Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species

Article abstract of DOI:10.1016/S0968-0896(02)00103-7

New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37, 39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44-53, 55-67), -6-carbonitrile (54) were prepa

Full text of DOI:10.1016/S0968-0896(02)00103-7

Bioorganic & Medicinal Chemistry 10 (2002) 2589–2596
Synthesis of Some New 2-Substituted-phenyl-1H-benzimidazole-
5-carbonitriles and Their Potent Activity Against Candida Species
Hakan Goker,a,b,* Canan Kus,a David W. Boykin,b Sulhiye Yildizc and Nurten Altanlarc
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey
bDepartment of Chemistry, Georgia State University, Atlanta, GA 30303, USA
cDepartment of Microbiology, Faculty of Pharmacy, Ankara University, 06100, Tandogan, Ankara, Turkey
Received 11 February 2002; revised 4 March 2002; accepted 20 March 2002
Abstract—New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37,
39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44–53, 55–67), -6-carbonitrile (54) were
prepared and evaluated in vitro against Candida species. The cyano substituted compounds 53, 57, 58 and 61 exhibited the greatest
activity with MIC values of 3.12 mg/mL, values similar to that of fluconazole. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Chemistry
The synthesis of benzimidazoles has received much
attention owing to the varied biological activity exhib-
ited by a number of these compounds. As contributions
to this field, in the last decade we reported the prepa-
ration, antifungal and anti-histaminic activity1 of a large
series of benzimidazoles. Among them, 4-[5-chloro-
1- (4-chlorobenzyl) -1H-benzimidazol-2-yl]-N-(2-diethyl-
amino-ethyl)-benzamide I and 2,5-bis-[2-(5-amidino)-
benzimidazoyl]pyrrole II, exhibited potent antifungal
activity.2,3 In connection with these studies, this report
describes the preparation and antifungal evaluation of
2-substituted-phenyl-1H-benzimidazole-5-carbonitriles.
The synthetic pathways for preparation of the benzi-
midazoles listed in Tables 1 and 2 are shown in Schemes
1 and 2. Compounds 32 and 33 were obtained by the
N1-alkylation of 2 which was prepared in good yield by
condensation of o-phenylenediamine with the Na2S2O5
adduct of 4-fluorobenzaldehyde in DMF.4 Compounds
34, 35 and 38 were also prepared in a similar manner 2.
The carboxyl group of 35 was converted to ethyl ester
36 and the N-isopropyl-carboxamide 37, first by acid
chloride formation using SOCl2, then reaction with
EtOH and isopropylamine, respectively. 39 was also
obtained in the analogous way, starting from 38.
Nucleophilic displacement of the chloro group of
4-(CF3 and/or Cl)-nitrobenzenes by reaction with
butylamine in DMF gave 5 and 6, respectively. Their
reduction with H2, Pd/C produced 7, 8. Condensation
of the aromatic o-diamines with the Na2S2O5 adduct of
appropriate benzaldehydes gave 40, 41 and 43. The
nitrile group of 57 was converted to carboxyaldehyde
42, by using DIBAL, in a 33% yield. Compounds 44–67
were obtained by the same route as 40, 41, 43 (Schemes
2 and 4). Related intermediates 9–17 and 18–27 are given
in Table 3. Compound 63 was prepared by etherification
of 62. Since compound 53 exhibited significant anti-
fungal activity, it was planned to relocate the CNgroup
from C-5 to C-6. For this purpose, firstly we have
attempted alkylation of compound 44, with n-propyl
bromide under strong basic conditions (NaH 95%,
*Corresponding author. Tel.: +90-312-222-0471; fax: +90-312-213-
1081; e-mail: goker@pharmacy.ankara.edu.tr
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00103-7

2590
H. Goker et al. / Bioorg. Med. Chem. 10 (2002) 2589–2596
¨
Table 1. In vitro antifungal activities and formulas of 32–67
Compd
R1
R2
R3
Fungi
C. albicans
C. glabrata
C. krusei
C. parapsilosis
GIZ MIC MFC GIZ MIC MFC GIZ MIC MFC GIZ MIC MFC
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
Mic
Flu
5,6-H
5,6-H
5-CH3
(CH2)2CH3
CH2–CH2¼CH2
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
H
H
H
H
4-OCH
2,4-
4-F
4-F
4-F
H
H
H
4-F
4-F
H
4-F
H
4-F
4-F
4-Cl
2-Cl
N
N
N
N
N
N
N
N
14
N
11 12.5
N
9
NI
NI
N
I
I
I
I
I
I
I
I
N
N
N
N
N
N
N
N
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
N
>25
N
>25
N
NT
NT
NT
N
N
NT
N
I
I
I
I
I
I
I
I
N
N
N
N
N
N
N
N
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
I
I
I
I
I
I
I
I
N
N
N
N
N
N
N
N
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
N
I
I
I
I
I
I
I
I
5-COOH
5-COOEt
5-CONHCH(CH3)2
5-COOH
5-CONH2
5-Cl
N
6.25 12.5
N
6.25 12.5
NI
NI
16
T
14 12.5
25
25
5-CF3
5-COH
5-NO2
5-CN
5-CN
5-CN
5-CNH
5-CNH
5-CN
5-CNCH
5-CN(CH
5-CN(CH
5-CN(CH
6-CN(CH
5-CN(CH
5-CN(CH
5-CN(CH
5-CN(CH
5-CN(CH
5-CN(CH
5-CN(CH
5-CNCH
5-CNCH
5-CNCH(CH
5-CNCH
5-CN
I
N
N
T
12.5
T
I
I
N
N
I N
15 12.5
T
T
N
N
I
I
13 12.5
T
NI
NI
NI
T
T
NI
T
T
25
I
N
I
N
NT
NT
NT
I
I
NT
I
I
NI
NI
NI
NT
NT
NT
NI
NI
NI
I
I
NI
I
I
11 25
12 12.5
12
NT
NT
NT
N
N
T
T
I
I
N
N
N
N
N
N
T
T
N
N
I
I
3
di-Cl
4-OH
4-F
3-NO2
H
4-F
4-F
3-F
2-F
H
4-F
2,5-di-F
3,4-di-F
4-F
4-F
4-F
4-F
4-F
N
NI
N
H
2CH3
2)2CH3
2)2CH3
2)2CH3
2)2CH3
2)2CH3
2)2CH3
2)3CH3
2)3CH3
2)2CH3
2)2CH3
2)2CH2 Cl
2CH2OH
2CH2OCH3
NI
NT
NT
N
N
T
T
50
25
50
T
I
I
50
50
N
N
N
N
N
N
T
T
N
N
I
I
N
N
22 12.5
20 6.25
NI 25
N
N
23
24
N
NI 25
NI 25
13 50
10 12.5
50
25
25
25
18
6.25
N
N
NTꢀ
6.25 15 12.5
I
I
12.5
N
N
18
6.25 19
N
N
6.25 12.5
I
I
N
N
N
N
T
T
20
24
T
T
18
NI
NI 25
T
T
NI
NI
I
I
N
N
NTꢀ
T
T
N
N
I
I
T
N ꢀ
T
13
6.25 15 12.5
T
T
NTꢀ
3.12
25
I
I
25
3.12
3.12
3.12
I
I
N
N
N
N
N
I
I
13
NI
NI 12.5
I
N
N
T
T
N
N
I
I
N
N
3.12 25
NT
6.25 25
N
17
NI
21
N
NI 12.5
NT
6.25 12.5
NT
6.25 12.5
NT
NI
NI 25
50
I
I
25
25
)
I
I
NT
NT
T
T
N
N
NT
NT
0.19
N
N
N
N
N
N
T
T
N
N
I
I
3 2
2CH2CH(CH3)2
cyclohexyl
2Ph
N
N
I
4-F
4-F
NI
NI
35
15
NI
NI
NT
NT
0.19
NI
NI
0.39 46
6.25 12.5 13
NT
NT
5-CNCH
0.19
3.12
0.56 34
6.25 16 12.5
0.39 35
25 16
0.39
6.25 12.5
0.78
GIZ, growth inhibition zone (mm); MIC 100, minimum inhibitory concentrations (mg/mL); MFC, minimum fungicidal concentrations (mg/mL); NI, no
inhibition; NT, not tested; NT*, since the compound 57 has no good solubility, it has not been tested by the tube dilution method; Mic, miconazole;
Flu, fluconazole.
DMF, at rt) (Scheme 3). As expected, due to the tauto-
merism of the imidazole moiety alkylation occurred at
both the 1 and 3 positions;5 two regioisomers, 53 and
54, were formed as a solid mixture which has no sharp
mp. Generally, alkylations of benzimidazoles give simi-
lar yields of both regioisomers, rarely giving a different
ratio,5 it has been reported that,6 when 5(6)- or
4(7)-substituted benzimidazoles are alkylated, the pro-
duct ratios depends on the resonance electronic effects
as well as position of the substituent. Here, propylation
of 44 (Scheme 3), gave a 2:1 ratio of 1,6- (54) and the
1,5-isomers (53), according to the NMR data of the
mixture. Since the compound 53 was synthesised as
described in Scheme 2 by an unambiguous method and
therefore readily allows for isomeric identification in the
NMR spectra of the mixture. The partial regioselectivity
of alkylation of 44 may be attributed to the electron
withdrawing effect of the cyano group, since a similar
result was noted on alkylation of 4-nitrobenzimidazole.6
Further studies are necessary to fully understand the
influence of electron-withdrawing groups on N-alkyl-
ation of benzimidazoles.
We were unable to separate the regiosiomers from each
other by crystallisation or chromatography. Therefore,
it was necessary to develop a selective synthesis for the

Table 2. Physical and spectral data for compounds 32–67
Comp.
Mp (ꢁC)
Yield (%)
Formulas
Calculated
Found
1H NMR
Mass (62 or 70 eV, EI)
Isolation
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
82–83
98–99
95
81
C
16H15FN2
(DMSO-d6) 0.5–0.8 (t, 3H), 1.4–1.9 (m, 2H),
4.1–4.4 (t, 2H), 7.1–7.9 (8H)
254 (M+, 100), 239 (23), 224 (66),
211 (22.6), 129 (16.2), 77 (44.5)
EtOAc/n-hexane (1:3) cc
EtOAc/n-hexane (1:3) cc
Crys. EtOH (60%)
C: 75.59H: 5.94 N: 11.02
C: 75.59H: 6.05 N: 11.00
79
C16H13FN2
(DMSO-d6) 4.8 (3H), 5.2 (d, 1H), 6.0 (m, 1H),
7.2 (2H), 7.4 (m, 2H), 7.5 (m, 1H), 7.7 (d, 1H, J0=8.3),
7.8 (2H)
(DMSO-d6) 0.7 (t, 3H, J=7.3), 1.65 (m, 2H),
2.4 (s, 3H), 4.2 (t, 2H, J=7.2), 7.1 (dd, 1H, Jo=8.6,
Jm=1.28), 7.4 (3H), 7.5 (d, 1H, Jo=8.1), 7.8 (2H)
(DMSO-d6) 0.715 (t, 3H), 1.67 (m, 2H), 4.29
(t, 2H), 7.57–7.79 (6H), 7.91 (dd, 1H, J0=8.5, Jm=1.5),
8.25 (s, 1H)
251 (Mꢂ1, 76.5), 236 (7.34), 225 (4.5),
C: 76.19H: 5.19 N: 11.10
C: 76.38H: 5.18 N: 11.06
211 (42.2), 121 (17.8), 90 (23.9), 41 (100)
41
C17H17FN2
269 (M+1, 62.9), 253 (9.7), 239 (57.7),
225 (9.8), 121 (31.9), 77 (8.84), 41 (100)
C: 76.11H: 6.34 N: 10.44
C: 75.84H: 6.37 N: 10.57
217
57
C
17H16N2O2
ESI: 281 (M+1, 100)
ESI: 309 (M+1, 100)
Crys. isopropanol
C: 72.84H: 5.75 N: 9.99
C: 72.39H: 5.72 N: 9.90
91–92
77
C
19H20N2O2
(DMSO-d6) 0.715 (t, 3H), 1.35 (t, 3H), 1.67 (q, 2H),
4.313 (m, 4H), 7.58–7.9(7H), 8.27 (s, 1H)
EtOAc/n-hexane (1:3) cc
EtOAc cc
C: 74.00H: 6.54 N: 9.08
C: 73.81H: 6.57 N: 9.08
210–211
81
C
20H23N3O
(DMSO-d6) 0.7 (t, 3H), 1.2 (d, 6H), 1.7 (m, 2H),
4.1 (m, 1H), 4.35 (t, 2H), 7.66 (3H), 7.77 (d, 1H, J0=7.9),
7.85 (2H), 7.91 (dd, 1H, J0=8.5, Jm=1.5), 8.25 (2H)
(DMSO-d6) 0.74 (t, 3H), 1.12 (m, 2H), 1.63 (m, 2H),
4.31 (t, 2H), 7.39–7.9 (6H), 8.24 (s, 1H)
320.5 (M+, 5.49), 263 (24.3), 220 (8.92),
102 (4.43), 77 (4), 41 (100)
C: 74.74H: 7.21 N: 13.07
C: 74.47H: 7.05 N: 13.02
250
185–186
65–67
75.4
91
C
18H17FN2O2
ESI: 313 (M+1, 100)
ESI: 312 (M+1, 100)
Crys. isopropanol
C: 69.22H: 5.49 N: 8.97
C: 69.39H: 5.49 N: 9.09
C18H18FN3O.0.2HOH
C: 68.60H: 5.88 N: 13.34
C: 68.63H: 5.83 N: 13.27
(DMSO-d6) 0.7 (t, 3H), 1.1 (m, 2H), 1.6 (m, 2H),
4.3 (t, 2H), 7.2–8.05 (6H), 8.25 (s, 1H)
Crys EtOH (50%)
49
C17H17ClN2
(DMSO-d6) 0.7 (t, 3H), 1.05 (m, 2H), 1.6 (m, 2H),
4.3 (t, 2H), 7.25 (d, 1H, J0=8.6), 7.5 (3H),
7.7 (dd, 1H, J0=8.6, Jm=1.6), 7.8 (3H)
(CDCl3) 0.7(t, 3H), 1.07(m, 2H), 1.6 (m, 2H),
4.05(t, 2H), 7.0(2H), 7.2 (d, 1H,J0=8.5),
7.4(d, 1H, J0=8.5), 7.55(2H), 7.9(s, 1H)
(CDCl3) 0.8 (t, 3H), 1.2 (m, 2H), 1.7 (m, 2H),
4.3 (t, 2H), 7.4 (d, 1H, J0=8.5), 7.5 (3H), 7.7 (2H),
7.9 (dd, 1H J0=8.4, Jm=1.3), 8.3 (s, 1H), 10 (s, 1H)
(DMSO-d6) 7.4 (2H), 7.7 (d, 1H), 8.1 (d, 1H),
-8.2 (2H), 8.4 (s, 1H)
284 (M+, 100), 286 (M+2, 27), 255 (77),
241 (99), 163 (60.7)
EtOAc/n-hexane (1:4) cc
EtOAc/n-hexane (1:3) cc
EtOAc/n-hexane (2:3) cc
Crys. EtOH (70%)
C: 71.80H: 6.02 N: 9.85
C: 71.62H: 6.16 N: 9.70
C18H16F4N2
C: 64.28H: 4.80 N: 8.33
55–56
53.5
33
336 (M+, 40.2), 307 (8.6), 293 (35.9),
280 (23), 121 (22.1), 95 (15.9), 83 (100)
C: 64.34H: 4.90 N: 8.24
.
94–95
C
18H18N2O 0.15HOH
278 (M+, 100), 249 (15.7), 235 (42.6),
221 (12.4), 157 (1.8), 77 (6.5)
C: 76.90H: 6.56 N: 9.97
C: 76.98H: 6.71 N: 9.39
.
C13H8FN3O2 0.7HOH
264–265
238–240
237–239
125–126
67.6
78
ESI: 258 (M+1, 100)
C: 57.86H: 3.51 N: 15.57
C: 57.87H: 3.54 N: 15.52
.
C
14H8FN3 1.5HOH
(DMSO-d6) 7.4–8.35 (7H), 13.4 (br.s., 1H).
(DMSO-d6) 7.55–8.32 (7H), 13.5 (br.s., 1H).
(DMSO-d6) 7.5–8.3 (7H), 13.3 (s, 1H).
237 (M+, 100), 218 (2), 121 (18.2),
96 (7.6), 75 (15.7)
EtOAc/n-hexane (1:1) cc
Crys. EtOAc/n-hexane (50%)
EtOAc/n-hexane (1:3) cc
C: 63.60H: 4.10 N: 15.90
C: 63.29H: 3.92 N: 15.91
.
64.2
56.9
C
14H8ClN3 1.85HOH
C: 58.58H: 4.11 N: 14.6
253 (M+, 100), 255 (27.8), 217 (18.8),
149 (2.8), 137 (14.1), 115 (10.5),
109 (16.6), 89 (15.9), 75 (19.4)
253 (M+, 100), 255 (30.2), 218 (26.5),
137 (12.4), 116 (5.9), 89 (10.7), 75 (16.95)
C: 58.52H: 4.12 N: 14.4
.
C
14H8ClN3 0.4HOH
C: 64.45H: 3.40 N: 16.10
C: 64.73H: 3.45 N: 16.13
C15H11N3O
47
48
218–219lit.12 221
248–250
76.3
64.8
(DMSO-d6) 3.85 (s, 3H), 7.1–8.2 (7H), 13.3 (br.s., 1H).
(DMSO-d6) 7.55–8.3 (6H), 13.3 (br.s., 1H).
249 (M+,100), 234 (33.9), 206 (44.8),
133 (5.3), 90 (8.9)
287 (M+, 80), 289 (51.3), 291 (8.2),
252 (10.9), 217 (17.8), 171 (9.3), 144 (3.7),
126 (4.5), 115 (10.5), 100 (10.6)
235 (M+, 9.5), 207 (7.5), 179 (4.2), 119 (36.7),
103 (9.5), 91 (33.5), 76 (34.2), 41 (100)
265(M+, 100), 250 (53), 237 (55.7), 170 (16.7),
143 (12.9), 121 (84), 95 (22.5), 75 (30.3)
Crys. isopropanol. (70%)
Crys. EtOH
C14H7Cl2N3
C: 58.33H: 2.43 N: 14.58
C: 58.39H: 2.70 N: 14.42
C14H9N3O
49a
50
Lit.13 317
140
80.2
64.2
(DMSO-d6) 6.9 (2H), 7.5 (1H), 7.65 (1H), 8.02 (3H).
Crys. EtOH (70%)
Crys. EtOH
.
C16H12FN3 0.5HOH
C: 70.06H: 4.78 N: 15.30
C: 70.05H: 4.72 N: 15.29
(DMSO-d6) 1.3 (t, 3H), 4.3 (q, 2H), 7.4 (2H),
7.7 (dd, 1H, J0=8.5, Jm=1.57),
7.8–7.9 (3H), 8.2 (d, 1H, Jm=1.3)
(continued )

Table 2 (continued)
Comp.
Mp (ꢁC)
Yield (%)
Formulas
Calculated
Found
1H NMR
Mass (62 or 70 eV, EI)
Isolation
.
17H14N4O2 0.25HOH
C: 65.60H: 4.70 N: 18.02
C: 65.61H: 4.71 N: 18.11
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
130–1
178
51
C
(DMSO-d6) 0.7 (t, 3H), 1.7 (m, 2H), 4.3 (t, 2H),
7.7 (d, 1H), 7.9 (2H), 8.2 (2H), 8.3 (d, 1H), 8.6 (s, 1H)
307 (M+1, 1.95), 231 (2.78), 218 (1.5), 149 (3.2),
115 (2.7), 102 (8.4), 76 (19.4), 41 (100)
Crys. EtOH (70%)
Crys. EtOH (60%)
Crys. EtOH (60%)
Crys. EtOH (60%)
Crys. EtOH (60%)
EtOAc/n-hexane (1:3) cc
EtOAc/n-hexane (1:3) cc
Crys. EtOH (60%)
EtOAc/n-hexane (1:3) cc
EtOAc/n-hexane (1:3) cc
Crys. EtOH (50%)
Crys. EtOH (60%)
Crys. EtOH (85%)
Crys. EtOH
68.7
77. 8
81
C
17H15N3
(DMSO-d6) 0.7 (t, 3H), 1.6 (m, 2H), 4.3 (t, 2H),
7.6 (3H), 7.7 (d, 1H, J0=8.3), 7.8 (2H),
7.9 (d, 1H, J0=8.4), 8.2 (s, 1H)
261(M+, 4.9), 232 (5.9), 154 (3.9),
103 (7.7), 77 (18.6), 41 (100)
C: 78.16H: 5.74 N: 16.09
C: 77.87H: 5.72 N: 16.16
142–144
160–162
152–153
133–134
158–160
103–104
115–116
110
C
17H14FN3
(DMSO-d6) 0.72 (t, 3H), 1.66 (m, 2H), 4.32 (t, 2H),
7.44 (2H), 7.7 (d, 1H, J0=9), 7.84–7.88 (m, 2H),
7.90 (dd, 1H, J0=8.5 Jm=1.2, H-6), 8.23 (s, 1H, H-4)
(DMSO-d6) 0.73 (t, 3H), 1.68 (m, 2H), 4.31 (t, 2H),
7.43 (2H), 7.61 (d, 1H, J0=8.3), 7.82–7.88 (m, 3H),
8.36 (s, 1H, H-7)
(DMSO-d6) 0.7 (t, 3H), 1.6 (m, 2H), 4.3 (t, 2H),
7.4 (2H), 7.6 (2H), 7.7 (d, 1H, J0=8.4),
7.9 (dd, 1H, J0=8.4, Jm=1.6), 8.2 (s, 1H)
(DMSO-d6) 0.7 (t, 3H), 1.6 (m, 2H), 4.3 (t, 2H),
7.5 (2H), 7.8 (3H), 8.0 (d, 1H, J0=8.4), 8.3 (s, 1H)
279 (M+, 56.9), 264 (13.7), 250 (73.5),
237 (24.8), 154 (19.7), 121 (37.7), 102 (33),
75 (40.6), 41 (100)
279(M+, 17.1), 264 (5), 250 (34.4),
237 (7.2), 154 (7), 121 (8.6), 102 (5.4),
75 (12.7), 41 (100)
279 (M+, 5.2), 264 (1.4), 250 (7.5),
237 (1.5), 154 (2), 121 (8.3), 101 (3.2),
95 (7.5), 75 (14), 41 (100)
C: 73.11H: 5.05 N: 15.04
C: 73.08H: 5.11 N: 14.88
C
17H14FN3
C: 73.11H: 5.05 N: 15.04
C: 73.13H: 5.01 N: 14.98
60.9
53.2
57.5
64.5
58
C
17H14FN3
C: 73.11H: 5.05 N: 15.04
C: 73.25H: 5.11 N: 15.04
C
17H14FN3
ESI: 280 (M+1, 100)
C: 73.11H: 5.05 N: 15.04
C: 73.20H: 5.13 N: 15.02
C18H17N3
C: 78.52H: 6.22 N: 15.27
C: 77.95H: 6.21 N: 15.17
(DMSO-d6) 0.7 (t, 3H), 1.1 (m, 2H), 1.6 (m, 2H),
4.3 (t, 2H), 7.5 (3H), 7.6 (d, 1H, J0=8.4), 7.7 (2H),
7.9 (d, 1H, J0=8.4), 8.2 (s, 1H)
(DMSO-d6) 0.7 (t, 3H), 1.1 (m, 2H), 1.6 (m, 2H),
4.3 (t, 2H), 7.4 (2H), 7.7 (d, 1H, J0=8.4), 7.8–7.9 (3H),
8.2 (s, 1H)
(DMSO-d6) 0.7 (t, 3H), 1.6 (m, 2H), 4.2 (t, 2H),
7.55 (2H), 7.65 (1H), 7.72 (dd, 1H, J0=8.4, Jm=1.6),
7.95 (d, 1H, J0=8.4), 8.2 (s, 1H)
(DMSO-d6) 0.7 (t, 3H), 1.6 (m, 2H), 4.3 (t, 2H),
7.6–7.7 (3H), 7.9 (2H), 8.2 (s, 1H)
ESI: 276 (M+1, 100)
.
C18H16FN3 0.35HOH
294 (M+1, 6), 264(2), 250 (13), 237 (3.6),
154 (1.6), 121 (9), 95 (3.2), 41 (100)
C: 72.15H: 5.61 N: 14.02
C: 72.03H: 5.47 N: 13.96
C
17H13F2N3
ESI: 298 (M+1, 100)
ESI: 298 (M+1, 100)
C: 68.68H: 4.40 N: 14.14
C: 68.48H: 4.34 N: 14.05
C17H13F2N3
C: 68.68H: 4.40 N: 14.14
59
C: 68.95H: 4.66 N: 14.07
.
111–112
155–157
127–128
190–191
132
53.7
67
C
17H13ClFN3 0.1HOH
(DMSO-d6) 2.1 (m, 2H), 3.5 (t, 2H), 4.4 (t, 2H),
7.4 (2H), 7.7 (d, 1H, J0=8.4), 7.8–7.9 (3H), 8.2 (s, 1H)
313 (M+, 26.6), 315 (11.5), 279 (9.9),
264 (26.2), 250 (83.9), 154 (18.9), 121 (36.7),
95 (10.3), 75 (12.1), 41 (100)
281 (M+, 12.4), 250 (100), 236 (6.2),
154 (14.7), 121 (6.6), 94 (2.5), 75 (2.9)
C: 64.70H: 4.21 N: 13.30
C: 64.57H: 4.20 N: 13.22
.
C16H12FN3O 0.75HOH
C: 65.18H: 4.61 N: 14.25
(DMSO-d6) 3.75 (t, 2H), 4.3 (t, 2H), 7.4 (2H), 7.65
(dd, 1H, J0=8.4, Jm=1.48), 7.8 (d, 1H, J0=9),
7.95 (2H), 8.2 (d, 1H, Jm=1.23)
(CDCl3) 3.3 (s, 3H), 3.8 (t, 2H, J=5.25), 4.4
(t, 2H, J=5.27), 7.25 (2H), 7.59 (2H),
7.8 (2H), 8.15 (s, 1H)
(DMSO-d6) 1.6 (d, 6H), 4.65 (m, 1H), 7.4 (2H), 7.6
(dd, 1H, J0=8.4, Jm=1.46), 7.8 (2H),
8.0 (d, 1H, J0=8.4), 8.2(s, 1H)
(DMSO-d6) 0.75 (d, 6H), 1.4 (m, 1H), 1.5 (m, 2H),
4.3 (t, 2H), 7.4 (2H), 7.7 (dd, 1H, J0=8.5, Jm=1.5),
7.85 (3H), 8.2 (s, 1H)
C: 65.46H: 4.57 N: 14.14
.
77
C17H14FN3O 0.1HOH
295 (M+, 74), 263 (15), 249 (100), 236 (13),
222 (21), 154 (21), 121 (6), 94 (4)
C: 68.70H: 4.82 N: 14.14
C: 68.69H: 4.91 N: 14.03
.
17H14FN3 0.5HOH
79.4
72.5
72
C
280 (M+1, 9.7), 264 (3.14), 237 (21.5),
121 (13.36), 95 (4.4), 75 (4.68), 43 (100)
C: 70.80H: 5.24 N: 14.57
C: 70.76H: 5.01 N: 14.65
C19H18FN3
C: 74.25H: 5.90 N: 13.67
307 (M+, 100), 264 (15.7), 250 (85.6),
237 (18.6), 154 (12.7), 121 (12.2),
102 (17.8), 95 (8.2)
319 (M+, 14), 237 (37.8), 121 (16.1),
115 (14.6), 83 (35.5), 55 (100)
Crys. EtOH
C: 74.34H: 6.01 N: 13.67
.
211–212
C
20H18FN3 0.4HOH
(DMSO-d6) 1.2–1.4 (m, 3H), 1.6 (1H), 1.8–1.9 (4H),
2.2 (m, 2H), 4.2 (m, 1H), 7.4 (2H), 7.6 (dd, 1H, J0=8.6,
Jm=1.65), 7.73 (2H), 8.1 (d, 1H, J0=8.6), 8.2
(d, 1H, Jm=1.47)
Crys. EtOH
C: 73.56H: 5.80 N: 12.86
C: 73.72H: 5.69 N: 12.89
67
153
80.6
C21H14FN3
C: 77.05H: 4.31 N: 12.84
C: 76.88H: 4.51 N: 12.79
(DMSO-d6) 5.6 (s, 2H), 6.9–7.7 (11H), 8.27 (s, 1H)
327 (M+, 17.6), 237 (2.9), 121 (6.5),
91 (100), 75 (7.2)
Crys. EtOH (50%)
cc, column chromatography; ESI, Elektrospray ionization.
aCompound 4913 was prepared according to the literature method.

H. Goker et al. / Bioorg. Med. Chem. 10 (2002) 2589–2596
¨
2593
Scheme 1. Reagents: (a) Na2S2O5 adduct of 4-fluorobenzaldehyde; (b) n-propyl or allyl bromide/NaH/DMF; (c) Na2S2O5 adduct of benzaldehyde;
(d) for 36; SOCl2/EtOH for 37; SOCl2/isopropylamine; (e) SOCl2/NH3; (f) butylamine/DMF; (g) H2, Pd/C; (h) DIBAL.
(ATTC 10231), Candida glabrata (Clinical isolate),
Candida krusei (ATCC 6258), Candida parapsilosis
(ATCC 22019) by agar diffusion method, which was
already reported by us.2 All the synthesised compounds
were solved in 1,2-propylene glycol (1500 mg/mL),
0.02 mL (one drop) of these solutions was dropped to
paper disk (6 mm in diameter) and placed on an agar
plate containing bacteria or fungi cells. Propylene glycol
as a control has no inhibition zone. The diameter of the
growth inhibition zone around the paper disc was mea-
sured after incubation. The results obtained indicate
that most of these compounds were only poorly active
or completely in active against bacteria. However, com-
pounds 40, 42, 52, 53, 57, 58, 61 and 63 showed good
activity against Candida species with >20 mm growth
inhibition zone, which was better than fluconazole, in
the control experiments (Table 1). In addition, the tube
dilution method9 was also employed for the active
compounds in agar diffusion method. Related com-
pounds were dissolved in propylene glycol (15.6%) at
100 mg/mL concentration as starting dose. The most
active compound 58 exhibits an MIC value of 3.12 mg/
mL against C. albicans, C krusei and C. parapsilosis.
The data (Table 1) show that, introduction of electron-
withdrawing groups such as, aldehyde, chlorine and
cyano at C-5 gives a good profile of antifungal activity.
In contrast, no significant activity was found for tri-
fluoromethyl, carboxyl, ester and amide. Consequently,
there is not a clear correlation between electron attract-
ing effects of substituents and antifungal activity. Since
Scheme 2. Reagents: (a) corresponding amines; (b) H2, Pd/C; (c) cor-
responding Na2S2O5 adduct of the benzaldehydes/DMF.
other isomer 54 and the approach is outlined in Scheme
4. Compound 287 was prepared by chlorination of
4-aminobenzonitrile with N-chlorosuccinimide. The
amino group of compound 28 was converted to nitro
29,8 by diazotation followed by nitritation. Compound
54 was prepared in similar manner with 53 starting from
29 (Scheme 4).
Biological Results
All described benzimidazoles, 32–67, were tested in vitro
for antibacterial activity against Gram positive Bacillus
subtilis (ATCC 6633) and Staphylococcus aureus (ATCC
25923), Gram negative Escherichia coli (ATCC 25922)
bacteria and antifungal activity against Candida albicans

2594
H. Goker et al. / Bioorg. Med. Chem. 10 (2002) 2589–2596
¨
Table 3. Formulas, mp and yields of 9–17 and 18–27
Compd
R2
Formula
Mp (ꢁC)
Yield (%)
9
–CH2CH3
–CH2CH2CH3
–CH2CH2CH2CH3
–CH2CH2CH2Cl
–CH2CH2OH
–CH(CH3)2
–CH2CH2CH(CH3)2
Cyclohexyl
Benzyl
C9H9N3O2
C10H11N3O2
C11H13N3O2
C10H10ClN3O2
C9H9N3O3
C10H11N3O2
C12H15N3O2
C13H15N3O2
C14H11N3O2
134–135
116–117
71–72
152–153
135
110–113
100–101
110–111
130
Lit.17 (131–132)
Lit.17 (116)
88.6
96.4
92.7
58
10
11
12
13
14
15
16
17
Lit.17 (69)
Lit.17 (135)
Lit.2 (110–113)
91
93.8
94.3
93.2
52.6
Lit.18 (110–111)
Lit.19 (128)
18
19
20
21
22
23
24
25
26
27
–H
–CH2CH3
C7H7N3
C9H11N3
115
129
115–116
102–103
115
132–133
97–98
99–100
143–144
128
Lit.20 (114–116)
Lit.2 (115–116)
94
85.5
95.6
90.9
91
89.5
95
91.7
89.3
85.7
–CH2CH2CH3
–CH2CH2CH2CH3
–CH2CH2CH2Cl
–CH2CH2OH
–CH(CH3)2
–CH2CH2CH(CH3)2
Cyclohexyl
Benzyl
C10H13N3
C11H15N3
C10H12ClN3
C9H11N3O
C10H13N3
C12H17N3
C13H17N3
C14H13N3
Lit.2 (97–98)
Scheme 3. Reagents: (a) n-propyl bromide/NaH/DMF.
substitutions on the phenyl ring result in lowering of the
antifungal activity. However, fluoro substituents are tol-
erated (cf., 53 to 52), although, they do not significantly
enhance the activity. Multiple fluoro substitutions result
in lowering of the activity (cf., 59 and 60 to 53). There
are striking differences in antifungal activity with the
location of the cyano group at position C-5 or C-6. The
1,5-isomer, compound 53, has potent antifungal activity
against C. albicans, whereas the 1,6-isomeric analogue
54 shows little antifungal activity. In contrast, com-
pound 54 has better activity against C. glabrata than
53.
Scheme 4. Reagents: (a) N-chlorosuccinimide; (b) NaNO2/HCl–
Cu2O/NaNO2; (c) propylamine; (d) H2, Pd/C; (e) Na2S2O5 adduct of
the p-fluorobenzaldehydes/DMF.
the cyano substituted compounds exhibited the greatest
antifungal activity, a number of analogues, 44–67 were
made with this substituent at C-5 or C-6. Compounds
with n-butyl, n-propyl and 3-chloropropyl at the N1
position exhibited the best results. Little or no activity
was found for the non N1-substituted derivatives 44–
49. Substitution on the 2-phenyl group of this system
plays a role in the antifungal activity. Many of the
Conclusion
This work demonstrates that compounds 52–54, 57, 58
and 61 having butyl or propyl at N-1, phenyl or
p-fluorophenyl rings at C-2 and cyano at C-5 or C-6
show similiar activity with fluconazole against Candida
species in vitro. In vivo studies of compound 58 and its
mechanism of action are in progress.

H. Goker et al. / Bioorg. Med. Chem. 10 (2002) 2589–2596
¨
2595
Experimental
and butylamine (3 g, 41 mmol) in DMF (5 mL) were
heated on the water bath for 3 h. The mixture was
allowed to cool, the resultant yellow precipitate was fil-
tered and washed with water. Crystallisation of the
crude product from EtOH–H2O gave methyl 4-butyl-
amino-3-nitrobenzoic acid,21 mp 50–51 ꢁC, yield 55%,
C12H16N2O4. Reduction of this ester (1.5 g, 6 mmol) in
similar manner with 3 gave 4 as violet colour, mp
95–97 ꢁC, yield 95%, C12H18N2O2.
Melting points were measured with a capillary melting
point apparatus (Buchi SMP and Buchi 9100) and are
uncorrected. 1H NMR were recorded on a Varian
GX400 spectrometer (Atlanta) in DMSO-d6, chemical
shifts (d) are in ppm relative to TMS, and coupling
constants (J) are reported in Hertz. Mass spectra were
taken on Micromass UK. Platform II LC-Ms spectro-
meters by using EI (62 or 70 eV) were performed by
TUBlTAK (Instrumental Analyse Lab., Ankara, Tur-
key) and Georgia Institute of Technology (Atlanta, GA,
USA) by using ESI. Microanalyses were performed by
Atlantic Microlab Inc, (Norcross, Atlanta, GA, USA).
Column chromatography was accomplished on silica gel
60 (40–63mm particle size) (Merck). Compound 5,10 6,2
7,10 82 were prepared according to the literature methods.
Synthesis of (9–17). To a solution of 4-chloro-3-nitro-
benzonitrile (2 g, 10.98 mmol) in DMF (3 mL), an
appropriate amine (41 mmol) was added on ice bath.
After being warmed to rt, the reaction mixture was
heated on a water bath until the starting material was
consumed (determined by TLC, 1–3 h). The mixture
was cooled to ice bath (0–4 ꢁC) and water was added.
The resultant yellow precipitate was filtered, washed
with water, crystallised from EtOH. For the synthesis
of 12, 3-chloropropylamine HCl (1.42 g, 10.98 mmol)
and anhydrous K2CO3 (1.5 g, 10.98 mmol) was used,
crude product was crystallised from CHCl3–EtOH
(20:80).
N-Propyl-2-amino-4-methylaniline (1). Mixture of
4-chloro-3-nitrotoluene (5 mL) and propylamine
(30 mL) were heated in sealed tube at 100 ꢁC, for 10 h.
Excess of propylamine was removed and 4-methyl-
2-nitro-N-propylaniline was obtained as red-coloured
oily residue. The spectral data were consistent with lit-
erature.11 The oily residue was dissolved in EtOH
(40 mL), and the solution hydrogenated using 10% Pd/
C as a catalyst at room temperature at 35 psi. The
reaction was stopped after cessation of H2 uptake. The
catalyst was filtered through a bed of Celite, washed with
EtOH, and concentrated to provide 1 as a dark brown-
coloured oil, which was used in subsequent steps without
purification.
The melting points and yields for these compounds are
listed in Table 3.
Synthesis of (18–27). Appropriate nitro derivatives
(8 mmol) in EtOH (75 mL) were reduced by hydro-
genation using 40 psi of H2 and 10% Pd/C (200 mg)
until cessation of H2 uptake. The catalyst was filtered
off on a bed of Celite, washed with EtOH, and the fil-
trate was concentrated. The crude diamines were used
directly without purification. The melting points and
yields for these compounds are listed in Table 3.
Synthesis of (2, 34, 35, 40, 41, 43–48, 50–62, 64–67)
4-Nitro-3-propylaminobenzonitrile (30). To a solution of
compound 298 (0.3 g, 1.65 mmol) in DMF (1 mL), pro-
pylamine (7 mmol) was added on ice bath. After being
warmed to rt, the reaction mixture was heated on a
water bath for 2 h until the starting material was con-
sumed. The mixture was cooled to ice bath (0–4 ꢁC) and
water was added. The resultant yellow precipitate was
filtered, washed with water, crystallised from EtOH, mp
Appropriate benzaldehydes (15 mmol) were dissolved in
50 mL EtOH and sodium metabisulfite (1.6 g) in 10 mL
water was added in portions. The reaction mixture was
stirred vigorously and more EtOH was added. The mix-
ture was kept in a refrigerator for a several hours. The
precipitate was filtered and dried (yield over 90%). The
mixture of these salts (2 mmol) and appropriate
1,2-phenylenediamines in DMF (5 mL) were heated at
130 ꢁC for 4 h. The reaction mixture was cooled, poured
into the water, and the solid was filtered. Purification
procedure and some spectral findings of the synthesized
compounds are given in Table 1. Mp of 2 255–256 ꢁC.
Lit.14 258 ꢁC.
105 ꢁC, yield 85%, IR v (CN) 2235 cmꢂ1
.
4-Amino-3-propylaminobenzonitrile (31). Compound 30
(0.3 g, 8 mmol) in EtOH (75 mL) was reduced by
hydrogenation using 40 psi of H2 and 10% Pd/C
(40 mg) until cessation of H2 uptake. The catalyst was
filtered off on a bed of Celite, washed with EtOH, and
the filtrate was concentrated in vacuo. The crude amine
was crystallised from EtOH–H2O as white-coloured
compound, mp, 113 ꢁC, yield 90%, IR v 2216 (CN)
3-Amino-4-propylaminobenzoic acid (3). 3-Nitro-4-pro-
pylaminobenzoic acid15 (8.91 mmol) was dissolved in
EtOH (40 mL), and the solution hydrogenated at room
temperature at 35 psi catalytic amount of 10% Pd/C. The
reaction was stopped after cessation of H2 uptake. The
reaction mixture was filtered through a bed of Celite,
washed with EtOH, and the product concentrated to
provide dark violet-coloured powder, which was used in
subsequent steps without purification, mp 140 ꢁC.
cmꢂ1
.
Synthesis of 32 and 33. A mixture of 2 (0.5 g,
2.36 mmol), n-propylbromide or allyl bromide
(2.45 mmol) and NaH (90%) (0.13 g) in DMF (5 mL)
was stirred at 60 ꢁC for 5 h. The reaction mixture was
poured into water and extracted with EtOAc. The
extract was washed with water, dried over Na2SO4 and
concentrated in vacuo.
Methyl 3-amino-4-butylaminobenzoic acid (4). Mixture
of methyl 4-chloro-3-nitrobenzoic acid16 (2 g, 9 mmol)

2596
H. Goker et al. / Bioorg. Med. Chem. 10 (2002) 2589–2596
¨
Ethyl 1-propyl-2-phenyl-1H-benzimidazol-5-carboxylate
(36). Compound 35 (0.2 g, 0.71 mmol) in SOCl2
(15 mL) was heated at reflux for 2 h at 80 ꢁC. The excess
of SOCl2 was evaporated completely, and the residue
was dissolved in EtOH (10 mL), heated for 1 h, and
EtOH was evaporated.
support for acquisition of the NMR spectrometers used
in this work.
References and Notes
N-Isopropyl 1-propyl-2-phenyl-1H-benzimidazol-5-car-
boxamide (37). Compound 35 (0.2 g, 0.71 mmol) in
SOCl2 (15 mL) was heated under reflux for 2 h at 80 ꢁC.
Excess of SOCl2 was evaporated, and the residue was
dissolved in CH2Cl2 (10 mL). Isopropylamine (0.8 mL)
was added, and the mixture was heated at reflux for 1 h,
then EtOH was evaporated.
1. Goker, H.; Kilcigil, G. A.; Tuncbilek, M.; Kus, C.; Ertan,
R.; Kendi, E.; Ozbey, S.; Fort, M.; Garcia, C.; Farre, A. J.
Heterocycles 1999, 51, 2561.
2. Goker, H.; Tuncbilek, M.; Suzen, S.; Kus, C.; Altanlar, N.
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 148.
3. Poeta, M. D.; Schell, W. A.; Dykstra, C. C.; Jones, S.;
Tidwell, R. R.; Czarny, A.; Bajic, M.; Bajic, M.; Kumar, A.;
Boykin, D.; Perfect, J. R. Antimicrob. Agents Chemother.
1998, 42, 2495.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazol-5-carboxylic
acid (38). Compound 4 and the Na2S2O5 salt of
p-fluorobenzaldehyde were allowed to react in a similar
manner as 2. After 4 h, the reaction mixture was made
alkaline with 5% NaOH (10 mL) solution and heated
on a water bath for 1 h, then the reaction mixture was
acidified with acetic acid, and the product precipitated.
4. Ridley, H. F.; Spickett, R. G. W.; Timmis, G. M. J. Het-
erocyclic Chem. 1965, 2, 453.
5. Goker, H.; Olgen, S.; Ertan, R.; Akgun, H.; Ozbey, S.;
Kendi, E.; Topcu, G. J. Heterocyclic Chem. 1995, 32, 1767.
6. Grimmett, M. R. In Imidazole and Benzimidazole
Synthesis; Meth-Cohn, O., Ed.; Academic: London, 1997;
p 202.
7. Nickson, E. T.; Roche-Dolson, C. A. Synthesis 1985, 669.
8. Tsuji, K.; Nakamura, K.; Konishi, N.; Okumura, H.;
Matsuo, M. Chem. Pharm. Bull. 1992, 40, 2399.
9. Shadomy, S.; Pfaller, M. A. Laboratory Studies with
Antifungal Agents: Susceptibility Tests and Quantitation in
Body Fluids. In Manual of Clinical Microbiology, 5th ed.;
Balows, A., Hausler, W. J., Hermann, K. L., Isenberg, H. D.,
Shadomy, H. J., Eds.; ASM, Washington, DC, 1991; Chapter
117, p 1173.
10. Hori, M.; Suzuki, K.; Yamamoto, T.; Nakajima, F.;
Ozaki, A.; Ohtaka, H. Chem. Pharm. Bull. 1993, 41, 1832.
11. Gardiner, J. M.; Loyns, C. R.; Schwalbe, C. H.; Barrett,
G. C.; Lowe, P. R. Tetrahedron 1995, 51, 4101.
12. Sun, Q.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie,
E. J. J. Med. Chem. 1995, 38, 3638.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazol-5-carboxamide
(39). 39 was prepared in similar manner as 37, from 38
(0.2 g, 0.64 mmol) and 5 mL of NH4OH (25%) as a col-
ourless powder.
1-Butyl-2-(phenyl)-1H-benzimidazol-5-carboxaldehyde
(42). To solution of 57 (0.3 g, 1.02 mmol) in dry
CH2Cl2 (20 mL), 3 mL of DIBAL (1.0 M solution in
CH2Cl2) was added, and the mixture was heated at
reflux for 3 h under nitrogen atmosphere. Cool dilute
H2SO4 acid (15 mL) was added and stirred overnight.
CH2Cl2 was removed, and the residue was neutralised
with dilute Na2CO3 solution and extracted with EtOAc.
13. Tidwell, R. R.; Geratz, J. D.; Dann, O.; Volz, G.; Zeh, D.;
Loewe, H. J. Med. Chem. 1978, 21, 613.
5-Cyano-2-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-benzi-
midazole (63). A mixture of 62 (0.28 g, 1 mmol), iodo-
methane (0.213 g, 1.5 mmol) and NaH (90%) (0.1 g) in
DMF (4 mL) was stirred at rt, for 2 h. The reaction
mixture was poured into water, the precipitate was fil-
tered and washed with water.
14. Latif, N.; Mishriky, N.; Assad, F. M.; Meguid, S. A.
Indian J. Chem. 1982, 21, 872.
15. Edwards, T. R. G.; Gani, D. Tetrahedron 1990, 46, 935.
16. Miller, W. J. Amer. Chem. Soc. 1954, 76, 448.
17. Blanksma, W. Recl. Trav. Chim. Pays-Bas 1941, 60, 811.
18. Inerney, M.; Proc, R. Ir. Acad. Sect. B 1970, 69, 21.
19. Ciba-Geigy; DD Patent 137939, 1979; GE; DE Patent
2807008, 1978; Chem. Abstr. 1979, 90, 7597.
20. Fairley, T. A.; Tidwell, R. R.; Donkor, I.; Naiman, N. A.;
Ohemeng, K. A.; Lombardy, R. J.; Bentley, J. A.; Cory, M.
J. Med. Chem. 1993, 36, 1746.
Acknowledgements
This work was supported in part by NIH Grant NIAID
AI 46365 and the Georgia Research Alliance provided
21. Pan, P. C.; Sun, C. M. Bioorg. Med. Chem. Lett. 1999, 9,
1537.