This work has been digitalized and published in 2013 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons Attribution4.0 International License.

Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschungin Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung derWissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht:Creative Commons Namensnennung 4.0 Lizenz.

Synthesis of 3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylic Acid Derivatives as Expected Antischistosomal Agents Nabil M. Omar*, Hassan H. Farag, and Farghaly A. Omar Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Assiut, Assiut, Egypt Z. Naturforsch. 34b, 1427-1430 (1979); received March 8/May 28, 1979 Antischistosomal agents, Peptide Synthesis

Several ester and amide derivatives of 3-(l-methyl-5-nitro-2-benzimidazolyl)acrylic acid have been prepared for testing as potential antischistosomal agents. The starting acid was conveniently synthesized from the corresponding aldehyde derivative through the Knövenagel-Döbner reaction. The utility of EEDQ as a coupler for the synthesis of peptides has been successfully extended to the coupling of N-heterocyclic acrylic acid derivatives and various amines.

Introduction

Schistosomiasis still remains a great challenge to medicinal chemists as no antischistosomal drug has yet emerged, that could gain general acceptance and wide-spread use [1]. Impairment of both parasite and host normal metabolic processes and frequent hepatotoxic long-term effects have raised doubts about the real effectiveness and safety of even such accepted drugs as Niridazole (Ambilhar®) and Lucanthone (Meracil-D®) [2, 3].

Among the vast collection of novel drugs, that have shown potentially useful antischistosomal activity, Furapromidium (I) has been ascribed with unusual promise [4], The early introduction of this simple amide into oral chemotherapy of bilhariasis in China has motivated the synthesis and anti-schistosomal testing of several acrylamides of other nitro heterocycles [5, 6]. For the monocyclic hetero-systems investigated, antischistosomal activity was shown to be markedly affiliated to the ease of the reduction of the 5-nitroheterocycle residue during its interaction with the biologic receptors of the schistosome. In this concern, the significance of the 2-acrylamide moiety for the antischistosomal activ-ity of Furapromidium (I) is supposed to involve definite electronic + M contributions, that lead to activation of the 5-nitrofuran function of I as a reducible centre [7]. Although several benzimidazole derivatives such as Thiabendazol, Mebendazol and Cambendazol are widely used as efficient anthel-mintics [8, 9], the antischistosomal potentiality of nitrobenzimidazolylacrylic acid derivatives remains so far unexplored. In fact, such derivatives are not yet reported.

* Reprint requests to Dr. N. M. Omar. 0340-5087/79/1000-1427/$ 01.00/0

It is the objective of the present communication to report the synthesis of various ester and amide derivatives of 3-(l-methyl-5-nitro-2-benzimidazo-lyl)acrylic acid, compounds (3-20), to be tested as potential antischistosomal agents.

CH,

N

° 2 N - ^ Ö V C H = C H C O N H C 3 H 7 0 CH=CHCONRR'

3-20

Results and Discussion The route adopted for the synthesis of the

designed acrylamide derivatives involved the fol-lowing transformations, Scheme 1.

CH3

Scheme 1.

SE0 2

CH=CHC0NRR' amidation 0 2

' J § @ > -

1 CH3

CH,(C00H),

CH=CH-C00H

l,2-Dimethyl-5-nitrobenzimidazole [10] was oxi-dized with selenium dioxide in dioxane at 100 °C to l-methyl-5-nitrobenzimidazole-2-carboxaldehyde (1). The NMR, IR and MS data of this compound are in full agreement with its structure. Previously, this aldehyde was reported as the product of similar oxidation of l,2-dimethyl-5-nitrobenzimidazole in boiling toluene [11], however with a totally different melting point (188 °C) than that determined in the current investigation (223 °C). The lack of structural evidence for the toluene-method oxidation product makes its actual nature questionable.

1428 N. M. Omar et al. • Synthesis of 3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylie Acid Derivatives 1428

The synthesis of 3-(l-methyl-5-nitro-2-benzimida-zolyl)acrylic acid (2) was achieved through conden-sation of aldehyde (1) with malonic acid under the conditions of the Knövenagel-Döbner reaction [12]. That the obtained acrylic acid derivative exists as the E-isomer is established from its NMR spectrum, that showed the A B system of the - C H = CHCOOH function as a pair of doublets with a typical J -value (16 cps) of trans proton coupling [13]. Our trials to synthesize compound 2 by condensation of 1,2-dimethyl-5-nitrobenzimidazole with chloral hydrate and subsequent alkaline hydrolysis of the conden-sation product were almost futile; most of the starting benzimidazole derivative was recovered unreacted.

The ester and amide derivatives (3-20) of the newly synthesized acrylic acid derivative (2) were readily prepared by reacting the acid with the appropriate alcohol or amine derivative in the presence of sulfuric acid or N-ethoxycarbonyl-2-ethoxydihydroquinoline (EEDQ) respectively. The latter has been frequently employed as a convenient coupling reagent for peptide synthesis [14]. Apart from its superiority to dicyclohexylcarbodiimide, which failed to bring about the amidation of 2, EEDQ by-products (quinoline and CO2) offered no problems during the separation of the produced acrylamide derivatives, compounds 6-20.

The structure of the obtained acrylic acid ester and amide derivatives was confirmed by micro-analytical as well as by NMR and IR spectral data, that revealed the exclusive existence of these derivatives as the trans form. Preliminary para-sitological investigation of compounds 3-20 as potential antischistosomal agents is in progress.

Experimental Melting points were obtained by means of a Mel-

Temp block and are uncorrected. Elemental micro-analyses, IR, NMR, and MS measurements were performed at Institut für Pharmazeutische Chemie, Münster, West Germany and Faculty of Science, Cairo, Egypt, using Perkin-Elmer autoanalyzer, IR-237 Perkin-Elmer, Varian A-60 and Hitachi-PE MS appliances. Intermediate EEDQ was prepared as reported [15].

1 - Methyl-5- nitrobenzimidazole-2-carboxaldehyde (1) A solution of 0.11 mole of l,2-dimethyl-5-nitro-

benzimidazole in 500 ml of dioxane was treated, while effectively stirred, with 0.15 mole of finely powdered selenium dioxide over a period of 30 min.

The reaction mixture was heated on a steam bath for 5 h, filtered while hot and cooled to afford ca. 70% of crude 1 as yellowish fluffy needles, m.p. 220-222 °C. Another crop of the aldehyde was obtained by treatment of the mother liquor with 10% aqueous solution of NaHC03 , total yield, 80%, m.p. 222-223 °C (from dimethylformamide). C9H7N3O3 (205)

Calcd C 52.68 H 3.41 N 20.49, Found C 52.38 H 3.36 N 20.74.

Molecular ion peak (M+): 205. IR spectrum (KBr): 2885 (aldehydic proton), 1690 (carbonyl), 1510 and 1350 (nitro), 1610, 1585, 1500 and 725 cm-* (benz-imidazole ring [16]). NMR spectrum (d) in dimethyl-formamide-d7: 4.26 (singlet, N-CH3 ) , 8.03 (doublet, J76 = 10 cps) 8.30 and 8.46 (two doublets, J6? = 10 and Je4 = 3 cps) and 8.64 (doublet, J4e = 3 cps) in addition to a sharp singlet at 10.16 (H in CHO).

3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylic acid (2) To a solution of 0.06 mole of malonic acid in

25 ml of pyridine, that contained few drops of piperidine, was added 0.05 mole of pure 1 and the reaction mixture heated on a steam bath till no evolution of CO2 was observed. Cooling of the solution resulted in the precipitation of crude 2 as orange-colored cubic crystals, (41%), m.p. 295 °C (from acetic acid). C11H9N3O4 (247)

Calcd C 53.44 H 3.64 N 17.52, Found C 53.07 H 3.72 N 17.00.

Molecular ion peak (M+): 247. IR spectrum (KBr): 3100-2500 (bonded hydroxyl), 1705 (carbonyl), 1520 and 1330 (nitro), 1600, 1580, 1500 and 730 (benz-imidazole ring) and 980 cm - 1 (trans H in CH=CH) . NMR spectrum (6) in dimethylsulfoxide-d6: 4.10 (singlet, N-CH3 ) , 7.20 and 7.85 (two doublets, each integrating for single proton, JCH=CH : 16 cps, trans), 7.90 (doublet, J 7 6 = 10 cps), 8.30 and 8.46 (two doublets, J67 = 10 and Je4 = 3 cps) and 8.64 (doublet, J46 = 3 cps).

Alkyl 3-(l-methyl-5-nitro-2-benzimidazolyl)• acrylates (3-5, Table I)

To a suspension of 0.01 mole of compound 2 in 25 ml of the appropriate alcohol was added 5.0 ml of H2SO4 (d, 1.84) and the reaction mixture refluxed for 5 h. The clear solution when cooled and carefully neutralized with 10% aqueous Na2C03 solution afforded the corresponding ester as a colorless crystalline product.

3-( l-Methyl-5-nitro-2-benzimidazolyl )acrylamides (6-20, Table I)

To a solution of 0.003 mole of pure 2 in 30 ml of dimethylformamide was added an equimolar amount of EEDQ in 25 ml of absolute ethanol. The solution

N. M. Omar et al. • Synthesis of 3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylie Acid Derivatives 1429

was left at ambient temperature for ca. 10 min, 0.003 mole of the appropriate amine added and the reaction mixture was refluxed for 2 h. The crude amides were readily obtained as yellow-orange

colored precipitates when dimethylformamide was removed in vacuum, and the concentrate left was diluted with water. Recrystallization was effected using the proper solvents, Table I.

Table I. 3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylic acid ester and amide derivatives.

CH3

Compound

-CH=CH-C0-R

R m.p. [ ° C ] * Molecular Microanalysis [ % ] * *

formula C H N

2 1 0 - 2 1 L A C I 2 H N N 3 0 4 5 5 . 1 7 4 . 2 1 1 6 . 0 9

5 5 . 5 1 4 . 5 0 1 5 . 6 5

1 7 9 - 1 8 0 B C I 3 H I 3 N 3 0 4 5 6 . 7 2 4 . 7 2 1 5 . 2 7

5 6 . 8 0 5 . 1 0 1 4 . 8 0

2 0 6 - 2 0 7 A C I 4 H 1 5 N 3 0 4 5 8 . 1 3 5 . 1 9 1 4 . 5 3

5 7 . 9 0 5 . 5 0 1 4 . 1 8

2 9 0 - 2 9 2 B C I 3 H I 4 N 4 0 4 5 3 . 7 9 4 . 8 5 1 9 . 3 1

5 4 . 0 4 5 . 0 7 1 8 . 9 8

2 2 7 - 2 2 8 A C 1 4 H 1 6 N 4 O 3 5 8 . 3 3 5 . 5 5 1 9 . 4 4

5 8 . 6 7 5 . 7 2 1 8 . 9 9

2 2 3 - 2 2 4 A C I 5 H 1 8 N 4 0 3 5 9 . 6 0 5 . 9 6 1 8 . 5 4

5 9 . 8 6 5 . 9 2 1 7 . 9 3

2 0 2 - 2 0 4 B C I 5 H 1 8 N 4 0 3 5 9 . 6 0 5 . 9 6 1 8 . 5 4

5 9 . 6 6 5 . 9 3 1 8 . 3 6

1 8 8 - 1 8 9 C C I 8 H 2 3 N S 0 3 6 0 . 5 0 6 . 4 4 1 9 . 6 0

6 0 . 2 0 6 . 4 8 1 9 . 5 1

2 6 0 - 2 6 1 D C I 7 H I 4 N 4 0 3 6 3 . 3 3 4 . 3 4 1 7 . 3 9

6 2 . 9 5 4 . 3 5 1 7 . 2 3

2 8 8 - 2 8 9 B C I 7 H I 3 C 1 N 4 0 3 5 7 . 7 3 3 . 6 5 1 5 . 6 5

5 7 . 0 3 4 . 0 8 1 5 . 0 5

2 4 4 - 2 4 6 E C 1 7 H 1 3 N 5 O 5 5 5 . 5 8 3 . 5 4 1 9 . 0 0

5 5 . 7 6 3 . 6 5 1 9 . 1 6

2 4 7 - 2 4 9 C C 2 0 H I 4 B r N 5 O 3 4 9 . 5 8 3 . 0 9 1 4 . 4 0

4 9 . 9 0 3 . 0 0 1 4 . 6 8

2 6 7 - 2 6 8 F C I 3 H I O N E 0 3 S 4 7 . 0 1 3 . 6 2 2 5 . 3 5

4 7 . 7 0 3 . 8 0 2 5 . 2 7

2 5 5 - 2 5 6 B C I 5 H I 6 N 4 0 3 6 0 . 0 0 5 . 3 3 1 8 . 6 6

5 9 . 7 0 5 . 8 0 1 9 . 0 2

2 1 2 — 2 1 3 A C I 6 H I 8 N 4 0 3 6 1 . 1 4 5 . 7 1 1 7 . 8 2

6 1 . 0 3 5 . 8 1 1 7 . 4 3

2 5 5 - 2 5 6 B C I 5 H I 6 N 4 0 4 5 6 . 8 6 5 . 0 6 1 7 . 7 2

5 6 . 7 0 5 . 0 7 1 7 . 5 0

2 4 0 - 2 4 2 8 C I 6 H 1 9 N 5 0 3 5 8 . 1 8 6 . 0 6 2 1 . 2 3

5 7 . 7 0 5 . 9 0 2 0 . 9 4

2 5 6 - 2 5 7 A C I ? H 2 O N 4 0 3 6 2 . 1 9 6 . 0 9 1 7 . 0 7

6 1 . 8 0 5 . 8 5 1 6 . 9 0

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

-OCH3

-OC2H5

-OCH(CH3)2

HN-(CH2)2OH

HN-CH(CH3)2 I

HN-(CH2)3CH3 I

-N(C2H5)2

HN-<CH2.2-Q

rsci H ^ g )

02NY

N—N H N J Q )

- O

- O

-N 0

-N N-CH3

- O

* Crystallization solvents: a aqueous ethanol, b absolute ethanol, c aqueous acetone, d isopropanol, e water, f dimethylformamide, B dimethylsulfoxide.

** Upper figures are the calculated values.

1430 N. M. Omar et al. • Synthesis of 3-(l-Methyl-5-nitro-2-benzimidazolyl)acrylie Acid Derivatives 1430

[1] L. M. Werbel, in J. L. Rabinowitz and R. M. Myerson (eds.): Topics in Medicinal Chemistry, Vol. III, p. 125, Wiley-Interscience, New York 1970.

[2] A. Abdallah, M. Saif, M. Abdel-Meguid, A. Badran, F. Abdel-Fattah, and I. M. Aly, J. Egypt. Med. Assoc. 49, 145 (1966).

[3] Z. Farid, J. H. Smith, S. Bassily, and H. A. Spark, Brit. Med. J. 2, 88 (1972).

[4] H. H. Liu, L. C. Chang, M. L. Hus, H. D. Chang, K. C. Cheng, and M. Yen, Sei. Sinica 13, 523 (1964).

[5] D. W. Henry, V. H. Brown, M. Cory, J. G. Johanson, and E. Bueding, J. Med. Chem. 16, 1287 (1973).

[6] N. M. Omar and H. H. Farag, Proc. XIII , Conf. Pharm. Sei., p. 95, Cairo 1974.

[7] P. B. Hulbert, E. Bueding, and C. H. Robinson, J. Med. Chem. 16, 72 (1973).

[8] H. D. Brown, A. R. Martzuk, I. R. lives, L. H. Peterson, S. A. Harris, L. H. Sarett, J. R. Egerton,

J. J. Yakistis, W. C. Campell, and A. C. Cuckler, J. Am. Chem. Soc. 83, 1764 (1961).

[9] D. R. Hoff, M. H. Fischer, R. J. Bochis, A. Lusi, F. Waksmunski, J. R. Egerton, J. J. Yakistis, A. C. Cuckler, and W. C. Campell, Experientia 26, 550 (1970).

[10] L. Josef and J. Julca, J. Org. Chem. 57, 1101 (1962).

[11] M. L. Bris and H. Wahl, Bull. Soc. Chim. 1959, 343.

[12] G. Jones, in R. Adams (ed.): Organic Reactions, Vol. 15, pp. 218-225, J. Wiley Inc., New York 1967.

[13] F. Nugent, The Practice of NMR Spectroscopy, Plenum Press, New York-London 1974.

[14] B. Belleau and G. Malek, J. Am. Chem. Soc. 90, 1615 (1968).

[15] L. Fieser and M. Fieser, Reagents for Organic Syntheses, Vol. 2, p. 191, J. Wiley Inc., New York 1969.

[16] K. Morgan, J. Chem. Soc. 1961, 2343.