Synthesis of Novel N-Substituted Imidazolecarboxylic Acid Hydrazides as Monoamine Oxidase Inhibitors

Article abstract of DOI:10.1016/j.farmac.2004.12.007

Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides (15a,b) were synthesized as analogues of isocarboxazide, which is a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the compounds showed any inhibition of MAO B activity up to a high concentration of 100 μM. An MAO A activity was only slowly inhibited at this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.

Full text of DOI:10.1016/j.farmac.2004.12.007

Il Farmaco 60 (2005) 237–240
http://france.elsevier.com/direct/FARMAC/
Synthesis of Novel N-Substituted Imidazolecarboxylic Acid Hydrazides
as Monoamine Oxidase Inhibitors
Farzin Hadizadeh a,b,c,*, Razieh Ghodsi a,b
a Pharmacy Faculty, Mashhad University of Medical Sciences, Mashhad, Iran
b Pharmaceutical Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
c Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Received 21 October 2004; revised and accepted 6 December 2004
Abstract
Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides (15a,b) were synthesized as analogues of isocarboxazide, which is
a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the
compounds showed any inhibition of MAO B activity up to a high concentration of 100 µM. An MAO A activity was only slowly inhibited at
this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Monoamine oxidase; Inhibitors; 5-imidazolecarboxylic acid hydrazides
1. Introduction
deaminated by MAO-B. Because of their role in the metabo-
lism of monoamine neurotransmitters, the MAO-A and
MAO-B are thought to be involved in psychiatric and neuro-
logical disorders such as depression and Parkinson’s disease,
respectively [9].
An MAO (EC 1.4.3.4) is an outer mitochondrial mem-
brane FAD containing enzyme [1] found in nearly all tissues.
On the basis of their substrate and inhibitor specificities, two
major isoforms have been described, the MAO-A and the
MAO-B [2,3] made up of different polypeptides [4]. The
structure of human MAO-B was recently resolved [5], and
the molecular determinants required for MAO selectivity were
investigated [6,7]. The MAOs are responsible for the major
neurotransmitter degrading in the central nervous system
(CNS) and peripheral tissues [8]. An MAO-A preferentially
catalyzes the oxidative deamination of serotonin (5-HT),
adrenaline (A) and noradrenaline (NA) and is selectively
inhibited by clorgyline (1) and moclobemide (2).An MAO-B
mainly catalyzes the oxidative deamination of b-phenyl-
ethylamine and benzylamine and is selectively inhibited by
selegiline (3). Both isoforms act either on dopamine (DA) in
vitro or on tyramine. In mankind, dopamine is preferentially
The early MAO inhibitors such as isocarboxazid (4) and
tranylcypromine (5) were nonselective and irreversible.
Because of their adverse actions, the therapeutic applications
of first generation MAO inhibitors have been diminished
[10–12]. Today efforts toward the development of monoam-
ine oxidase inhibitors are focused on selective MAO-A or
MAO-B inhibitors. Selective MAO-B inhibitors are being
examined in the treatment of, for example, schizophrenia,
Alzheimer’s disease, and Parkinson’s disease. The MAO-A
inhibitors are effective in the treatment of depression.
Our interest in heterocyclic bioisoestes of CNS agents
motivated us toward synthesis novel imidazole-containing
analogue of isocarbosazid (4) in which imidazole has been
replaced for isoxazole moiety in the drug. Our goal was to
obtain selective MAO inhibitor from nonselective one. We
report here the synthesis of novel N-substituted imidazolecar-
boxylic acid hydrazides (Scheme 1) and their MAO inhibi-
tory activities.
* Corresponding author. Tel.: +98 511 8823252; fax: +98 511 8823251.
E-mail address: fhadizadeh@yahoo.com (F. Hadizadeh).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.12.007

238
F. Hadizadeh, R. Ghodsi / Il Farmaco 60 (2005) 237–240
2.1.5. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic
acid methyl ester(12a)
To crude viscous liquid 11a was added dropwise at ice
bath, dry methanol (5 ml, 123.8 mmol) and then stirred over-
night at room temperature. The resulting mixture was bas-
ified by adding saturated solution of sodium bicarbonate and
extracted with chloroform (3 × 100 ml). Chloroform was
evaporated to give 2.91 g of 1-benzyl-2-methylsulfanyl-
imidazole-5-carboxylic acid methyl ester (12a), yield 92%;
oily; IR(KBr): m 1713 cm–1(C=O); H-NMR(CDCl3): 7.80
(s, 1H, H4-imidazole), 7.30–7.27(m, 5H, arom), 5.50 (s, 2H,
CH2N), 3.70(s, 3H, CH3O), 2.67(s, 3H, CH3).
1
Scheme 1
.
2. Experimental procedures
2.1.6. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic
acid methyl ester(12b)
2.1. Chemistry
It was prepared from 11b as described for 12a, yield 94%;
oily; IR (KBr): m 1713 cm–1(C=O); 1H-NMR(CDCl3): 7.80
(s, 1H, H4-imidazole), 7.30–7.27(m, 5H, arom), 5.50 (s, 2H,
CH2N), 3.70(s, 3H, CH3O), 3.14(q, 2H, CH2S), 1.28(t, 3H,
CH3).
Melting points were determined on Capillary Electrother-
mal Apparatus and are uncorrected. The IR spectra were
obtained on Perkin-Elmer Model paragon 1000. H-NMR
spectra were obtained on Bruker Ac-80 spectrophotometer
and chemical shifts (d) are in ppm relative to internal tetram-
ethylsilane. Compounds 7, 8 and 9 were synthesized as it has
been reported previously [13], but compound 10 was pre-
pared through a modified procedure.
1
2.1.7. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic
acid hydrazide(13a)
To a solution of compound 12a (3 g, 11.45 mmol) in etha-
nol (5 ml), hydrazine hydrate (80%, 1.25 ml, 45.02 mmol)
was added. After 30 min the precipitate was isolated by fil-
tration and crystallized from ethanol to give 13a , yield
80%; m.p. 92–95 °C; IR(KBr): m 3315, 3240 (NH),
2.1.1. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic
acid(10a)
1
1651 cm–1(C=O); H-NMR (DMSO-d6): 7.65(s, 1H, H-C4
Compound 9a (2.9 g, 11.78 mmol), sodium hydroxide
(1.45 g, 36.25 mmol) and distilled water (100 ml) were heated
at 150 °C for 15 min. Then a solution of silver nitrate (2.9 g,
17.05) in water (10 ml) was added. The resulting mixture was
refluxed at 100 °C overnight. Then hydrochloric acid (2 N)
was added to adjust pH between 3 and 4. The precipitate was
filtered to give 0.96 g of 1-benzyl-2-methylsulfanylimidazole-
5-carboxylic acid (10a), yield 90%; mp 225–227 °C; IR(KBr):
m 1700 cm–1(C=O); 1H-NMR(CDCl3): 7.87 (s, 1H, H4-
imidazole), 7.33–7(m, 5H, arom), 5.47(s, 2H, CH2N), 2.67(s,
3H, CH3).
imidazole), 7.32–7.01(m, 5H, arom), 5.54(s, 2H, CH2N), 2.52
(s, 3H, CH3).
2.1.8. 1-Benzyl-2-ethylsulfanylimidazole-5-carboxylic acid
hydrazide(13b)
It was prepared from 12b as described for 13a, yield
86.7%; m.p. 72–73 °C; IR (KBr): 3320, 3260 (NH),
1
1653 cm–1(C=O); H-NMR (DMSO-d6): 7.65(s, 1H, H-C4
imidazole), 7.32–7.01(m, 5H, arom), 5.54(s, 2H, CH2N),
3.14(q, 2H, CH2S), 1.28(s, 3H, CH3).
2.1.9. 1-Benzylidene-2-(1-benzyl-2-methylsulfanylimida-
zole-5-carbonyl)hydrazine(14a)
2.1.2. 1-Benzyl-2-ethylsulfanylimidazole-5-carboxylic
acid(10b)
Benzaldehyde (1.6 g, 15 mmol) was added to a solution of
10 ml of ethanol containing 13a (2.7 g, 10.3 mmol). The solu-
tion was stirred for 10 min at which time product began to
crystallize. On cooling at 4 °C for 12 h, the solid was filtered
off under vacuum and the solid filter cake was washed using
2 ml of cold ethanol in each washing and was recrystallized
from ethanol to give 14a, yield 77%; m.p. 181–184 °C;
IR(KBr): m 3432 (NH), 1648 cm–1(C=O); 1H-NMR (DMSO-
d6): 11.67(s, 1H, N=CH), 8.3(s, 1H, CONH), 7.9(s, 1H, H-C4
imidazole), 7.8–6.8 (m, 10H, arom), 5.58 (s, 2H, CH2N), 2.56
(s, 3H, CH3).
It was prepared as described for 10a, yield 68%; mp 158–
160 °C; IR(KBr): m 1694 cm–1(C=O); 1H-NMR(CDCl3): 7.87
(s, 1H, H4-imidazole), 7.32–7.01(m, 5H, arom), 5.47(s, 2H,
CH2N), 3.14 (q, 2H,CH2S), 1.28(t, 3H, CH3).
2.1.3. 1-Benzyl-2-methylsulfanylimidazole-5-carbonyl
chloride(11a)
Compound 10a (3 g, 12.09 mmol) and thionyl chloride
(1.5 ml, 20.29 mmol) were refluxed for 1 h. After evaporat-
ing thionyl chloride in vacuum, acid halide 11a was remained
as a viscous liquid, which was used directly in the next step.
2.1.10. 1-Benzylidene-2-(1-benzyl-2-ethylsulfanylimida-
zole-5-carbonyl)hydrazine(14b)
2.1.4. 1-Benzyl-2-ethylsulfanylimidazole-5-carbonyl
chloride(11b)
It was prepared from 13b as described for 14a, yield
It was prepared from 10b as described for 11a.
79.75%; m.p. 175–177 °C; IR(KBr): m 3432 (NH), 1648 cm–1

F. Hadizadeh, R. Ghodsi / Il Farmaco 60 (2005) 237–240
239
Scheme 2
.
1
(C=O); H-NMR (DMSO-d6): 11.2 (s, 1H, N=CH), 8.3(S,
chloride (6) was stirred with 1,3-dihydroxyacetone dimmer
and potassium thiocyanate to give 5-hydroxymethyl-2-
mercapto-1-benzylimidazole (7). Subsequent alkylation of
compound 7 with alkyl halides afforded 2-alkylsulfanyl-1-
benzyl-5-hydroxymethylimidazole (8). Oxidation of 8 with
manganese dioxide gave 9, which was further oxidized by
boiling in alkaline solution of silver nitrate to give
2-alkylsulfanyl-1-benzylimidazole-5-carboxylic acid (10).
Compound 10 was converted to its acid halide (11), which
was then reacted with methanol to give its methyl ester (12).
Addition of hydrazine hydrate to 12 gave the corresponding
hydrazide (13). Condensation of 13 with benzaldehyde
afforded 14 which was later reduced by lithium aluminum
hydride to give title 1-benzyl-2-alkylsulfanylimidazole-5-
carboxylic acid N’-benzyl-hydrazide (15). Scheme 2
1H, CONH), 7.9(s, 1H, H-C4 imidazole), 7.8–6.8 (m, 10H,
arom), 5.5 (s, 2H, CH2N), 3.1(q, 2H, CH2S), 1.2 (t, 3H, CH3).
2.1.11. 1-Benzyl-2-(1-benzyl-2-methylsulfanylimidazole-5-
carbonyl)hydrazine(15a)
Compound 14a was added portionwise to 5 ml of anhy-
drous tetrahydrofuran containing lithium aluminum hydride
(63 mg, 1.66 mmol). The reaction mixture was stirred over-
night. The excess lithium aluminum hydride was decom-
posed with 0.86 ml of ethyl acetate. Then 0.5 ml of water was
added to decompose the complex. The solid was separated
by filtration and the tetrahydrofuran was evaporated in vacuum
until a solid remained. The residue was recrystallized from
methanol to give the title 15a yield 627%; m.p. 135–138 °C;
IR(KBr): m 3432 (NH), 1648 cm–1(C=O); 1H-NMR (DMSO-
d6): 8.23(s, 1H, CONH), 7.67(s, 1H, H-C4 imidazole), 7.6–
6.9 (m, 10H, arom), 5.5 (s, 2H, CH2N), 3.6–2.9 (m, 3H, NH,
CH2N), 2.5 (s, 3H, CH3).
3.2. Biology
Title compounds (15a,b) were sent to the Department of
Biochemistry of Emory University and tested on recombi-
nant human MAO A and MAO B for their inhibitory activi-
ties [14]. Neither of the compounds showed any inhibition of
MAO B activity up to a high concentration of 100 µM. An
MAO A activity was only slowly inhibited at this high con-
centration after prolonged incubation with either compound.
This suggests any observed inhibition is not very specific.
2.1.12. 1-Benzyl-2-(1-benzyl-2-ethylsulfanylimidazole-5-
carbonyl)hydrazine(15b)
It was prepared from 14b as described for 15a, yield 59.7%;
m.p. 126–128 °C; IR(KBr): m 3432 (NH), 1648 cm–1(C=O);
1H-NMR (DMSO-d6): 8.29(s, 1H, CONH), 7.93 (s, 1H, H-C4
imidazole), 7.8–6.8 (m, 10H, arom), 5.6 (s, 2H, CH2N), 3.7–
2.9 (m, 5H, NH, CH2N, CH2S), 1.3 (t, 3H, CH3).
Acknowledgements
3. Results and Discussion
This work was supported by a grant from Research Coun-
cil of Mashhad University of Medical Sciences. We should
also thank Professor Dale E. Edmondson and his colleagues
(Emory University, US) for carrying out the biological assay
of title compounds.
3.1. Chemistry
Compounds 7–9 and 13 were synthesized as it has been
previously reported [13], but compounds 10 and 12 were syn-
thesized again through a new method. Benzylamine hydro-

240
F. Hadizadeh, R. Ghodsi / Il Farmaco 60 (2005) 237–240
[8] J.C. Shih, K. Chen, M.J. Ridd, Monoamine oxidase: from genes to
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