nitrobenzyl)acetamide (4 h)
Yield 68–70%, m.p. 105–106 ꢁC. HPLC: 96.5% purity. IR ꢀmax
(cmꢂ1): 3112.49–3028.13 (aromatic C–H), 2997.16–2914.06
(aliphatic C–H), 1660.71 (C¼O amide), 1636.62–1429.25
(C¼N, C¼C), 840.96 (1,4-disubstitutedbenzene), 783.10 (1,3-
disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d
4.19 (2H, s, CO-CH2), 5.04 (2H, s, N-CH2), 7.30–7.38 (3H, m,
Ar-H), 7.44–7.48 (3H, m, Ar-H), 7.56 (1H, t, J ¼ 7.9 Hz, Ar-H),
7.69 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.76 (1H, d, J ¼ 8.0 Hz, Ar-H),
8.00 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.09–8.12 (2H, m, Ar-H). 13C-
NMR (125 Mhz, DMSO-d6, ppm) d 37.18, 52.56, 117.12 (d, J ¼
22.6 Hz), 121.46, 122.30, 122.78, 123.25, 124.95, 126.78, 130.34,
130.98 (d, J ¼ 8.8 Hz), 135.14, 135.19, 137.92, 139.82, 148.30,
152.88, 161.93 (d, J ¼ 244.3 Hz), 166.25, 167.29. HRMS (m/z):
[M + H]+ calcd for C22H16FN3O3S2: 454.0690; found 454.0692.
Yield 65–67%, m.p. 134–136 ꢁC. HPLC: 99.0% purity. IR ꢀmax
(cmꢂ1): 3112.77–3010.59 (aromatic C–H), 2956.40–2891.09
(aliphatic C–H), 1660.71 (C¼O amide), 1604.02–1427.32
(C¼N, C¼C), 842.89 (1,4-disubstitutedbenzene), 785.03 (1,3-
disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d
4.18 (2H, s, CO-CH2), 5.04 (2H, s, N-CH2), 7.32 (2H, t, J ¼
8.6 Hz, Ar-H), 7.41–7.48 (3H, m, Ar-H), 7.58 (1H, t, J ¼ 7.9 Hz,
Ar-H), 7.69 (1H, d, J ¼ 7.5 Hz, Ar-H), 7.79 (1H, s, Ar-H), 8.04
(1H, d, J ¼ 8.6 Hz, Ar-H), 8.09 (1H, s, Ar-H), 8.13 (1H, d, J ¼
9.1 Hz, Ar-H). 13C-NMR (125 Mhz, DMSO-d6, ppm) d 37.31,
52.56, 117.16 (d, J ¼ 22.6 Hz), 120.92, 122.36, 122.80, 123.33,
124.95, 130.33, 130.98 (d, J ¼ 8.8 Hz), 131.66, 133.97, 135.25,
137.89 (d, J ¼ 2.3 Hz), 139.82, 148.30, 153.74, 161.92 (d, J ¼
244.2 Hz), 167.12, 169.17. HRMS (m/z): [M + H]+ calcd for
C22H15ClFN3O3S2: 488.0300; found 488.0313.
2-((5-Chlorobenzo[d]thiazol-2-yl)thio)-N-(4-chlorophenyl)-N-(4-
nitrobenzyl)acetamide (4e)
2-((5-Methoxybenzo[d]thiazol-2-yl)thio)-N-(4-chlorophenyl)-N-
(4-nitrobenzyl)acetamide (4i)
Yield 63–65%, m.p. 175–177 ꢁC. HPLC: 98.0% purity. IR ꢀmax
(cmꢂ1): 3101.59–3009.65 (aromatic C–H), 2994.10–2895.60
(aliphatic C–H), 1664.57 (C¼O amide), 1619.91–1425.40
Yield 66–68%, m.p. 163–165 ꢁC. HPLC:499.9% purity. IR ꢀmax
(cmꢂ1): 3097.89–3004.19 (aromatic C–H), 2982.00–2818.65

4
B. Kaya et al.
J Enzyme Inhib Med Chem, Early Online: 1–8
(aliphatic C–H), 1660.71 (C¼O amide), 1633.49–1427.32 (C¼N, MAO activity assay
C¼C), 840.96 (1,4-disubstitutedbenzene). 1H-NMR (500 Mhz,
Enzyme activity assay was performed according to the procedure
reported by Matsumoto et al.,27 with slight modifications. The
entire materials used in enzymatic assay were purchased from
Sigma-Aldrich Chemicals (Sigma-Aldrich Corp., St. Louis, MO).
All of the pipettings in the assay were performed by Biotek
Precision robotic system (BioTek Instruments, Inc., Winooski,
VT). In order to prevent light effect on MAO enzymes the assay
was performed in 96-well black plates. Phosphate buffer (0.1 M,
pH ¼ 7.4) was used for the preparation of stock solutions (5 mg/
ml) of both human recombinant MAO-A and MAO-B enzymes.
Enzyme stock solutions was further diluted with assay buffer to
DMSO-d6, ppm) d 3.85 (3H, s, OCH3) 4.22 (2H, s, CO-CH2), 5.05
(2H, s, N-CH2), 7.02 (1H, dd, J ¼ 8.8 Hz–2.0 Hz, Ar-H), 7.33
(1H, d, J ¼ 2.0 Hz, Ar-H), 7.48–7.54 (6H, m, Ar-H) 7.87 (1H, d,
J ¼ 8.8 Hz, Ar-H), 8.13 (2H, d, J ¼ 8.3 Hz, Ar-H). 13C-NMR
(125 Mhz, DMSO-d6, ppm) d 37.16, 52.74, 56.00, 105.04,
114.18, 122.62, 123.96, 126.77, 129.48, 130.33, 130.51, 133.47,
140.63, 145.38, 147.19, 154.19, 159.19, 167.14, 167.20. HRMS
(m/z): [M + H]+ calcd for C23H18ClN3O4S2: 500.0500; found
500.0503.
2-((5-Methoxybenzo[d]thiazol-2-yl)thio)-N-(4-fluorophenyl)-N-
(4-nitrobenzyl)acetamide (4j)
get
a final concentration 0.006 mg/ml for MAO-A and
0.015 mg/ml for MAO-B. Kynuramine was dissolved in sterilized
Yield 66–68%, m.p. 175–177 ꢁC. HPLC:499.9% purity. IR ꢀmax distilled water to get stock solution (25 mM) and then diluted with
(cmꢂ1): 3071.46–3029.03 (aromatic C–H), 2919.18–2895.38 assay buffer to get a final concentration of 40 mM for MAO-A
(aliphatic C–H), 1662.64 (C¼O amide), 1617.98–1419.61 enzyme and 20 mM for MAO-B enzyme. Synthesized compounds
(C¼N, C¼C), 846.75 (1,4-disubstitutedbenzene). 1H-NMR and reference drugs (moclobemide for MAO-A enzyme and
(500 Mhz, DMSO-d6, ppm) d 3.85 (3H, s, OCH3), 4.19 (2H, s, selegiline for MAO-B enzyme) were diluted to 10ꢂ3 M and
CO-CH2), 5.03 (2H, s, N-CH2), 7.02 (1H, dd, J ¼ 8.7 Hz–1.7 Hz, 10ꢂ4 M concentrations (100 ml/well) using 2% DMSO. The
Ar-H), 7.30–7.33 (3H, m, Ar-H), 7.49–7.55 (4H, m, Ar-H), 7.87 addition of the compounds dilutes was followed by the addition of
(1H, d, J ¼ 8.7 Hz, Ar-H), 8.13 (2H, d, J ¼ 8.3 Hz, Ar-H). 13C- either MAO-A or MAO-B enzyme (50 ml/well). After 10-min
NMR (125 Mhz, DMSO-d6, ppm) d 37.24, 52.86, 55.99, 105.03, incubation at 37 ꢁC, kynuramine (50 ml/well) was added and
114.15, 117.16 (d, J ¼ 22.6 Hz), 122.67, 123.94, 126.75, 129.52, enzyme–substrate reaction was initiated. The plate was incubated
130.90 (d, J ¼ 8.9 Hz), 138.04 (d, J ¼ 2.6 Hz), 145.45, 147.18, for 20 min at 37 ꢁC, and then, reaction was terminated by using of
154.21, 159.18, 161.93 (d, J ¼ 244.5 Hz), 167.16, 167.22. HRMS 2 N NaOH (75 ml/well). The fluorimetric read from top was
(m/z): [M + H]+ calcd for C23H18FN3O4S2: 484.0796; found performed by BioTek-Synergy H1 multimode microplate reader
484.0790.
(BioTek Instruments, Inc., Winooski, VT) at 310/380 nm excita-
tion/emission wavelength pair. The same procedure was followed
for further concentrations (10ꢂ5–10ꢂ9 M, 100 ml/well) of the
inhibitors and selected compounds indicating ꢃ50% inhibition at
initial concentrations (10ꢂ3 and 10ꢂ4 M, 100ml/well). The IC50
value was calculated from the plots of enzyme activity against
concentrations by applying regression analyses on GraphPad Prism
Version 5.
2-((5-Methoxybenzo[d]thiazol-2-yl)thio)-N-(4-chlorophenyl)-N-
(3-nitrobenzyl)acetamide (4k)
Yield 62–65%, m.p. 140–143 ꢁC. HPLC:499.9% purity. IR ꢀmax
(cmꢂ1): 3093.67–3031.09 (aromatic C–H), 2941.18–2891.01
(aliphatic C–H), 1662.64 (C¼O amide), 1625.69–1429.25
(C¼N, C¼C), 840.96 (1,4-disubstitutedbenzene), 783.10 (1,3-
disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d
3.84 (3H, s, OCH3) 4.20 (2H, s, CO-CH2), 5.05 (2H, s, N-CH2),
Enzyme kinetic studies
7.00 (1H, dd, J ¼ 8.8 Hz–1.8 Hz, Ar-H), 7.28 (1H, d, J ¼ The same materials were used in MAO-inhibition assay. The
1.8 Hz, Ar-H), 7.45 (2H, d, J ¼ 8.2 Hz, Ar-H), 7.53–7.58 (3H, compound 4 h was prepared at IC50 concentration that calculated
m, Ar-H) 7.69 (1H, d, J ¼ 8.8 Hz, Ar-H), 7.85 (1H, d, J ¼ in enzyme assay and then added to the wells (100 ml/well). Stock
8.8 Hz, Ar-H), 8.10–8.13 (2H, m, Ar-H). 13C-NMR (125 Mhz, solution (25 mM) of kynuramine 0.1 M phosphate buffer was
DMSO-d6, ppm) d 37.22, 52.43, 56.00, 104.97, 114.17, 122.56, diluted to final concentrations of 40, 20, 10, 5, 2.5 and 1.25 mM
122.82, 123.22, 126.71, 130.31, 130.38, 130.61, 133.47, 135.13, and then added to the wells (50 ml/well) that contain the test
139.77, 140.48, 148.31, 154.21, 159.15, 167.12, 167.20. HRMS compound. The monoamine oxidase-B enzyme was added to the
(m/z): [M + H]+ calcd for C23H18ClN3O4S2: 500.0500; found plate (50 ml/well) and this step was followed by a 20-min
500.0497.
incubation period at 37 ꢁC. The plate was read at 310/340 nm
excitation/emission wavelength pair28. Control measurement
without inhibitor was also determined simultaneously. The results
were analysed as Lineweaver–Burk plots using Microsoft Office
Excel 2013.
2-((5-Methoxybenzo[d]thiazol-2-yl)thio)-N-(4-fluorophenyl)-N-
(3-nitrobenzyl)acetamide (4 l)
Yield 68–70%, m.p. 140–143 ꢁC. HPLC:499.9% purity. IR ꢀmax
(cmꢂ1): 3108.25–3003.99 (aromatic C–H), 2992.71–2831.04
(aliphatic C–H), 1670.35 (C¼O amide), 1619.91–1419.61
Theoretical calculation of ADME parameters
(C¼N, C¼C), 848.68 (1,4-disubstitutedbenzene), 783.10 (1,3- In order to evaluate pharmacokinetic profiles of the synthesized
disubstitutedbenzene). 1H-NMR (500 Mhz, DMSO-d6, ppm) d compounds, some physicochemical parameters that are used for
3.83 (3H, s, OCH3), 4.18 (2H, s, CO-CH2), 5.04 (2H, s, N-CH2), determination of ADME properties were calculated using the
7.00 (1H, dd, J ¼ 8.8 Hz–2.0 Hz, Ar-H), 7.28–7.33 (3H, m, Ar- Molinspiration property calculation program29.
H), 7.46–7.47 (2H, m, Ar-H), 7.58 (1H, t, J ¼ 7.9 Hz, Ar-H),
8.86 (1H, d, J ¼ 8.8 Hz, Ar-H), 8.10–8.13 (2H, m, Ar-H). 13C- Results and discussion
NMR (125 Mhz, DMSO-d6, ppm) d 37.31, 52.55, 55.98, 104.97,
Chemistry
114.13, 117.14 (d, J ¼ 22.5 Hz), 122.54, 122.80, 123.26,
126.70, 130.35, 130.99 (d, J ¼ 8.7 Hz), 135.20, 137.87, 139.80, Target molecules (4a–g) were synthesized in four steps as shown
148.30, 154.24, 159.15, 161.93 (d, J ¼ 244.5 Hz), 167.18, in Figure 2. Initially, N-(3 or 4-nitrobenzylidene)-4-substituted
167.27. HRMS (m/z): [M + H]+ calcd for C23H18FN3O4S2: anilines (1a–d) were synthesized via condensation of appropriate
484.0796; found 484.0786.
benzaldehyde and aniline in ethanol with catalytic amount of

DOI: 10.3109/14756366.2016.1161621
Synthesis of novel 2-substituted benzothiazole derivatives
5
EtOH
R
N
R
R
1
CHO
H N
1
3
R
2
3
CH3COOH
R
R
2
2
1a-d
NaBH
4
N
R
R
R
1
N
R
3
1
3
H
MeOH
R
R
2
2
1a-d
2a-d
ClCH COCl
2
R
3
N
R
1
N
H
R
1
R
3
TEA/THF
R
O
2
R
2
Cl
3a-d
2a-d
R
R
4
N
K CO
3
2
3
N
R
1
HS
N
R
1
R
3
R
4
Acetone
N
S
S
O
S
R
R
2
O
2
Cl
4a-l
3a-d
Figure 2. The synthetic pathway of the compounds (4a–l).
glacial acetic acid. Secondly, compounds 1a–d in methanol was Monoamine oxidase inhibitory activity
reduced to N-(3 or 4-nitrobenzyl)-4-substituted anilines (2a–d) by
The synthesized 2–(5-substituted-benzothiazol-2-ylsulfanyl)-N-
(substitutedbenzyl)-N-(4-substitutedphenyl)acetamide derivatives
(4a–l) were investigated for their MAO-A and MAO-B inhibitory
activity by an in vitro flurometric method. The fundamental of the
activity determination is based on the ability of both MAO-A and
MAO-B enzymes to metabolize non-fluorescent kynuramine,
which is a suitable substrate for both isozymes, to the fluorescent
product 4-hydroxyquinoline. Both enzymes were pre-incubated
with test compounds and the MAO-inhibitory effect of the test
compounds was correlated with the amount of 4-hydroxyquino-
line formed. The read of the activity was performed by using
proper excitation/emission wavelength pair27. DMSO was con-
sidered as control (100% activity). Moclobemide and selegiline
were used as reference drugs. The inhibitory activity results are
listed in Tables 1 and 2.
In general, it was observed that the synthesized compounds
are more potent against MAO-B enzyme when compared with
MAO-A enzyme. The compounds 4 h, 4k and 4 l displayed
considerable inhibitory activity against MAO-A enzyme, whereas
compounds 4c, 4d and 4 h indicated remarkable inhibition profile
against MAO-B enzyme. Due to their inhibition potency (450%)
at 10ꢂ3 and 10 ꢂ4 M, related compounds were tested at further
concentrations (10ꢂ5–10ꢂ9 M) and their IC50 values were
calculated (Tables 1 and 2). Compound 4 h was the most active
derivative with a 17.00 mM and 2.95 mM IC50 values against
MAO-A and MAO-B enzymes, respectively.
using NaBH4. In the third step, 2-chloro-N-(3- or 4-nitrobenzyl)-
N-(4 substitutedphenyl)acetamides (3a–d) were synthesized by
acetylation of the compounds 2a–d in tetrahydrofuran (THF) with
chloroacetyl chloride. Finally, bimolecular nucleophilic substitu-
tion (SN2) reaction between appropriate 5-substituted benzothia-
zole-2-thiol derivatives and the compounds 3a–d give the 12 new
N-(3- or 4-nitrobenzyl)-N-(4-substitutedphenyl)-2-((5-substituted-
benzo[d]thiazol-2-yl)thio)acetamides (4a–l).
Structures of the obtained compounds were elucidated by
spectral data. In the IR spectra, significant stretching bands
belonging to C¼O were observed between 1670–1660 cmꢂ1. The
stretching bands for C¼N and C¼C were recorded in the region
of 1593–1419 cmꢂ1. Stretching bands at 783–786 cmꢂ1 and 839–
857 cmꢂ1 were observed for 1,3-disubstituted and 1,4-disubsti-
tuted benzenes, respectively. In the 1H-NMR spectra, a singlet
peak between 4.18–4.23 ppm was assigned for the protons of
acetamide (–NHCOCH2) moiety. A singlet peak at 5.03–5.06 ppm
was recorded for methylene (–CH2) protons of benzylamine
(–NCH2Ph). The methoxy (–OCH3) protons in compounds 4 g–l
were assigned as a singlet at about 3.84 ppm. The protons
belonging to nonsubstituted benzothiazole were observed at 7.38–
8.05 ppm as two doublets and one triplet. Substituted benzothia-
zole peaks were determined as two doublet and one doublet of
doublet at 7.01–8.05 ppm. Nitrobenzene protons near to nitro
group observed at 8.11–8.13 ppm as a doublet or multiplet
depending on 1,4 or 1,3-disubstitutednitrobenzene, respectively.
Other aromatic protons recorded as multiplet around 7.50 ppm. In
the 13C-NMR spectra, peaks between 37.08–37.31 ppm and
52.43–52.88 ppm was observed for the methylene (-CH2) carbons
of acetamide (-NHCOCH2) and benzylamine (-NCH2Ph) moi-
eties. The peaks belonging to methoxy (-OCH3) carbons in
compounds 4 g–l were observed at about 56.00 ppm. Aromatic
carbons were generally observed at 104.97–162.02 ppm. The
The MAO-B enzyme kinetic of the most active compound 4 h
was studied. The nature of MAO-B inhibition, caused by this
compound, was investigated by the graphical analysis of steady-
state inhibition data (Figure 3). According to reciprocal plots
(Lineweaver–Burk plots) compound 4 h was found as a mixed
type inhibitor, due to different intercepts on both the y- and
x-axes. The values of Km and Vmax were calculated by non-linear
carbonyl of acetamide and second carbon of benzothiazole were regression according to literature28 and found as 185.19 and
observed between 166.21–167.18 ppm and 169.21–167.17 ppm, 578.57, respectively.
respectively. According to HPLC analysis, purity ratio was found
between 96.5–99.9%. Peak purity index of all compounds were
also checked and no impurity was determined in observed peaks.
In the design of the target compounds (4a–l), the substitution
pattern was performed on three regions to discuss substitution
effect on biological activity. These were 3- or 4-nitrobezyl,

6
B. Kaya et al.
Table 1. Inhibitory activity (%) of the compounds against MAO-A enzyme.
MAO-A Inhibition %
J Enzyme Inhib Med Chem, Early Online: 1–8
Comp.
10ꢂ3
M
10ꢂ4
M
10ꢂ5
M
10ꢂ6
M
10ꢂ7
M
10ꢂ8
M
10ꢂ9
M
IC50 (mM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
37.04 1.95
49.09 2.82
44.18 1.19
52.23 2.98
42.32 0.88
43.59 2.52
64.18 3.21
71.39 2.98
58.16 2.45
55.42 2.13
60.14 2.66
58.37 ’2.01
94.12 2.76
34.09 1.27
44.77 1.78
39.54 1.24
42.77 2.04
37.76 1.21
41.57 1.75
45.48 1.53
54.83 1.96
40.69 1.98
40.96 1.86
50.82 2.04
51.32 1.96
82.14 2.69
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
41000
41000
41000
4100
41000
41000
4100
17.00 0.89
4100
43.15 2.25
n.d
n.d
31.47 1.51
36.12 1.43
60.45 2.55
35.63 1.22
n.d
n.d
27.62 0.95
30.47 1.21
36.15 1.98
28.65 0.96
n.d
n.d
23.17 0.86
27.67 1.05
22.13 1.33
25.49 1.57
n.d
n.d
17.48 0.72
21.98 0.89
18.16 0.81
18.77 0.59
n.d
n.d
16.04 0.77
20.54 0.91
14.12 0.72
4100
26.03 1.22
18.54 1.04
6.06 0.26
4l
Moclobemide
Table 2. Inhibitory activity (%) of the compounds against MAO-B enzyme.
MAO-B Inhibition %
10ꢂ6 10ꢂ7
n.d n.d
Comp.
10ꢂ3
M
10ꢂ4
M
10ꢂ5
M
M
M
10ꢂ8
M
109 M
IC50 (mM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Selegiline
72.66 2.13
59.16 2.11
80.24 2.77
77.24 2.01
61.21 1.78
70.32 1.56
61.05 1.59
91.14 1.92
58.30 1.25
53.80 1.45
71.41 2.01
68.15 1.48
98.94 2.06
41.91 2.06
48.16 1.87
57.80 2.11
59.71 1.88
45.92 1.71
38.38 1.36
45.07 1.25
76.27 1.65
48.91 1.12
45.80 1.43
41.65 1.76
44.61 1.28
94.73 1.97
n.d
n.d
n.d
n.d
n.d
n.d
4100
4100
24.11 1.42
13.54 0.70
4100
4100
4100
2.95 0.09
4100
4100
4100
4100
0.038 0.002
n.d n.d
40.34 1.99
42.42 1.34
28.66 0.86
34.54 1.32
21.14 0.77
23.22 1.04
18.77 0.45
16.69 0.60
11.00 0.42
13.08 0.56
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
62.14 1.43
n.d
n.d
46.47 1.05
n.d
n.d
31.47 0.98
n.d
n.d
27.27 0.75
n.d
n.d
15.69 0.62
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
86.96 1.82
n.d
79.22 1.71
n.d
65.36 1.12
n.d
43.27 1.02
n.d
14.70 0.25
Figure 3. Lineweaver–Burk plots for com-
pound 4 h (IC50 ¼2.95 mM). Substrate
(kynuramine) concentrations used: 40, 20, 10,
5, 2.5 and 1.25 mM. 1/V: 1/velocity of reac-
tion [1/(nmoles/min/mg protein)], 1/S: 1/
substrate concentration (1/mM).
4-chloro or 4-florophenyl and 5-methoxy or 5-chlorobenzothioa- hand, an important finding was observed with 3- or 4-nitrobezyl
zole-2-thiol substructures. It was observed that there is no fragment. It was determined that 3-nitro substition at this part
significant relationship between enzyme inhibitory activity and increases the inhibitory activity significantly against both enzyme
substituent type on benzothiazole and phenyl rings. On the other types when compared 4-nitro substitution.

DOI: 10.3109/14756366.2016.1161621
Synthesis of novel 2-substituted benzothiazole derivatives
7
Table 3. Substituent pattern and some physicochemical parameters of the compounds 4a–l used in prediction of ADME profiles.
Comp.
R1
R2
R3
R4
MW
log p
TPSA
HBA
HBD
Vol
Vio
4a
4b
4c
ꢂNO2
ꢂNO2
ꢂH
ꢂH
ꢂH
ꢂCl
ꢂF
ꢂH
ꢂH
469.98
453.52
469.98
453.52
504.42
487.96
504.42
487.96
500.00
483.55
500.00
483.55
6.18
5.66
6.15
5.66
6.83
6.32
6.81
6.29
6.21
5.69
6.18
5.67
79.03
79.03
79.03
79.03
79.03
79.03
79.03
79.03
88.26
88.26
88.26
88.26
6
6
6
6
6
6
6
6
7
7
7
7
0
0
0
0
0
0
0
0
0
0
0
0
377.78
369.17
377.78
369.17
391.31
382.78
391.31
382.71
403.32
394.72
403.32
394.72
1
1
1
1
2
1
2
1
2
1
2
1
ꢂNO2
ꢂNO2
ꢂH
ꢂCl
ꢂF
ꢂH
4d
4e*
4f
ꢂH
ꢂH
ꢂNO2
ꢂNO2
ꢂH
ꢂCl
ꢂF
ꢂCl
ꢂH
ꢂCl
4g*
4h
4i*
4j
ꢂNO2
ꢂNO2
ꢂH
ꢂCl
ꢂF
ꢂCl
ꢂH
ꢂCl
ꢂNO2
ꢂNO2
ꢂH
ꢂCl
ꢂF
ꢂOCH3
ꢂOCH3
ꢂOCH3
ꢂOCH3
ꢂH
4k*
4l
ꢂNO2
ꢂCl
ꢂH
ꢂNO2
ꢂF
The data were determined with Molinspiration calculation software27. Log p: octanol/water partition coefficient, TPSA: topological polar surface area,
H-BA: number of hydrogen acceptor, H-BD: number of hydrogen donor, Vol: molecular volume, Vio: number of violations,
*Not possess a pharmacokinetic profile that sticks the Lipinski’s rule.
9. De Colibus L, Li M, Binda C, et al. Three-dimensional structure of
human monoamine oxidase A (MAO A): relation to the structures of
Theoretical determination of ADME properties
The theoretical prediction of ADME properties (molecular
weight, log p, topological polar surface area (TPSA), number of
hydrogen donors and acceptors, volume) of all target compounds
(4a–l) was carried out and presented in Table 3 along with
violations of Lipinski’s rule30,31. This rule suggests that, an orally
active drug has no more than one violation. Thus, according to the
data in Table 3, compounds 4e, 4 g, 4i and 4k does not stick the
Lipinski’s rule due to two violations. On the other hand, all
calculated physicochemical parameters for the compound 4 h are
compatible with the Lipinski’s rule except log p value. Although
the log p (6.29) of compound 4 h exceeds Lipinski’s limit it shows
that the related compound has a lipophilic character which is
suitable to cross central nervous system (CNS). Furthermore,
TPSA, described to be a predictive indicator of membrane
penetration, is positive (79.03) and as MAO inhibitors have to
pass different membranes and reach the CNS, this supports the
potential of compound 4 h.
rat MAO A and human MAO B. Proc Natl Acad Sci USA 2005;102:
12684–9.
10. O’Carroll AM, Fowler CJ, Philips JP, et al. The deamination of
dopamine by human brain monoamine oxidase. Specificity for the
two enzyme forms in seven brain regions. Naunyn-Schmiedebergs
Arch Pharmacol 1983;322:198–202.
11. Legoabe LJ, Petzer A, Petzer JP. 2-Acetylphenol analogs as potent
reversible monoamine oxidase inhibitors. Drug Des Devel Ther
2015;9:3635–44.
12. Chirkova ZV, Kabanova MV, Filimonov SI, et al. Inhibition of
monoamine oxidase by indole-5,6-dicarbonitrile derivatives. Bioorg
Med Chem Lett 2015;25:1206–11.
13. Checkoway H, Franklin GM, Costa-Mallen P, et al. A genetic
polymorphism of MAO-B modifies the association of cigarette
smoking and Parkinson’s disease. Neurology 1998;50:1458–61.
14. Minders C, Petzer JP, Petzer A, Lourens AC. Monoamine oxidase
inhibitory activities of heterocyclic chalcones. Bioorg Med Chem
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Neural Transm 2001;108:707–16.
16. Nayak BV, Ciftci-Yabanoglu S, Bhakat S, et al. Monoamine oxidase
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2015;58:72–80.
Declaration of interest
17. Van Dyk AS, Petzer JP, Petzer A, Legoabe LJ. 3-Coumaranone
derivatives as inhibitors of monoamine oxidase. Drug Des Devel
Ther 2015;9:5479–89.
The authors declare no conflicts of interest.
18. Da Prada M, Zu¨rcher G, Wu¨thrich I, Haefely WE. On tyramine,
food, beverages and the reversible MAO inhibitor moclobemide. J
Neural Transm Suppl 1988;26:31–56.
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(MAO) inhibition by chestnut honey, pollen and propolis. J Enzyme
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