Doi:10.1016/j.farmac.2004.12.007 Synthesis of Novel N-Substituted Imidazolecarboxylic Acid Hydrazides 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 thecompounds showed any inhibition of MAO B activity up to a high concentration of 100 µM. An MAO A activity was only slowly inhibited atthis 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 An MAO (EC is an outer mitochondrial mem- MAO-B are thought to be involved in psychiatric and neuro- brane FAD containing enzyme found in nearly all tissues.
logical disorders such as depression and Parkinson’s disease, On the basis of their substrate and inhibitor specificities, two major isoforms have been described, the MAO-A and the The early MAO inhibitors such as isocarboxazid (4) and
MAO-B made up of different polypeptides The tranylcypromine (5) were nonselective and irreversible.
structure of human MAO-B was recently resolved and Because of their adverse actions, the therapeutic applications the molecular determinants required for MAO selectivity were of first generation MAO inhibitors have been diminished investigated The MAOs are responsible for the major Today efforts toward the development of monoam- neurotransmitter degrading in the central nervous system ine oxidase inhibitors are focused on selective MAO-A or (CNS) and peripheral tissues An MAO-A preferentially MAO-B inhibitors. Selective MAO-B inhibitors are being catalyzes the oxidative deamination of serotonin (5-HT), examined in the treatment of, for example, schizophrenia, adrenaline (A) and noradrenaline (NA) and is selectively Alzheimer’s disease, and Parkinson’s disease. The MAO-A inhibited by clorgyline (1) and moclobemide (2). An MAO-B
inhibitors are effective in the treatment of depression.
mainly catalyzes the oxidative deamination of b-phenyl- Our interest in heterocyclic bioisoestes of CNS agents ethylamine and benzylamine and is selectively inhibited by motivated us toward synthesis novel imidazole-containing selegiline (3). Both isoforms act either on dopamine (DA) in
analogue of isocarbosazid (4) in which imidazole has been
vitro or on tyramine. In mankind, dopamine is preferentially replaced for isoxazole moiety in the drug. Our goal was toobtain selective MAO inhibitor from nonselective one. Wereport here the synthesis of novel N-substituted imidazolecar-boxylic acid hydrazides (Scheme 1) and their MAO inhibi- * Corresponding author. Tel.: +98 511 8823252; fax: +98 511 8823251.
E-mail address: [email protected] (F. Hadizadeh).
0014-827X/$ - see front matter 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.12.007 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); 1H-NMR(CDCl ): 7.80
(s, 1H, H -imidazole), 7.30–7.27(m, 5H, arom), 5.50 (s, 2H, CH N), 3.70(s, 3H, CH O), 2.67(s, 3H, CH ).
2. Experimental procedures
2.1.6. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic acid methyl ester(12b)
It was prepared from 11b as described for 12a, yield 94%;
Melting points were determined on Capillary Electrother- oily; IR (KBr): m 1713 cm–1(C=O); 1H-NMR(CDCl ): 7.80 (s, 1H, H -imidazole), 7.30–7.27(m, 5H, arom), 5.50 (s, 2H, mal Apparatus and are uncorrected. The IR spectra were CH N), 3.70(s, 3H, CH O), 3.14(q, 2H, CH S), 1.28(t, 3H, obtained on Perkin-Elmer Model paragon 1000. 1H-NMR spectra were obtained on Bruker Ac-80 spectrophotometer and chemical shifts (d) are in ppm relative to internal tetram- 2.1.7. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic ethylsilane. Compounds 7, 8 and 9 were synthesized as it has
acid hydrazide(13a)
been reported previously but compound 10 was pre-
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- 2.1.1. 1-Benzyl-2-methylsulfanylimidazole-5-carboxylic tration and crystallized from ethanol to give 13a , yield
80%; m.p. 92–95 °C; IR(KBr): m 3315, 3240 (NH), Compound 9a (2.9 g, 11.78 mmol), sodium hydroxide
1651 cm–1(C=O); 1H-NMR (DMSO-d ): 7.65(s, 1H, H-C (1.45 g, 36.25 mmol) and distilled water (100 ml) were heated imidazole), 7.32–7.01(m, 5H, arom), 5.54(s, 2H, CH N), 2.52 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 wasrefluxed at 100 °C overnight. Then hydrochloric acid (2 N) 2.1.8. 1-Benzyl-2-ethylsulfanylimidazole-5-carboxylic acid was added to adjust pH between 3 and 4. The precipitate was hydrazide(13b)
filtered to give 0.96 g of 1-benzyl-2-methylsulfanylimidazole- It was prepared from 12b as described for 13a, yield
5-carboxylic acid (10a), yield 90%; mp 225–227 °C; IR(KBr):
86.7%; m.p. 72–73 °C; IR (KBr): 3320, 3260 (NH), m 1700 cm–1(C=O); 1H-NMR(CDCl ): 7.87 (s, 1H, H - 1653 cm–1(C=O); 1H-NMR (DMSO-d ): 7.65(s, 1H, H-C imidazole), 7.33–7(m, 5H, arom), 5.47(s, 2H, CH N), 2.67(s, imidazole), 7.32–7.01(m, 5H, arom), 5.54(s, 2H, CH N), 3.14(q, 2H, CH S), 1.28(s, 3H, CH ).
2.1.9. 1-Benzylidene-2-(1-benzyl-2-methylsulfanylimida- 2.1.2. 1-Benzyl-2-ethylsulfanylimidazole-5-carboxylic zole-5-carbonyl)hydrazine(14a)
Benzaldehyde (1.6 g, 15 mmol) was added to a solution of It was prepared as described for 10a, yield 68%; mp 158–
10 ml of ethanol containing 13a (2.7 g, 10.3 mmol). The solu-
160 °C; IR(KBr): m 1694 cm–1(C=O); 1H-NMR(CDCl ): 7.87 tion was stirred for 10 min at which time product began to (s, 1H, H -imidazole), 7.32–7.01(m, 5H, arom), 5.47(s, 2H, crystallize. On cooling at 4 °C for 12 h, the solid was filtered CH N), 3.14 (q, 2H,CH S), 1.28(t, 3H, CH ).
off under vacuum and the solid filter cake was washed using2 ml of cold ethanol in each washing and was recrystallized 2.1.3. 1-Benzyl-2-methylsulfanylimidazole-5-carbonyl 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- Compound 10a (3 g, 12.09 mmol) and thionyl chloride
d ): 11.67(s, 1H, N=CH), 8.3(s, 1H, CONH), 7.9(s, 1H, H-C (1.5 ml, 20.29 mmol) were refluxed for 1 h. After evaporat- imidazole), 7.8–6.8 (m, 10H, arom), 5.58 (s, 2H, CH N), 2.56 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- 2.1.4. 1-Benzyl-2-ethylsulfanylimidazole-5-carbonyl zole-5-carbonyl)hydrazine(14b)
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 (C=O); 1H-NMR (DMSO-d ): 11.2 (s, 1H, N=CH), 8.3(S, chloride (6) was stirred with 1,3-dihydroxyacetone dimmer
1H, CONH), 7.9(s, 1H, H-C imidazole), 7.8–6.8 (m, 10H, and potassium thiocyanate to give 5-hydroxymethyl-2- arom), 5.5 (s, 2H, CH N), 3.1(q, 2H, CH S), 1.2 (t, 3H, CH ).
mercapto-1-benzylimidazole (7). Subsequent alkylation of
compound 7 with alkyl halides afforded 2-alkylsulfanyl-1-
2.1.11. 1-Benzyl-2-(1-benzyl-2-methylsulfanylimidazole-5- benzyl-5-hydroxymethylimidazole (8). Oxidation of 8 with
manganese dioxide gave 9, which was further oxidized by
Compound 14a was added portionwise to 5 ml of anhy-
boiling in alkaline solution of silver nitrate to give drous tetrahydrofuran containing lithium aluminum hydride 2-alkylsulfanyl-1-benzylimidazole-5-carboxylic acid (10).
(63 mg, 1.66 mmol). The reaction mixture was stirred over- Compound 10 was converted to its acid halide (11), which
night. The excess lithium aluminum hydride was decom- was then reacted with methanol to give its methyl ester (12).
posed with 0.86 ml of ethyl acetate. Then 0.5 ml of water was Addition of hydrazine hydrate to 12 gave the corresponding
added to decompose the complex. The solid was separated hydrazide (13). Condensation of 13 with benzaldehyde
by filtration and the tetrahydrofuran was evaporated in vacuum afforded 14 which was later reduced by lithium aluminum
until a solid remained. The residue was recrystallized from hydride to give title 1-benzyl-2-alkylsulfanylimidazole-5- methanol to give the title 15a yield 627%; m.p. 135–138 °C;
carboxylic acid N’-benzyl-hydrazide (15). Scheme 2
IR(KBr): m 3432 (NH), 1648 cm–1(C=O); 1H-NMR (DMSO-d ): 8.23(s, 1H, CONH), 7.67(s, 1H, H-C imidazole), 7.6– 6.9 (m, 10H, arom), 5.5 (s, 2H, CH N), 3.6–2.9 (m, 3H, NH, Title compounds (15a,b) were sent to the Department of
Biochemistry of Emory University and tested on recombi- 2.1.12. 1-Benzyl-2-(1-benzyl-2-ethylsulfanylimidazole-5- nant human MAO A and MAO B for their inhibitory activi- carbonyl)hydrazine(15b)
ties Neither of the compounds showed any inhibition of It was prepared from 14b as described for 15a, yield 59.7%;
MAO B activity up to a high concentration of 100 µM. An m.p. 126–128 °C; IR(KBr): m 3432 (NH), 1648 cm–1(C=O);1 MAO A activity was only slowly inhibited at this high con- H-NMR (DMSO-d ): 8.29(s, 1H, CONH), 7.93 (s, 1H, H-C centration after prolonged incubation with either compound.
imidazole), 7.8–6.8 (m, 10H, arom), 5.6 (s, 2H, CH N), 3.7– This suggests any observed inhibition is not very specific.
2.9 (m, 5H, NH, CH N, CH S), 1.3 (t, 3H, CH ).
3. Results and Discussion
This work was supported by a grant from Research Coun- cil of Mashhad University of Medical Sciences. We should Compounds 7–9 and 13 were synthesized as it has been
also thank Professor Dale E. Edmondson and his colleagues previously reported but compounds 10 and 12 were syn-
(Emory University, US) for carrying out the biological assay thesized again through a new method. Benzylamine hydro- F. Hadizadeh, R. Ghodsi / Il Farmaco 60 (2005) 237–240 References
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