Synthesis and antimicrobial activities of 5-fluoro-1,2,6-trisubstituted benzimidazole carboxamide and acetamide derivatives

Article abstract of DOI:10.1002/1521-4184(200112)334:11<361::AID-ARDP361>3.0.CO;2-9

Some 5-fluoro-6-substitute-1 H-benzimidazole-2-carbamates (12a-e), 5-fluoro-6-substituted 1H-benzimidazole-2-acetate (13a-e) and 2-acetamide (14a-f) derivatives, 2-acetamido-5-fluoro-6-(morpholin-4-yl)-1-propyl-1H-benzimidazole (15), and 1-cyclopropyl-2-e

Full text of DOI:10.1002/1521-4184(200112)334:11<361::AID-ARDP361>3.0.CO;2-9

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 361–365
Canan Kusa), Hakan Gökera),
Benzimidazole carboxamides 361
Nurten Altanlarb)
Synthesis and antimicrobial activities of
5-fluoro-1,2,6-trisubstituted benzimidazole
carboxamide and acetamide derivatives
a) Department of Pharmaceutical
Chemistry, Faculty of Pharmacy,
Ankara University, 06100-Tandogan,
Ankara, Turkey
Some 5-fluoro-6-substitute-1H-benzimidazole-2-carbamates (12a–e), 5-fluoro-6-substi-
tuted 1H-benzimidazole-2-acetate (13a–e) and 2-acetamide (14a–f) derivatives, 2-
acetamido-5-fluoro-6-(morpholin-4-yl)-1-propyl-1H-benzimidazole (15), and 1-cyclo-
propyl-2-ethyl-5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazole (16) were synthe-
sized, and their antimicrobial and antifungal activities evaluated. Compound 12c exhib-
ited the best activity against Candida albicans.
b) Department of Microbiology,
Faculty of Pharmacy,
Ankara University, 06100-Tandogan,
Ankara, Turkey
Key Words: Benzimidazole carbamates; Benzimidazole acetates; Benzimidazole
acetamides; 1H-benzimidazole derivatives; Antifungal and antibacterial activity
Received: May 21, 2001 [FP585]
similar manner. Substitution of 9a–c with appropriate
Introduction
piperazine, piperidine derivatives, or morpholine gave o-ni-
The benzimidazole carbamates, an important group of
anthelmintic agents, act by blocking polymerization of mi-
crotubules in susceptible organisms and these compounds
were found to inhibit Pneumocystis carinii in in vitro and in
vivo culture systems[1,2]. Anthelmintic benzimidazoleswere
also examined against Giardia lamblia[3], Cryptococcus
neoformans[4], and Trichomonas vaginalis[5] and they are
approved as useful for the treatment of these infections.
Albendazole was found to be useful for treating systemic
infections and it was established that albendazole is highly
effective a therapeutic agent in the treatment of cysticer-
cosis[6] and echinococcosis[7].
troanilines (10a–g), and their reduction afforded o-phenyl-
enediamine derivatives (11a–g). Because of the instability
of 11a–g, these compounds were used for the next step
without purification, except 11c[11] (Scheme 1).
The benzimidazole carbamate derivatives (12a–e) were
prepared by direct condensation of the corresponding 4,5-
disubstituted-o-phenylenediamines (11c–e) with 1,3-dicar-
balkoxy-S-methyl-isothiourea[14–16]. The reaction of 11a–c,
11f–g with ethyl β-amino-β-ethoxyacrylate hydrochlo-
ride[17] gave the desired ester derivatives of benzimida-
zoles 13a–e. Amidification of these esters with several
N,N-dialkylaminoethyl or propylamine derivatives gave the
acetamidobenzimidazoles 14a–f. The reaction of ester 13e
with ammonia gave 15 (Scheme 1).
Many derivatives of benzimidazole are well known as anti-
microbial[8,9] and antifungal[10] agents and show a wide
variety of biological activity as well as anthelmintic potency.
The synthesis of the compounds having both fluorine and
piperazine substituents at 5- and 6-positions have been
reported[11] because of the influence on antibacterial activ-
ity of these groups for the second generation fluoroquinol-
ones. In order to obtain more potent compounds, these
observations prompted us to synthesis some new benzim-
idazole carbamate, benzimidazole acetate and acetamide
derivatives having 5-fluoro and 6-substitute piperazine,
piperidine or morpholine and evaluate their antimicrobial
and antifungal activities against Bacillus subtilis, Staphylo-
coccus aureus, Escherichia coli, and Candida albicans.
Catalytic hydrogenation of 13a, in the presence of palla-
dium on charcoal (Pd/C) in DMF gave 16 (Scheme 1).
Conformational analysis of 16 was performed with its X-ray
crystallography data[18]. Structures and formulas, purifica-
tion procedures, physical, and spectral data of the targeted
compounds are shown in Table 1 and Table 2, respectively.
Compounds 12a–e, 13b–e, 14a–f, 15, and 16 were evalu-
ated for their in vitro antimicrobial and antifungal activity
against B. subtilis, S. aureus, E. coli, and C. albicans by the
agar diffusion method which was already reported by us[19]
using a 2000 µg/ml solution in propylene glycol (Table 1).
All the compounds showed the growth inhibition zone
against C. albicans. Among them, methyl 5-fluoro-6-(4-me-
thylpiperidin-1-yl)-1H-benzimidazole-2-carbamate (12c)
exhibited the best antifungal activity with 15 mm inhibition
zone diameter, which was less than those of fluconazole
and ketoconazole. In addition compounds 13b–e, 14a–f
also exhibited moderate activity against B. subtilis. An-
thelmintic activities of the synthesized compounds are be-
ing investigated and the results will be published later.
Results and discussion
Synthesis of the compounds 9a[12], 9b[13] has previously
been reported, and the compound 9c was prepared in a
———
Correspondence: Prof. H. Göker, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Ankara University, 06100-Tan-
dogan, Ankara, Turkey.
E-mail: goker@pharmacy.ankara.edu.tr
Fax: +90 312 213 1081
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/1111/0361 $17.50 +.50/0

362 Benzimidazole carboxamides
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 361–365
Table 1. Structure, antibacterial and antifungal activitya of 12a–e, 13b–e, 14a–f, 15, and 16.
————————————————————————————————————————————————————————————–
Comp
R
R1
R2
n
b
c
d
e
B.s.
S.a.
E.c.
C.a.
————————————————————————————————————————————————————————————–
12a
12b
12c
12d
12e
13b
13c
13d
13e
14a
14b
14c
14d
14e
14f
15
N-Methylpiperazine
N-Methylpiperazine
4–Methylpiperidine
4-Methylpiperidine
N-Phenylpiperazine
3-Methylpiperidine
N-Methylpiperazine
3-Methylpiperidine
Morpholine
Methyl
Ethyl
*
*
*
11
11
15
13
9
*
*
*
Methyl
Ethyl
*
*
*
*
*
*
Ethyl
*
*
*
Cyclopropyl
H
12
9
9
*
10
*
12
11
11
11
12
10
13
10
10
11
12
11
18
24
*
H
11
11
9
*
8
9
*
n-propyl
H
*
N-Methylpiperazine
N-Methylpiperazine
3-Methylpiperidine
3-Methylpiperidine
N-Methylpiperazine
N-Methylpiperazine
Ethyl
2
2
2
2
2
3
9
*
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Methyl
Methyl
Ethyl
10
8
*
9
*
*
11
10
7
*
Ethyl
*
*
Methyl
*
*
NT
NT
*
NT
NT
*
NT
NT
*
16
F
K
*
*
*
A
13
15
11
————————————————————————————————————————————————————————————
a Growth-inhibition zone diameter (mm); b Bacillus subtilis; c Staphylococcus aureus; d Escherichia coli; e Candida albicans; *No activity;
NT: not tested; F: fluconazole; K: ketoconazole; A: ampicilline.
Synthesis of 10a–g
Experimental
Silica gel plates (Merck F254) and silica gel 60 (Merck; 230–400
mesh ATSM) were used for analytical and column chromatog-
raphy, respectively. Melting points (uncorrected) were deter-
A solution of 9a–c (2.5 mmol) in a mixture of triethylamine
(0.5 ml) and appropriate piperazine, piperidine derivatives, or
morpholine (5 mmol) was stirred at 60 °C overnight. The result-
ing suspension was partitioned between water and EtOAc (1:2).
The organic layer was subsequently washed with water, then
dried over anhydrous Na2SO4 and evaporated (Table 2).
mined with
a Büchi SMP-20 melting point apparatus.
Microanalyses were performed on a Leco CHNS 932 analyzer
and satisfactory results within ±0.4% of calculated values
(C,H,N) were obtained. All the instrumental analyses were
performed by Tubitak (Instrumental Analysis Lab., Ankara) with
a Bruker AC400NMR spectrophotometer and VG Platform II
mass spectrometer. The HCl salts of the acetamide derivatives
were prepared by using ethanolic HCl. 2,5-difluoroacetanilide
(2)[20], 2,5-difluoro-4-nitroacetanilide (3)[21], 2,5-difluoro-4-ni-
troaniline (4)[21], 2,5-difluoro-4-chloronitrobenzene (5)[21], N-(3-
Synthesis of substituted o-phenylenediamines 11a–g
A solution of 10a–g (1.98 mmol) in concentrated hydrochloric
acid (10 ml) was treated portionwise with SnCl2 (11.85 mmol)
and the resulting solution was stirred at room temperature for
30 min. The reaction mixture was poured into ice-water and
neutralized with 10% NaOH solution, extracted with EtOAc,
washed with water, dried over anhydrous Na2SO4, and evapo-
rated and used for the next step without further purification
because of their instablity, except 11c[11] (Table 2).
chloro-4-fluorophenyl)acetamide (7)[12]
,
and N-(5-chloro-
4-fluoro-2-nitrophenyl)acetamide (8)[12] were synthesized ac-
cording to the methods given in the literature.
5-Chloro-4-fluoro-2-nitro-N-propylaniline 9c
A solution of 5 (0.5 g, 2.58 mmol) in a mixture of triethylamine
(5 ml) and n-propylamine (0.23 g, 3.9 mmol) was stirred overnight
at room temperature. The reaction mixture was diluted with EtOAc
and extracted with water. The organic layer was dried over anhy-
drous Na2SO4 and evaporated. The residue was crystallized from
EtOH, affording 0.5 g (83%) of 9c. Mp 86–88 °C. NMR (CDCl3) δ
1.08 (t,3H), 1.8 (m,2H), 3.25 (q,2H), 6.9 (d,1H, Jm = 6 Hz) , 7.9(br.s,
1H), 8.0 (d,1H, Jo = 9 Hz), 8.2 (br.s,1H). Anal. (C9H10ClFN2O2)
C,H,N.
Synthesis of 1H-benzimidazole-2-carbamate derivatives
12a–e
Appropriate 1,3-dicarbalkoxy-S-methylisothiourea (2 mmol) was
added to a solution of 11c–e (1 mmol) in ethanol (15 ml) and
refluxed for 8 h under a nitrogen atmosphere.The reaction mixture
was cooled and the separated solid was filtered off (Table 2).

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 361–365
Benzimidazole carboxamides 363
Scheme 1. Synthesis of the target compounds. a: Acetic anhydride/pyridine, b: conc.H2SO4/conc.HNO3, c: H2SO4/H2O, d: NaNO2/HCl,
CuCl, e: cyclopropylamine, n-propylamine/triethylamine, f: appropriate piperazines, piperidines or morpholine, g: SnCl2/HCl or H2.Pd/C,
DMF, h: 1,3-dicarbalkoxy-S-methylisothiourea/EtOH, i: ethyl β-amino-β-ethoxyacrylate hydrochloride/DMF, j: appropriate ethylenediamines,
k: NH4OH m: H2.Pd/C, DMF.
(2 mmol) was stirred and heated at 100 °C for 7 h. The reaction
mixture was dissolved in EtOAc and extracted with water.The
organic layer was dried and evaporated (Table 2).
Synthesis of ethyl 1H-benzimidazole-2-acetate derivatives
13a–e
A solution of 10a–c, 10f–g (1 mmol) in 0.5 ml DMF was hydro-
genated over 10% Pd/C at 50 °C for 4 h. At the end of the
reduction, the catalyst was filtered through a bed of Celite and
the filtrate was evaporated. The unstable residue was dissolved
in DMF (0.5 ml) and reacted with ethyl β-amino-β-ethoxyacryl-
ate hydrochloride (2 mmol). The reaction mixture was stirred at
50 °C for 3 h under nitrogen atmosphere. Water was sub-
sequently added and the mixture extracted with EtOAc. The
organic layer was washed with water and dried over anhydrous
Na2SO4 and evaporated (Table 2).
2-Acetamido-5-fluoro-6-(morpholin-4-yl)-1-propyl-
1H-benzimidazole 15
A solution of 13e (0.3 g, 0.86 mmol) and NH4Cl (0.46 g, 8.6
mmol) in EtOH (10 ml) was saturated with NH3 for 1 h. The
resulting suspension was stirred at room temperature for 24 h,
then concentrated NH4OH (10 ml, 50%) was added, and the
suspension was further stirred at 50 °C for 24 h. The solvents
were evaporated under reduced pressure. The residue was
taken up in EtOAc and washed with 10% aqueous NaCl solu-
tion. The organic layer was dried, evaporated, and chroma-
tographed (10% MeOH/ EtOAc) affording 0.17g (62 %) of 15
after crystallization from EtOAc/n-hexane. Mp 185–187 °C.
NMR (DMSO-d6) δ 0.9 (t,3H), 1.69–1.75 (m,2H), 3.0 (4H),
3.73 (6H), 4.25 (t,2H), 7.16 (d, 1H, Jm = 7.7 Hz), 7.32 (d, 1H,
Synthesis of 1H-benzimidazole-2-acetamide derivatives
14a–f
A mixture of related ethyl 1H-benzimidazole-2-acetates 13a–d
(1 mmol) and appropriate ethylene or propylenediamines

364 Benzimidazole carboxamides
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 361–365
Table 2. Formulas, purification procedures, physical and spectral data of compounds 10a–g, 11c, 12a–e, 13a–e, and 14a–f.
Comp. Formula
Purification procedure
Yield
(%)
Mp
°C
NMR
Mass
(70 eV)
(δ ppm)
a
10a
131
.
+.
10b
C
H
FN O
3
CHCl : n-Hexane (1 : 2)
3
(flash chrom.) then
recrystallization (ethanol)
59
80-82
(CDCl ) 0.65(m,2H), 0.9(m,2H), 1.05 (d,3H),
3
1.15(m,1H), 1.8(m,4H), 2.6 (t,2H), 2.9(m,1H),
294(M+1, 10), 293( M , 2),
247(35), 148(9), 69(12),
55(100).
15 20
0.3 H O
2
2
3.7(t,2H), 6.5(d,1H, J = 8 Hz),
m
7.8(d,1H,J =14 Hz), 8.3(br.,s.1H).
o
b
10c
10d
150-151
119-121
.
.
.
+.
C
H
FN O
3
CHCl : n-Hexane (1 : 2)
3
(flash chrom.) then
recrystallization (ethanol)
CHCl : n-Hexane (1 : 2)
3
(flash chrom.) then
recrystallization (ethanol)
CHCl : n-Hexane (1 : 2)
3
(flash chrom.) then
61
58
63
32
(CDCl ) 1.0(d,3H),1.35(m,1H),1.6-1.8 (m,4H),
3
253(M , 18), 109(16),
12 16
0.3 H O
2
2
2
3
2.8(m,2H), 3.7(m,2H), 6.0(3H),
69(13), 55(58), 41(100).
2
7.8(d,1H,J =14 Hz).
o
+.
10e
10f
C
H
FN O
4
173-175
117-119
185
(CDCl ) 3.3(4H), 3.4(4H), 6.2(3H), 6.9-
316(M ,23), 183(12),
3
16 17
2.5 H O
7.3(5H), 7.9(d,1H,J =14Hz)
132(47), 105(100), 91(28),
77(73), 51(25).
o
2
+.
C
H
FN O
3
(CDCl ) 0.9(d,3H), 1.1(m,1H), 1.9(4H),
3
2.4(t,1H), 2.8(t,1H), 3.5-3.7(m,2H), 6.0(3H),
253(M , 58), 252(27),
12 16
0.5 H O
109(33), 83(48), 69(31),
55(100 ).
283(M ,68), 254(43.7), 236
(43), 196(46), 83(60),
43(100).
2
recrystallization (ethanol)
Recrystallization (ethanol)
7.7(d,1H,J = 14 Hz).
o
+.
10g
C
C
H
FN O
3
(CDCl ) 1.1(t,3H), 1.7-1.8(m,2H), 3.2 (q,2H),
3
13 18
3.3(t,4H), 3.9(t,4H), 6.0(d,1H, J =8Hz), 7.8
m
(d,1H,J =14Hz), 8.3(br.s.1H).
o
c
11c
12a
94-95
.
.
+.
H
FN O
5
5
Recrystallization (ethanol)
Recrystallization (ethanol)
60
58
(DMSO-d - CDCl ) 2.4(s,3H), 2.6(4H),
307(M ,7), 236(10), 204(18),
191(3), 177(9), 150 (5), 97(6),
83(60), 71(100 ).
322(M+1, 18), 250(14),
204(8), 178(35), 150(15),
123(12), 97(10), 85(15),
71(100 ).
6
3
14 18
2
2
>280
0.25 C H OH
3.0(4H), 3.9(s,3H), 7.1(d,1H,J =7.8Hz),
m
2
7.2(d,1H,J = 12.5 Hz), 11(br.s, 1H).
o
12b
C
H
FN O
5
5
(DMSO-d ) 1.3(t,3H), 2.3(s,3H), 2.5 (4H),
6
15 20
>280
0.25 C H OH
3.3(4H), 4.25(q,2H), 7.0 (d,1H,J =7.9Hz),
m
2
7.2(d,1H,J =12.5Hz), 11.3(br.s, 1H ).
o
.
.
.
12c
12d
12e
C
H
FN O
4
5
Recrystallization (ethanol)
Recrystallization (ethanol)
Recrystallization (ethanol)
53
44
42
(DMSO-d - CDCl ) 1.0(d,3H), 1.4-3.4 (9H),
3.9(s,3H), 6.9(d,1H,J =7.6 Hz), 7.1(d,1H,
m
307 (M+1, 23), 274(12),
204(16), 177(14), 150(8), 122
(7), 85(15), 83(24), 59(100).
321(M+1,100), 319(43),
273(31), 247(40), 203(11),
177(21), 150(9), 83(10).
384(M+1,2), 204(3), 177(11),
132(14), 105(100), 91(22),
77(56), 63(13), 51(15),
45(54).
6
3
15 19
2
2
2
>280
>280
>280
0.25 C H OH
2
J = 12 Hz), 11.5(br.s, 1H).
o
C
H
FN O
4
5
(DMSO-d - CDCl ) 0.9(d,3H), 1.5(3H), 1.8-
6 3
3.4(9H), 4.4(q, 2H), 7.1(d, 1H, J =7.9 Hz),
m
16 21
0.25 C H OH
2
7.3(d,1H,J =12.4 Hz), 11.4 (br.s 1H).
o
C
H
FN O
5
(DMSO-d - CDCl ) 1.3(t,3H), 2.5(4H),
6 3
3.1(4H), 4.25(q,2H), 6.7-7.3(7H), 11.3(br.s
1H).
20 22
0.5 H O
2
d
13a
13b**
142-144
*
+.
C
C
H
FN O
3
CHCl : n-Hexane (1 : 2)
3
(flash chrom.)
58
53
359(M , 100), 286(21),
20 26
2
2
216(9), 187(11), 119(6),
69(9), 55(29), 41(58).
321(M+1, 14), 249(5),
176(11), 149(3), 121(3),
85(5), 71(64), 56(12),
43(100).
13c**
H
FN O
4
CHCl : n-Hexane (1 : 2)
3
*
16 21
(flash chrom.)
+.
13d**
13e
C
C
H
FN O
3
CHCl : isopropanol (10 : 2)
3
(flash chrom.)
44
32
*
319(M ,100), 246(37),
17 22
2
3
176(68), 148(52), 121(25),
69(47).
+.
H
FN O
3
EtOAc : n-Hexane (1 : 1)
(flash chrom.)
116-118
(CDCl ) 1.0(t,3H), 1.3(t,3H), 1.8-1.9(m, 2H),
3
3.1(t,4H), 3.9(t,4H), 4.0(s,2H), 4.1 (t,2H),
349(M ,100), 291(21),
18 24
276(27), 218(18), 105(24),
83(54), 43(97).
4.2(q,2H), 6.8(d,1H,J =8 Hz),
m
7.4 (d,1H,J = 12 Hz).
(D O) 1.3-1.4(t,6H), 3.1(s,3H), 3.3-3.8 (18H), 390(M ,2), 159(5), 130(14),
o
FN O .
3
3
2
CHCl : isopropanol (2 : 1)
3
then recrystallization
(ethanolic HCl)
CHCl : isopropanol (2 : 1)
3
then recrystallization
(ethanolic HCl)
21
21
25
*
*
*
+.
14a
14b
14c
C
H
2
20 31
6
HCl . 2.3 H O
7.5(d,1H,J =8 Hz), 7.6 (d,1H,
122(57), 104(100), 86(67),
m
2
J = 11.2 Hz).
76(61).
+.
(D O) 1.2-1.3(2H), 1.4-1.5(2H), 3.0-3.8(24H), 402(M ,23), 344(8), 331(14),
2
o
C
H
FN O .
21 31
6
2
HCl . 2.8 H O
7.6(d,1H,J =7Hz), 7.7(d,1H,J =11Hz).
314(20), 287(15), 216(8),
98(12), 70(100).
402 (M+1, 3), 331(3), 314(4),
288(3), 189(2), 71(3),
58(100).
m
o
C
H
FN O .
22 32
CHCl : isopropanol : NH
(D O) 1.0(d,3H), 1.2(2H), 1.4(2H), 1.9-2.3
2
(5H), 2.9-3.9 (17H), 7.8 (d,1H, J =11 Hz), 8.0
o
3
3
5
HCl . 5H O
(20 : 5 : 0.1) then
recrystallization
(ethanolic HCl)
CHCl : isopropanol (2 : 1)
3
then recrystallization
(ethanolic HCl)
CHCl : isopropanol (3 : 2)
3
then recrystallization
(ethanolic HCl)
2
(d,1H,J = 6.4 Hz).
m
14d***
14e
C
HCl
H
FN O .
5
24
13
65
*
*
*
(D O) 1.1(d,3H), 1.2(2H), 1.3-1.4(8H), 2.0-
2
2.2(5H), 3.3-4.0(15H), 7.8(d,1H, J =11.3 Hz),
o
8.0 (d,1H,J =6.5 Hz), 8.2 (s,1H).
m
(D O) 1.1(2H), 1.1-1.3(8H), 2.4-3.5(20H),
2
3.9(s,2H), 7.1(d,1H,J =7.7 Hz), 7.4(d,1H,J
m
=12.5 Hz).
(DMSO-d ) 1.1(2H), 1.3(2H), 1.9(2H),
6
430(M+1, 1), 331(2),
113(1.5), 99(4), 86(100),
58(17).
24 36
+.
C
H
FN O .
6
2
2
430(M ,3), 331(6), 314(3),
23 35
HCl . 2 H O
86(100), 70(11), 58(19).
o
FN O .
22 33
CHCl : isopropanol : NH
416 (M , 38), 314(30),
+.
14f
C
H
3
3
6
1.6 H O
(2 : 1 : 0.1)
2.5-3.6(22H), 4.1(s,2H), 7.4(d,1H,
287(3), 83(7), 70(24),
58(100).
2
J
=7.4 Hz), 7.7(d,1H,J = 11.6Hz).
m o
a)
[13]
b)
: 130 °C , Ref
[12]
c)
: 152-153 °C , Ref
[11]
d) [13]
: 96-97 °C , Ref : 143-145 °C , * : Hygroscopic and with no sharp mp, ** : Since these intermediates
Ref
are gummy solids no attempt was made to perform elemental and NMR analysis, ***: It is very hygroscopic and does not give satisfactory elemental analysis results.

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 361–365
Benzimidazole carboxamides 365
Jo = 12.8 Hz). MS: m/z 320 (M+.,10), 276 (4), 235 (4), 176 (4),
44 (100 ). Anal. (C16H21FN4O2) C,H,N.
[7] D. H. Taylor, K. S. Richards, and D. L. Morris. J. Helminthol.
1989, 63, 349–352.
[8] R. A. Coburn, M. T. Clark, R. T. Evans, R. J. Genco,
1-Cyclopropyl-2-ethyl-5-fluoro-6-(4-methylpiperazin-1-yl)-
1H-benzimidazole 16
J. Med. Chem. 1987, 30, 205–208.
[9] E. A. M. Badawey, Y. M. Gohar, Farmaco 1992, 47, 489–496.
A suspension of 13a (0.3 g, 0.8 mmol) in DMF (0.5 ml) was
hydrogenated over 10% Pd/C. After dilution with EtOAc and
filtration, the solution was extracted with water and the organic
layer dried and evaporated. The residue was purified by column
chromatography (CHCl3) and recrystallized from isopropanol,
yielding 0.16 g (66%) of 16, mp 172–174 °C. NMR (DMSO-d6)
δ 0.9 (2H), 1.2 (2H), 1.3–1.4 (t, 3H), 2.2 (s, 3H), 2.5 (4H), 2.9–
3.0 (q, 2H), 3.3 (4H), 7.1 (d, 1H, Jm = 7.8 Hz), 7.3 (d, 1H,
Jo = 12.8 Hz). MS: m/z 302 (63.97), 287 (7.26), 232 (14.15),
217 (18.01), 203 (25.37), 189 (5.38), 175 (8.55), 148 (4.92),
121 (5.19), 108 (2.42), 101 (2.99), 98 (2.72), 71 (100). Anal.
(C17H23FN4) C,H,N.
[10] L. Garuti, G. Giovanninetti, A. Ferranti, A. Chiarini, G. Bertoc-
chi, P. Sabatino, P. Brigidi. Pharmazie 1987, 42, 378–381.
[11] M. M. El-Abadelah, S. S. Sabri, M. H. Abu Zarga, R. J.
Abdel-Jalil. Heterocycles 1995, 41, 2713–2728.
[12] M. M. El-Abadelah, M. Z. Nazer, N. S. El-Abadla, H. Meier,
Heterocycles 1995, 41, 2203–2219.
[13] C. Hubschwerlen, P. Pflieger, J.-L. Specklin, K. Gubernator,
H. Gmünder, P. Angehrn, I. Kompis, J. Med. Chem. 1992, 35,
1385–1392.
[14] H. L. Klopping. U.S. 1960, 2,933,504, April 19. Chem. Abstr.
1961, 55, 9431e.
References
[1] M. S. Bartlett, T. D. Edlind, M. M. Durkin, M. M. Shaw, S. F.
Queener, J. W. Smith, Antimicrobial Agents Chemotherapy
1992, 36, 779–782.
[15] H. L. Klopping. U.S. 1960, 2,933,502, April 19; Chem. Abstr.
1961, 55, 3617f.
[16] R. Dubey, S. Abuzar, S. Sharma, R. K. Chatterjee, J. C.
[2] M. S. Bartlett, T. D. Edlind, C. H. Lee, R. Dean, S. F. Queener,
M. M. Shaw, J. W. Smith, Antimicrobial Agents Chemother-
apy 1994, 38, 1834–1837.
Katiyar, J. Med. Chem. 1985, 28, 1748–1750.
[17] S. A. Glickman, A. C. Cope, J. Am. Chem. Soc. 1945, 67 ,
1017–1020.
[3] T. D. Edlind, Tu L. Hang, and P. R. Chakraborty, J. Infectious
Diseases 1990, 162, 1408–1411.
[18] S. Özbey, C. Kus, H. Göker, Anal. Sci. 2001, 17, 1019–1020.
[4] M. C. Cruz, M. S. Bartlett, T. D. Edlind, Antimicrobial Agents
[19] H. Göker, M. Tunçbilek, G. Ayhan, N. Altanlar, Farmaco 1998,
Chemotherapy 1994, 38, 378–380.
53, 415–420.
[5] S. K. Katiyar, V. R. Gordon, G. L. Mclaughlin, T. D. Edlind,
[20] F. Swarts, Bull. Classe Sci. Acad. Roy. Belg. 1913, 241–278.
Antimicrobial Agents Chemotherapy 1994, 38, 2086–2090.
[6] D. K. Schmidt, H. F. Jordaan, J. W. Schneider, J. Cilliers,
[21] G. C. Finger, R. E. Oesterling, J. Am. Chem. Soc. 1956, 78,
Int. J. Dermatol. 1995, 34, 574–579.
2593–2596.