Synthesis and tuberculostatic activity of new benzimidazole derivatives

Article abstract of DOI:10.1007/s10593-006-0135-x

The reactions of o-phenylenediamine and 3,4-diaminotoluene with such acids as 3-cyclohexylpropionic, 4-phenylbutyric, 4-cyclohexylbutyric, 3,3-diphenylpropionic, and 3,4-dimethoxyphenylacetic resulted in the formation of the corresponding 2-substituted be

Full text of DOI:10.1007/s10593-006-0135-x

Chemistry of Heterocyclic Compounds, Vol. 42, No. 5, 2006
SYNTHESIS AND TUBERCULOSTATIC ACTIVITY
OF NEW BENZIMIDAZOLE DERIVATIVES
H. Foks1, D. Pancechowska-Ksepko1, W. Kuzmierkiewicz1, Z. Zwolska2,
E. Augustynowicz-Kopec2, and M. Janowiec2
The reactions of o-phenylenediamine and 3,4-diaminotoluene with such acids as 3-cyclohexylpropionic,
4-phenylbutyric, 4-cyclohexylbutyric, 3,3-diphenylpropionic, and 3,4-dimethoxyphenylacetic resulted in
the formation of the corresponding 2-substituted benzimidazoles. These compounds were transformed
into methane- and benzenesulfonamide derivatives. The benzimidazole derivatives obtained were tested
in vitro for their tuberculostatic activity. Compounds with good activity (MIC 6.2-25 µg/ml) have been
found.
Keywords: benzimidazoles, methane- and benzenesulfonamides, tuberculostatics.
Among benzimidazole derivatives, the 2-substituted ones that have varied pharmacological activity (e.g.
antitumor, antiverminous, antiviral, hypotensive, spasmolytic, immunosuppressive, neuroleptic, analgesic,
antihistaminic) are particularly abundant [1]. Recently the antibacterial (including tuberculostatic) activity of
benzimidazole derivatives was reported too [2-6].
In the present study the syntheses of benzimidazole derivatives with cyclohexylalkyl and aralkyl
substituents in position 2 were accomplished. o-Phenylenediamine and 3,4-diaminotoluene as well as
3-cyclohexylpropionic, 4-phenylbutyric, 4-cyclohexylbutyric, 3,3-diphenylpropionic, and 3,4-dimethoxyphenyl-
acetic acids were the substrates used.
The Phillips method, i.e., the heating of substrates in NH4Cl, was tested first, but much better yields of
benzimidazoles 1-6 were obtained by fusion of the starting materials at 160-180°C, the process of which was
elaborated earlier by our team [7, 8]. In the next step compounds 1-6 reacted with methane- and benzenesulfonyl
chloride in anhydrous dioxane in the presence of triethylamine, giving the corresponding sulfonamide
derivatives 7-15 (Tables 1 and 2).
R
NH2
NH2
R
N
R2SO2Cl
R1(CH2)nCOOH
R
N
(CH2)nR1
(CH2)nR1
N
N
H
SO2R2
1–6
7–15
1-5, 7-13 R = H, 6, 14, 15 R = Me, 1, 3, 6, 7, 10, 11, 14, 15 R1 = cyclo-C6H11,
2, 8, 9 R1 = Ph, 4, 12 R1 = CHPh2, 5, 13 R1 = 3,4-(MeO)2C6H3, 7, 8, 10, 14 R2 = Me,
9, 11-13, 15 R2 = Ph; 1, 7 n = 2, 2, 3, 6, 8-11, 14, 15 n = 3, 4, 5, 12, 13 n = 1
_________________________________________________________________________________________
1
Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; e-mail:
2
hfoks@amg.gda.pl. Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases, 01-138
Warszawa, Poland. Published from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 697-700, May, 2006.
Original article submitted October 18, 2004; revision submitted February 15, 2006.
0009-3122/06/4205-0611©2006 Springer Science+Business Media, Inc.
611

TABLE 1. Characteristics of the Synthesized Compounds 1-15
Found, %
Calculated, %
H
Com-
pound
Empirical
formula
mp, °C,
solvent
Yield, %
C
N
1
C15H20N2
78.81
78.90
8.79
8.83
12.11
12.27
193-194
MeOH
22
45
56
41
69
47
61
40
54
73
46
38
50
66
67
2
C16H16N2
81.09
81.32
6.65
6.82
11.97
11.85
148-149
Benzene
3
C16H22N2
79.15
79.29
9.32
9.15
11.45
11.56
151-153
Dioxane
4
C21H18N2
84.42
84.53
6.15
6.08
9.15
9.39
198-200
Benzene
5
C16H16N2O2
C17H24N2
71.37
71.62
5.92
6.01
10.27
10.44
158-160
Benzene
6
79.38
79.64
9.28
9.44
10.82
10.93
143-145
Cyclohexane
106-107
MeOH
7
C16H22N2O2S
C17H18N2O2S
C22H20N2O2S
C17H24N2O2S
C22H26N2O2S
C27H22N2O2S
C22H20N2O4S
C18H26N2O2S
C23H28N2O2S
62.64
62.72
7.35
7.24
9.02
9.14
8
64.75
64.94
5.57
5.77
8.65
8.91
115-118
Cyclohexane
9
70.22
70.19
5.17
5.35
7.28
7.44
120-124
MeOH
10
11
12
13
14
15
63.57
63.72
7.41
7.55
8.48
8.74
103-107
Dioxane
69.92
69.08
6.89
6.85
7.11
7.32
125-130
MeOH
73.81
73.95
4.82
5.06
6.14
6.39
143-147
EtOH
64.72
64.69
5.28
4.94
6.62
6.86
115-117
EtOH
64.39
64.64
7.97
7.83
8.17
8.38
136-140
MeOH
69.48
69.66
7.32
7.12
6.89
7.06
152-153
MeOH
The compounds obtained were tested against the standard Mycobacterium tuberculosis H37Rv strain as
well as two strains isolated from tuberculosis patients: one resistant to isonicotinic acid (INH), ethambutol
(ETB), and rifampicin (RFP), the other fully susceptible to the tuberculostatics administered. Tuberculostatic
activity was determined in vitro by the classical test tube method with Youman's liquid medium containing 10%
of bovine serum.
Based on the minimum inhibiting concentration (MIC) values obtained, one may conclude that some of
the compounds tested exhibited a high tuberculostatic activity. The most active were compounds 1, 2, 4, 6, 7, 10,
14, as their MIC values were within the limits of 6.2-25 µg/ml (Table 3). The majority of the active compounds
possessed cyclohexylethyl or cyclohexylpropyl substituents in position C(2) of the benzimidazole system. The
presence of the sulfomethyl group at the nitrogen atom did not change the activity.
EXPERIMENTAL
1
Melting points were determined with the Reichert apparatus and are uncorrected. The H NMR spectra
were recorded with a Varian Gemini 200 (200 MHz) spectrometer in CDCl3 and given in the δ scale from TMS
(recalculated using CHCl3 signal).
612

TABLE 2. 1H NMR Spectra of Compounds 1-15
Com-
pound
δ, ppm (J, Hz)
1
2
0.88-1.82 (13H, m, CH2, C6H11); 2.96 (2H, t, J = 8, CH2); 7.22-7.52 (4H, m, C6 H5)
2.10-2.26 (2H, m, CH2); 2.70 (2H, t, J = 8, CH2); 2.91 (2H, t, J = 8, CH2);
7.11-7.57 (4H, m, C6H5)
3
4
5
0.80-1.93 (15H, m, (CH2)2C6H11); 2.94 (2H, t, J = 8, CH2); 7.21-7.57 (4H, m, C6 H5)
3.66 (2H, d, J = 8, CH2); 4.63 (1H, t, J = 8, CH); 7.15-7.47 (14H, m, C6H5)
3.78 (3H, s, CH3); 3.85 (3H, s, CH3); 4.21 (2H, s, CH2); 4.82 (3H, m, C6H5);
7.21 (2H, m, C6H5); 7.53 (2H, m, C6H5)
6
0.75-2.00 (15H, m, (CH2)2C6H11); 2.43 (3H, s, CH3); 2.85 (2H, t, J = 7, CH2);
6.82-7.56 (3H, m, C6H5)
7
0.96-1.87 (13H, m, CH2C6H11); 3.11-3.22 (5H, m, CH2 and CH3); 7.26-7.40 (2H, m, C6H5);
7.70-7.87 (2H, m, C6H5)
8
2.28 (2H, m, CH2); 2.83 (2H, t, J = 7, CH2); 3.18 (5H, m, CH2 and CH3);
7.19-7.88 (9H, m, C6H5)
9
2.24 (2H, m, CH2); 2.80 (2H, t, J = 7, CH2); 3.15 (2H, t, J = 7, CH2);
7.11-8.08 (14H, m, C6H5)
10
11
2.86-2.01 (15H, m, (CH2)2C6H11); 3.11 (2H, t, J = 8, CH2); 3.22 (3H, s, CH3);
7.26-7.88 (4H, m, C6H5)
0.81-1.98 (11H, m, C6H11); 2.25 (2H, m, CH2); 2.80 (2H, t, J = 7, CH2);
3.12 (2H, t, J = 7, CH2); 7.20-8.20 (9H, m, C6H5)
12
13
14
3.94 (2H, d, J = 7, CH2); 5.08 (1H, t, J = 7, CH); 7.12-7.99 (19H, m, C6H5)
3.73 (6H, s, CH3); 3.81 (2H, s, CH2); 6.51 (3H, m, C6H5); 7.26-7.93 (9H, m, C6H5)
0.85-2.00 (15H, m, (CH2)2C6H11); 2.46 (3H, s, CH3); 3.02-3.25 (5H, m, CH2 and CH3);
7.06-7.75 (3H, m, C6H5)
15
0.72-2.11 (15H, m, (CH2)2C6H11); 2.50 (3H, s, CH3); 3.15 (2H, t, J = 7, CH2);
7.06-7.95 (8H, m, C6H5)
TABLE 3. Tuberculostatic Activity of Compounds 1-15
MIC µg/ml
Drug-resistant strain
Compound
H37Rv
Drug-susceptible strain
1
2
3.1
6.2
12.5
6.2
25
6.2
25
6.2
12.5
25
3
6.2
25
4
12.5
25
5
50
6
6.2
25
6.2
6.2
50
6.2
7
25
8
25
25
9
12.5
6.2
12.5
100
25
50
12.5
12.5
12.5
100
25
10
11
12
13
14
15
25
25
100
50
12.5
25
6.2
25
6.2
25
Cyclohexylalkyl- and Arylalkylbenzimidazoles 1-6. o-Phenylenediamine (10 mmol) or
3,4-diaminotoluene (10 mmol) and the corresponding acid − 3-cyclohexylpropionic, 4-phenylbutyric,
4-cyclohexylbutyric, 3,3-diphenylpropionic, or 3,4-dimethoxyphenylacetic (10 mmol) were heated on Wood's
metal bath at 160-180°C for 1 h. On cooling down, 10% NaOH solution (10 ml) was added, and the whole
613

stirred and allowed to stand for 24 h. Then the precipitated compounds 1-6 were filtered off, washed with water
to the neutral reaction, dried, and purified by crystallization.
1-Methane- and 1-Benzenesulfonyl-2-substituted Benzimidazoles 7-15. Compounds 1-6 (5 mmol)
were dissolved in anhydrous dioxane (10 ml), treated with triethylamine (2 ml) and then dropwise with methane-
and benzenesulfonyl chloride (10 mmol), and the whole stirred while heating at 50°C for 5 h and then at
ambient temperature for another 12 h. The solvent was evaporated and some water with ice added. After a few
hours the precipitated compounds 7-15 were filtered off, washed with water, and crystallized.
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