Synthesis and antimicrobial activity of some new 2-phenyl-N-substituted carboxamido-1H-benzimidazole derivatives

Article abstract of DOI:10.1002/1521-4184(200105)334:5<148::AID-ARDP148>3.0.CO;2-S

Some 1H-benzimidazole-carboxamide derivatives were prepared and their antimicrobial activities against Staphyloccus aureus, Escherichia coli and Candida albicans evaluated. Compounds 18, 22, and 25 exhibited the best activity against Candida albicans.

Full text of DOI:10.1002/1521-4184(200105)334:5<148::AID-ARDP148>3.0.CO;2-S

148
Göker, Tunçbilek, Süzen, Kus, and Altanlar
Synthesis and Antimicrobial Activity of Some New
2-Phenyl-N-substituted Carboxamido-1H-benzimidazole Derivatives
a)
a)
a)
a)
b)
Hakan Göker , Meral Tunçbilek , Sibel Süzen , Canan Kus , and Nurten Altanlar
a) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey
b) Department of Microbiology, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey
Key Words: 1H-benzimidazolecarboxylic acid; 1H-benzimidazolecarboxamides; antifungal and antibacterial activity
[4]
spectively . These compounds were converted into acyl
Summary
chlorides with SOCl , and their reaction with several amines
2
gave the required benzimidazole carboxamides. Some physi-
cochemical properties and spectral findings of products 18–
25 and 30–33 are given in Table 1.
Some 1H-benzimidazole-carboxamide derivatives were prepared
and their antimicrobial activities against Staphyloccus aureus,
Escherichia coli and Candida albicans evaluated. Compounds 18,
22, and 25 exhibited the best activity against Candida albicans.
Introduction
In the last decade a large number of benzimidazole deriva-
tives were prepared in our laboratory for their antibacterial
and antimycotic activity. Among them, N′-(N,N-dialkylami-
noethyl)benzimidazole-5(6)-carboxamides I and II exhibited
[1,2]
potent antimicrobial activity
. In connection with these
studies, it was planned to modify the position of the amide
structure on the benzimidazole moiety in order to develop
new antimicrobial agents.
Cl
Cl
Scheme 1. Synthesis of the compounds 1–25. Reagents: (a) Corresponding
amines (b) For 4–6 H2,Pd/C, for 10 Zn/HCl (c) NaHSO3 (d) 1. SOCl2;
2. Corresponding amines.
N
N
N
N
H
Cl
Cl
N
N
N
H3C
N
H3C
Cl
O
O
CH3
I
II
Results and Discussion
Compounds 18–25, 30–33 were evaluated for antimicrobial
activity against Candida albicans, Staphylococcus aureus,
and Escherichia coli in vitro. Table 2 shows the results of in
vitro activity determination by a tube dilution method which
Chemistry
The synthetic pathway for preparation of N-substituted-4-
(1H-benzimidazol-2-yl)benzamides 18–25 and 1H-benzimi-
dazole-5(6)-carboxamides 30–33 listed in Table 1 are shown
in Scheme 1 and Scheme 2, respectively. The nucleophilic
substitution of o-chloronitrobenzene derivatives with corre-
sponding amines gave 1–3. Reduction of 1–2 and 3 with H ,
Pd/C, and Zn/HCl produced 4–6 and 10, respectively. Known
[5]
was already reported by us . The HCl salts of the prepared
compounds and others were dissolved in water and DMSO
(12.5 %), at concentrations of 200 µg/ml, respectively. Since
the solutions of 24, 31, and 32 in DMSO (12.5%) were not
2
[2]
clear at these concentrations, a paper disk method was used
[2,3]
compounds 7–9 were prepared as reported in ref.
. The
for them. A paper disk (8 mm in diameter) was soaked in a
2000 µg/ml solution of the test compounds in propylene
glycol and placed on an agar plate containing fungi orbacteria
cells. After incubation, the inhibition zone was measured.
None of them had inhibitory activity. Among the compounds
tested, 22 and 25 showed good activity against C. albicans
with 12.5 µg/ml which was close to fluconazole. This means
that introduction of a chlorine atom or trifluoromethyl group
at C-5, and the p-chlorobenzyl group allowed us to obtain the
reaction of aromatic o-diamines 4–10 with sodium bisulfite
adduct of 4-carboxybenzaldehyde (Scheme 1) and the reac-
tion of 3,4-diaminobenzoic acid derivatives with the sodium
bisulfite adduct of appropriate aldehydes (Scheme 2) gave
1H-benzimidazole-carboxylic acids 11–17 and 27–28, re-
———
Correspondence: Professor Hakan Göker, Ankara University, Faculty of
Pharmacy, Tandogan, 06100 Ankara, Turkey.
E-mail: goker@pharmacy.ankara.edu.tr
Fax: +90 312-213 10 81
desired profile of antifungal activity. These findings are also
[1,6,7]
confirmed by other work
. In addition, compounds 18
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0505/0148 $17.50 +.50/0

Carboxamido-1H-benzimidazole Derivatives
149
Table 1. Physical and spectral data of compounds 18–25 and 30–33.
M.p
(oC)
Yield
(%)
No
R1
R2
R3
R4
NMR
(δ ppm)
Mass
62 eV or 70 eV
(CDCl3) : 0.885(t,3H), 1.26(m,2H),
1.79(m,2H), 2.37(s,6H), 2.65(t,2H),
3.63(q,2H), 4.28(t,2H), 7.1(br s,1H),
7.5(d,1H), 7.58(dd,1H), 7.81(d,2H),
8.03(d,2H), 8.12(s,1H).
(CDCl3) : 1.67(d,6H), 2.31(s,6H),
2.58(t,2H), 3.6(q,2H), 4.82(m,1H),
7.1(t,1H), 7.55(dd,1H), 7.73(dd,3H),
8.02(d,2H), 8.16(s,1H).
432(M+., 0.65), 405(0.35),
363(0.79), 288(3.1), 109(4.5)
71(100).
CH3
105
(bubl)
135–140
18
F3C
(CH )
N
3 2
58.5
65
376(M+1, 2.2 ), 332(2.5),
288(32.5), 244(39), 217
(51.5), 109(58), 71(100)
H3C
CH3
85–90
(bubl)
19
NC
(CH )
N
N
3 2
(DMSO-d6) : 0.72(t,3H), 1.27(t,6H),
1.68(q,2H), 3.21(4H), 3.27(2H), 3.71
(t,2H), 4.38 (t,2H), 7.76(d,1H), 7.94
(d,2H), 8.01(d,1H), 8.16(d,2H), 8.3
(s,1H), 9.2(t,1H)
(CDCl3) : 1.36(t,6H), 3.1(4H), 3.18
(2H), 3.84(2H), 5.4(s,2H), 7.02(d,
2H), 7.17-7.351(m,5H), 7.76(d,2H),
7.86(d,1H), 8.14(d,2H), 8.78(s,1H)
403(M+.), 257(2.82),
244(7.2), 230(7.6), 86(100).
CH3
(C H )
2
5 2
214–216
20
21
NC
H
64
Cl
118
(bubl)
71.5
461(M+.), 345(2.5), 281(1.9),
125(47), 127(15.5), 86(100).
(C H )
N
2
5 2
(DMSO-d6) : 0.88 (t,6H), 2.42-2.506
(m,6H), 3.25(2H), 5.55(s,2H), 6.91(d,
2H), 7.246(m,3H), 7.478(d,1H),
7.72(3H), 7.87(d,2H), 8.42(s,1H).
(DMSO-d6) : 2.835(t,6H), 3.309(2H),
3.696(2H), 3.912(s,3H), 5.74(s,2H),
7.1(d,2H), 7.36(d,2H), 7.79(d,1H)
7.92(d,2H), 8.01(d,1H), 8.17(d,2H),
8.4(s,1H), 9.2(s,1H).
(DMSO-d6) : 3.87(s,3H), 4.59 (d,
J=4.4Hz, 2H), 5.67(s,2H), 7.01
(d,2H), 7.27(t,1H), 7.35(m,3H), 7.66
(d,1H), 7.77(t,1H), 7.85(d,2H),
7.9(d,1H), 8.06(d,2H), 8.342
(s,1H), 8.52(1H), 9.25(t,1H)
(CDCl3) : 2.18(s,6H), 2.45(t,2H),
3.45(q,2H), 5.35(s,2H), 6.9(d,2H),
6.98(br.s,1H), 7.19(d,1H), 7.24(d,
2H), 7.37(d,1H), 7.63(d,2H), 7.83
(d,2H), 8.05(s,1H)
Cl
Cl
495(M+.), 379, 254, 125(21),
127(6.8), 86(100).
140–142
22
23
24
Cl
69.5
80.4
59.5
(C H )
N
2
5 2
232
(bubl)
238–240
H3CO
490(M+.,0.88), 445(1),
447(0.33), 125(6.5),
127(2.5), 71(5.5), 58(100).
(CH )
N
3 2
O
O
510(M+. ,0.8), 376(2.4)
125(100), 127(34.3),
28(100).
Cl
H3CO
161–162
N
N
Cl
65–66
(bubl)
78.5
65.7
71.2
500(M+., 0.15), 414(1.1),
288(3.1), 125(8.96),
127(2.89), 57(100).
(CH )
3 2
25
F3C
(DMSO-d6) : 1.61(m,2H), 1.79(2H),
2.038(t,2H), 2.83(d,2H), 3.46(2H),
3.8(s,4H), 3.88(s,3H), 7.1-8.18(12H,
aromatic protons and NH)
105
(bubl)
470(M+., 0.16), 297(4.6),
205(21.7) , 44(100).
H
N
N
30
31
H
OCH3
OCH3
H
148–150
(DMSO-d6) : 4.47(d,J=5.3Hz,2H),
5.62(s,2H), 6.96(d,2H), 7.14(t,2H),
7.27(m,3H), 7.37(m,2H), 7.58 (m,
3H), 7.75(d,2H), 7.83(dd,1H), 8.3
(s,1H), 9.04(t,1H).
469(M+., 4.04), 471(M+2,
1.43), 345(7.3), 347(2.59),
91(100).
F
F
115–118
(bubl)
H
N
Cl
451(M+., 0.4), 255(3,7),
91(41), 44(100).
(DMSO-d6) : 4.48(2H), 5.2(s,2H),
7.12-8.21(17H, aromatic protons),
9.01(br s, 1H)
H
N
32
33
H
H
O
O
H
H
255–257 63.5
105–109 57.7
456(M+., 13.9), 299(21),
127(18), 16(100).
(DMSO-d6) 3.51-3.78(10H), 3.8(t,
J=4.62Hz,2H), 5.23(s,2H), 7.25-8.24
(12H, aromatic protons)
HO
N
N
R1
N
R2
R3
NHR1
+
NaO3S
R2
HO
HO
NH2
N
OH
O
R3
O
27 - 29
R1 = CH2 Ph 26
R1= H
R1= CH2 Ph R2= Cl
R1= H
R2= OCH3
R3= OCH3 27
R3= H
28
R2= OCH2 Ph R3= H
29
R1
N
R2
a
R4
N
O
R3
30 - 33
Scheme 2. Synthesis of the compounds 30–33. Reagents: (a) 1. SOCl2; 2. Corresponding amines.
Arch. Pharm. Pharm. Med. Chem. 334, 148–152 (2001)

150
Göker, Tunçbilek, Süzen, Kus, and Altanlar
Table 2. The in vitro antibacterial and antifungal activity of 18–25 and 30–33 (MIC, µg/ml)
—————————————————————————————————————————————————————————————–
No
Purification Method
Formulas
Antimicrobial activity
—————————————————————————
C. albicans
S. aureus
E. coli
—————————————————————————————————————————————————————————————–
.
.
18
CHCl3-Isopr-NH3 (100:20:0.5)
CHCl3-Isopr-NH3 (100:20:0.5)
CHCl3-Isopr-NH3 (100:50:1)
CH2Cl2-Isopropanol (10:7)
CHCl3-Isopr-NH3 (200:50:0.5)
CHCl3-Isopr-NH3 (200:60:0.5)
CHCl3-Isopropanol (3:2)
CHCl3-Isopr-NH3 (100:30:1)
CHCl3-Isopr-NH3 (100:50:0.5)
EtOAc- Isopropanol (10:5)
EtOAc
C23H27F3N4O 2.5HCl 0.8H2O
25
100
>100
25
50
>100
>100
50
>100
>100
>100
>100
>100
>100
PDM
>100
>100
PDM
PDM
>100
–
.
C22H25N5O H2O
19
. .
C24H29N5O 2HCl 0.75H2O
20
. .
C27H29ClN4O 3H2O 0.2C3H8O
21
.
22
C27H28Cl2N4O 0.5H2O
12.5
12.5
.
23
C27H27ClN4O3 2HCl . H2O
>100
PDM
50
PDM
25
24
C29H23ClN4O3
.
25
C26H24ClF3N4O 0.3C3H8O
12.5
.
.
30
C28H30N4O3 1.1H2O 0.3C3H8O .
>100
PDM
PDM
>100
25
.
31
C28H21ClFN3O 2H2O
PDM
PDM
>100
–
32
C28H22FN3O2
. .
C27H28N4O3 HCl 2H2O
33
CHCl3-Isopr-NH3 (100:50:1)
Fluconazole
Miconazole
Ampicilline
6.25
3.125
–
–
–
3.125
3.125
—————————————————————————————————————————————————————————————–
PDM: Paper Disk Method (no inhibition zone)
N-(p-Chlorobenzyl)-2-nitro-4-trifluoromethylaniline 3
and 22 exhibited moderate inhibitory activity against C. albi-
cans and S. aureus, respectively. Compounds 30–33 having
Preparation was same as for 1, except for use of p-chlorobenzylamine for
3 h at 90 °C. Mp 77–78 °C, yellow in colour, yield 75.9%, C14H10ClF3N2O2.
the amide function at the C-5 of benzimidazole ring have no
[1,2]
good activity. However in our previous studies
, we
showed potent antimicrobial activity with N,N-dialkylami-
noethyl amide function at the same position (Formula I and
II). All the compounds were inactive against E. coli.
Synthesis of 4–6 and 10
To the appropriate nitro derivatives (1, 2 and 3-nitro-4-propylaminoben-
zonitrile [8], 7.62 mmol) dissolved in EtOH (75 mL) was added 10% Pd/C
(100 mg) and the solution was hydrogenated at room temperature at 40 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 coloured solid. These products were used for the further steps without
crystallisation.
Experimental
Melting points were measured with a capillary melting point apparatus
1
(Buchi SMP and Buchi 9100) and are uncorrected. The H-NMR spectra
were recorded with Bruker GmbH DPX-400 (400 MHz) High Performance
Digital FT-NMR spectrophotometer, δ scale (ppm) from internal standard
tetramethylsilane. Chemical shifts are given as δ values (ppm). All J [Hz]
valueswereseen asexpected, ifnot statedotherwise. Massspectraweretaken
on Micromass UK Platform II LC-Ms spectrometers by using EI (62 or
70 eV). Elemental analyses were taken on a Leco 932 CHNS-O analyzer. All
instrumental analyses were performed by TUBITAK (Instrumental Analysis
Lab., Ankara). Column chromatography was accomplished on silica gel 60
(40–63 µm particle size) (Merck). Compound 26 and 29[1] were prepared
according to the literature method.
N-Butyl-4-trifluoromethyl-2-aminoaniline 4
Mp 42–44 °C, dark brown in colour, yield 90.9%, C11H15F3N2.
3-Amino-4-isopropylaminobenzonitrile 5
Mp 97–98 °C, grey in colour, yield 95%, C10H13N3.
3-Amino-4-propylaminobenzonitril 6
N-Butyl-2-nitro-4-trifluoromethylaniline 1
Mp 115–116 °C, violet in colour, yield 95.6%, C10H13N3.
To a solution of 4-chloro-3-nitrobenzotrifluoride (8.86 mmol, 2 g) in DMF
(3 ml), butylamine (41 mmol, 3 g) was added and heated for 4 h at 80 °C.
The mixture was allowed to cool and water was added. The resultant yellow
precipitated was filtered, washed with water, crystallised from EtOH (70%).
Mp 38 °C, yellow in colour, yield 90.5%, C11H13F3N2O2.
N-(p-Chlorobenzyl)-4-trifluoromethyl-2-aminoaniline 10
The mixture of 3 (0.8 g, 2.42 mmol) in 15 ml HCl (25%) and 10 ml EtOH
was stirred vigorously, and to this mixture zinc dust (2 g, 30.7 mmol) was
added in several portions at room temperature. After the addition of zinc dust
was completed, the mixture was heated on a water bath for a period of 2 h.
The reaction mixture was cooled and made alkaline with 10% NaOH
solution, then extracted with chloroform. The extract was washed with water,
dried over anhydrous Na2SO4 and evaporated. Residue was recrystallised
from EtOH-HOH. Mp 120–121 °C, white in colour, yield 55.5%,
C14H12ClF3N2.
4-(Isopropylamino)-3-nitrobenzonitrile 2
Preparation was exactly similar to that of 1 (Caution: cool the reaction
medium while adding isopropylamine), except that 4-chloro-3-nitrobenzoni-
trile and isopropylamine for 1 h at 35 °C. Mp 110–113 °C , yellow in colour,
yield 94%, C10H11N3O2.
Arch. Pharm. Pharm. Med. Chem. 334, 148–152 (2001)

Carboxamido-1H-benzimidazole Derivatives
151
Table 3 Physical and spectral data of compounds 11–17 and 27,28.
—————————————————————————————————————————————————————————————–
No
Formula
Mp
Yield NMR
(%) (δ ppm) (DMSO-d6)
Mass
EI (M+., %)
Purification
Method
(°C)
—————————————————————————————————————————————————————————————–
11
C19H17F3N2O2
253–255
76.5
0.73 (t,3H), 1.13 (m,2H),
1.64 (m,2H), 4.4 (t,2H),
7.65 (dd,1H), 7.93 (d,3H)
8.08 (s,1H), 8.15 (d,2H)
362(M+. , 15)
276(6.56), 109
(27.2), 41(100)
Crystallization
EtOH-H2O
12
13
C18H15N3O2
>290
87
84
1.6 (d,7Hz,6H), 4.71
(m, 1H), 7.65–8.25 (7H,
aromatic protons).
305(M+. , 6.56)
109 (27.2),
43(100)
Crystallization
EtOH–H2O
C18H15N3O2
263–264
0.73 (t,3H), 1.67 (m,2H),
4.36 (t,2H), 7.73 (dd,1H),
7.94 (d,3H), 8.15 (d,2H),
8.27 (s,1H).
305(M+. , 25.29)
233(19.2), 109
(30.2), 41(100)
Crystallization
EtOH-H2O
14
15
C21H15ClN2O2
234–235
64
73
5.62 (s,2H), 6.987–
8.064 (12H,aromatic
protons)
362 (M+., 2.02)
364 (M+2, 0.8)
237(9), 125(100),
127(35)
Crystallization
EtOH-H2O
C21H14Cl2N2O2 262
5.63 (s,2H), 6.97–8.062
(11H,aromatic protons)
396(M+., 14.51)
398(M+2, 12)
Crystallization
EtOH
400(M+4, 3.55)
125(100), 127(36)
16
17
C23H17ClN2O4
>290
74
69
3.874 (s,3H), 5.66 (s, 2H),
6.98–8.34 (11H,
420(M+., 10.1)
422(M+2, 3.6)
125(100), 127(32)
Crystallization
EtOH-H2O
aromatic protons)
C22H14ClF3N2O2 226–227
5.35 (s,2H), 6.83 (d,2H)
7.13 (d,2H), 7.25 (d,1H)
7.32 (dd,1H), 7.57 (d,
430(M+., 8.2)
432(M+2, 3)
125(100),
Crystallization
EtOH-H2O
2H), 7.89 (s,1H), 7.97 (d,2H)
127(27.3)
27
28
C16H14N2O4
200
(bubl)
55
78
3.83 (s,3H), 3.87 (s,3H)
7.11–8.15 (6H, aromatic
protons)
298(M+., 6.08)
43(100).
Column
chroma.
CH2Cl2:Isopropanol:CH3COOH
(50:5:0.1)
C21H15ClN2O2 249–250
5.64(s,2H), 6.99(d,2H),
7.27(m,3H), 7.61(m,3H),
7.78(m,2H), 7.88(dd,
1H), 8.31(d,1H)
361(M+., 0.12)
363(M+2, 0.06)
91(100)
Crystallization
EtOH-H2O
—————————————————————————————————————————————————————————————–
Synthesis of 11–17 and 27–29
Synthesis of 18–25 and 30–33
4-Carboxybenzaldehyde (for 11–17) or appropriate benzaldehydes (for
27–28) (15 mmol) were dissolved in 50 ml EtOH. Sodium bisulfite (1.6 g)
in water 10 ml was added to a cooled solution in portions, stirred vigorously
and added EtOH, cooled. The precipitate was filtered off and dried (yield
85–91%). The mixture of this salt (2 mmol) and appropriate 1,2-phenyl-
enediamines (4–10, 3,4-diaminobenzoic acid, and 26, 2 mmol) in DMF
(5 ml) were heated at 140 °C for 4 h. The reaction mixture was cooled,
poured into the water, and solid was filtered. Purification procedure and some
spectral findings of 11–17, 27–28 are given in Table 3.
Related benzimidazolecarboxylic acids 11–17, 27–29 (1.5 mmol) were
refluxed in benzene (5 ml) with SOCl2 (5 ml) for 2 h at 80 °C. Then solvent
and excess of SOCl2 were evaporated completely and the residue was
dissolved in chloroform (15 ml). Excess corresponding amine derivatives
(1 ml) was added and mixture was stirred and heated for 30 min at 50 °C.
Chloroform was added and washed with Na2CO3 (5%), then water, and
purified by column chromatography. Some physicochemical properties,
spectral findings, and purification methods, elemental analysis of 18–25,
30–33 are given in Table 1 and Table 2, respectively.
Arch. Pharm. Pharm. Med. Chem. 334, 148–152 (2001)

152
Göker, Tunçbilek, Süzen, Kus, and Altanlar
[5] G.A. Kilcigil, M. Tunçbilek, N. Altanlar, H. Göker, Farmaco 1999, 54,
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Arch. Pharm. Pharm. Med. Chem. 334, 148–152 (2001)