Synthesis and antimicrobial activities of novel 8-(1-alkyl//alkylsulphonyl/ alkoxycarbonyl-benzimidazol-2-ylmethoxy)-5-chloroquinolines

Article abstract of DOI:10.2298/JSC100817105C

The synthesis of a series of novel 8-(1-alkyl/alkylsulphonyl/ alkoxycarbonyl-benzimidazol-2-ylmethoxy)-5-chloroquinoline derivatives is reported. These derivatives were prepared by the condensation of o-phenylenediamine with [(5-chloroquinolin-8-yl)oxy]ac

Full text of DOI:10.2298/JSC100817105C

J. Serb. Chem. Soc. 76 (9) 1199–1206 (2011)
JSCS–4196
UDC 547.7+547.53–327+547.831+
542.913:615.28–188
Original scientific paper
Synthesis and antimicrobial activities of novel 8-(1-alkyl/
/alkylsulphonyl/alkoxycarbonyl-benzimidazol-2-
-ylmethoxy)-5-chloroquinolines
*
RAJU B. CHAUDHARI and SAHEBRAO S. RINDHE
PG Department of Chemistry; New Arts, Commerce and Science College,
Ahmednagar-414003, Maharashtra, India
(Received 8 July 2010, revised 7 January 2011)
Abstract: The synthesis of
a series of novel 8-(1-alkyl/alkylsulphonyl/al-
koxycarbonyl-benzimidazol-2-ylmethoxy)-5-chloroquinoline derivatives is re-
ported. These derivatives were prepared by the condensation of o-phenylene-
diamine with [(5-chloroquinolin-8-yl)oxy]acetic acid, followed by substitution at
nitrogen with different electrophilic reagents in presence of an appropriate base to
give a series of nitrogen heterocycles containing the benzimidazole and quinoline
1
nuclei. The structures of the compounds were confirmed based on H-NMR, 13C-
-NMR, IR and mass spectral data. Almost all the compounds exhibited promising
antibacterial activity against Salmonella typhimurium and Staphylococcus aureus.
Some of the compounds showed good antifungal activities against Aspergillus niger
but the antifungal activities against Candida albicans were disappointing.
Keywords: heterocyclic; benzimidazole; quinoline; antibacterial; antifungal.
INTRODUCTION
Heterocyclic compounds containing the benzimidazole nucleus are well re-
1–6
cognized for their different therapeutic activities.
Some of the important ex-
7
8
amples are lansoprazole (anti-ulcer), carbendazim (fungicide), thiabendazole (ant-
helmintic and fungicide), benperidol (antipsychotic), oxatomide (anti-allergic
and anti-asthmatic), etc. Similarly, compounds containing the quinoline nuc-
leus are also known for different therapeutic activities,
(antimalarial), chlorquinaldol (antibacterial and antifungal), etc. (Fig. 1).
Thus, substituted benzimidazoles and quinolines both have potential biolo-
gical activities. Hence, molecules containing both benzimidazole and quinoline
as building blocks of their chemical structure have increased probability of pos-
sessing still better biological activities. In an attempt to extend the study of this
9
10
11,12
such as chloroquine
13
14
*Corresponding author. E-mail: rajuc11@gmail.com
doi: 10.2298/JSC100817105C
1199
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1200
CHAUDHARI and RINDHE
class of heterocyclic compounds, a series of novel benzimidazole–quinoline com-
pounds was synthesized. All the compounds were characterized with modern
spectroscopic techniques. These compounds were subjected to biological screen-
ing, i.e., antibacterial and antifungal activity against standard bacterial and fungal
strains were determined. Their activities were compared with those of known
standard drugs.
O
N
N
N
S
NH
O
N
H
N
H
O
O
F
Carbendazim
Lansoprazole
N
F
F
OH
Cl
Cl
N
HN
N
Cl
Chlorquinaldol
Chloroquine
Fig. 1. Clinically used known drugs having either a benzimidazole or a quinoline nucleus.
RESULTS AND DISCUSSION
A series of novel heterocyclic compounds containing benzimidazole and qui-
noline nuclei was synthesized. Some other compounds of a similar type were
15
16
reported by Goldfarb, Bhat and Dynachim (formerly known as Chimetron S.
17,18
A. R. L.).
The intermediate [(5-chloroquinolin-8-yl)oxy]acetic acid (2) was
prepared by a process similar to the known literature procedures,
19–21
using 5-
chloro-8-hydroxyquinoline (a) and monochloroacetic acid methyl ester (b).
Ortho-phenylenediamine (OPDA) (1) was condensed with [(5-chloroquino-
22
lin-8-yl)oxy] acetic acid (2) in 4 M HCl under reflux (Phillips conditions), as
represented in Scheme 1. The reaction mixture was basified with aqueous sodium
hydroxide, filtered and the crude product was crystallized from ethanol. Based on
spectral and analytical data, the compound was assigned the structure 8-[(1H-
-benzimidazol-2-yl)methoxy]-5-chloroquinoline (3). Reaction of 3 with different
23–26
electrophiles
in the presence of an appropriate base yielded a series of novel
benzimidazoles 4a–n, as represented in Scheme 1.
Synthesis of compounds 4a–g was realized in DMF (N,N-dimethylform-
amide) using potassium tert-butoxide as the base. Complete conversion was
achieved within 20 to 60 min at 60 °C. The products were isolated by quenching
the reaction mass with cold water and filtering off the precipitated solid.
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SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF NOVEL BENZIMIDAZOLES
1201
A.
(i) K2CO3 / KI
O
O
Cl
N
O
N
Xylene Reflux
+
HO
Cl
HO
O
Cl
(ii) 4 M HCl Reflux
(a)
(b)
(2)
B.
NH2
NH2
(1)
N
O
N
N
4 M HCl
Reflux
+
N
H
O
Cl
HO
O
Cl
(3)
(2)
C.
R-X
N
N
N
N
Electrophile
N
O
Cl
N
H
O
Cl
Base / Solvent
R
(4a-4n)
(3)
Where, X = Halogen;
(4a, R = Methyl), (4b, R = Ethyl), (4c, R = Propyl), (4d, R = Butyl), (4e, R = Pentyl),
(4f, R =Benzyl), (4g, R =p-Bromobenzyl), (4h, R =methylsulfonyl), (4i, R =Phenylsulfonyl),
(4j, R = p-Toluenesulfonyl), (4k = R = Methoxycarbonyl), (4l, R = Ethoxycarbonyl),
(4m, R = Benzyloxycarbonyl), (4n, R = 2,2,2-Trichloroethoxycarbonyl).
Scheme 1. Synthetic route to compounds 4a–n.
Preparation of derivatives 4h–n from 3 was performed in pyridine as both
the base and solvent using the corresponding alkyl/aryl sulphonyl chlorides or
alkyl/aralkyl chloroformates. Reactions were fast and complete conversion could
be achieved in 30 to 40 min at room temperature. Reaction mass was then
quenched with water, neutralized with dilute hydrochloric acid and the product
was extracted with ethyl acetate. Partial concentration of the organic layer and
addition of diethyl ether into the concentrated mass resulted in precipitation of
the required product, which was collected by filtration. The crude products were
purified with a hot acetone–water mixture.
1
13
The compounds were characterized by H-NMR, mass, FTIR and C-NMR
of some representative derivatives. Yields and reaction conditions are given in
Table I. The melting points and spectral data are in the supplementary material to
this paper.
Antimicrobial activity
All the synthesized compounds were subjected to in vitro antibacterial and
antifungal activity determination.
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CHAUDHARI and RINDHE
Most of the compounds showed very good antibacterial activities against Sta-
phylococcus aureus (Gram-positive) and Salmonella typhimurium, and were almost
competitive with the standard drugs, chloramphenicol and ciprofloxacin. The re-
sults of the determination of the antibacterial activities are summarized in Table II.
TABLE I. Yields and reaction conditions of the synthesized compounds
Electrophile
Conditions
Substituent ‘R’
Compd. Yield, %
Methyl iodide
Ethyl iodide
n-Propyl bromide
n-Butyl bromide
n-Pentyl bromide
Benzyl bromide
4-Bromobenzyl bromide
Methanesulphonyl chloride
Benzenesulphonyl chloride
p-Toluenesulphonyl
chloride
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
t-BuOK/DMF/60 °C
Pyridine/RT
Methyl
Ethyl
n-Propyl
n-Butyl
n-Pentyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
83
78
73
68
61
85
81
62
60
52
Benzyl
4-Bromobenzyl
Methylsulphonyl
Phenylsulphonyl
4-Methylphenyl-
sulphonyl
Pyridine/RT
Pyridine/RT
4j
Methyl chloroformate
Ethyl chloroformate
Benzyl chloroformate
2,2,2-Trichloroethyl
chloroformate
Pyridine/RT
Pyridine/RT
Pyridine/RT
Pyridine/RT
Methoxycarbonyl
Ethoxycarbonyl
Benzyloxycarbonyl
2,2,2-Trichloroethoxy-
carbonyl
4k
4l
4m
4n
50
68
55
67
TABLE II. Antibacterial activities of the novel benzimidazole derivatives and standard anti-
bacterial drugs (zone of inhibition in mm)
S. aureus MTCC-96
S. typhimurium MTCC-98
Compound
Concentration, μg mL-1
25
11
10
11
14
11
10
10
10
12
13
10
13
11
11
15
14
19
50
15
14
12
16
13
12
12
11
14
15
11
15
12
14
17
19
21
100
18
17
13
17
18
16
15
13
17
16
14
18
13
16
19
20
22
250
20
18
15
19
20
17
19
14
19
18
15
19
15
17
22
21
22
25
12
13
11
15
12
15
14
15
12
12
15
12
14
12
15
12
18
50
16
14
14
17
15
15
16
16
15
12
17
13
16
13
17
18
19
100
18
15
17
18
19
18
18
18
19
15
20
17
17
15
18
19
20
250
21
16
19
18
23
19
21
20
21
18
21
19
21
17
20
21
21
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
Chloramphenicol
Ciprofloxacin
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SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF NOVEL BENZIMIDAZOLES
1203
Some of the compounds (4a, 4i, 4j and 4l) exhibited good antifungal activi-
ties against Aspergillus niger but the antifungal activities against Candida albi-
cans were poor as compared to the standard drug, griseofulvin. The results of the
determination of the antifungal activities are summarized in Table III.
TABLE III. Antifungal activities of the novel benzimidazole derivatives and standard anti-
fungal drug (zone of inhibition in mm)
A niger MTCC 282
C. albicans MTCC 227
Compound
Concentration, μg mL-1
50
18
19
17
17
15
17
18
17
17
18
19
18
19
17
18
23
100
18
22
18
21
17
18
20
18
20
21
23
20
19
18
20
25
250
19
22
20
22
18
19
22
20
21
23
23
20
21
22
22
25
500
21
24
21
23
19
20
23
21
22
25
24
21
24
23
23
28
50
11
12
13
11
10
11
12
12
11
12
11
12
11
11
11
21
100
13
13
14
13
13
12
13
14
13
14
12
15
13
15
12
22
250
15
15
16
16
14
15
14
16
15
15
14
17
15
16
14
22
500
17
16
17
17
17
16
16
17
16
17
15
18
16
17
17
24
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
Griseofulvin
EXPERIMENTAL
TLC analysis was performed using pre-coated silica gel plates and visualization under a
UV lamp. The melting points are uncorrected and were determined using a Polmon Melting
Point Apparatus model No. MP96. The NMR spectra were recorded on a Bruker Avance II
400 MHz NMR spectrometer. The mass spectra were obtained using a Waters Q-ToF Micro
spectrometer with an ESI source in the positive ion mode. The IR spectra were recorded on a
Perkin-Elmer Spectrum One FTIR spectrometer. Analytical and spectral data of synthesized
compounds are given in Supplementary material.
o-Phenylenediamine, 5-chloro-8-hydroxyquinoline, monochloroacetic acid methyl ester
and the electrophilic reagents were obtained from commercial suppliers. All the employed
solvents were of analytical grade.
Synthesis of [(5-chloroquinolin-8-yl)oxy]acetic acid (2)
A mixture of 5-chloro-8-hydroxyquinoline (a) (10 g, 0.056 mol), potassium carbonate
powder (9.7 g, 0.07 mol) and potassium iodide (0.7 g, 0.0042 mol) in xylene (110 mL) was
heated at reflux (140–144 °C) for 1 h with the simultaneous azeotropic removal of water.
Reaction mass was then cooled to 90 °C and monochloroacetic acid methyl ester (b) (7.86 g,
0.072 mol) was slowly added over 1 h at 90–95 °C. The reaction mass was then further heated
and refluxed for 5 h to obtain a clear brown-coloured solution, monitored by TLC. Xylene
was distilled off at 55–60°C under vacuum, the residue cooled to RT and water added (100
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1204
CHAUDHARI and RINDHE
mL). The resultant slurry was stirred at RT for 30 min, filtered and the solid washed with
water. The wet cake was taken in 30 mL water, pH adjusted to 3 to 3.5 with conc. HCl (around 5
mL) and stirred at 50 °C for 1 h. The reaction mass was cooled to RT, filtered and the solid
washed with water to afford 10.6 g of the title compound on drying.
Synthesis of 8-[(1H-benzimidazol-2-yl)methoxy]-5-chloroquinoline (3)
A mixture of OPDA (1) (15 g, 139 mmol) and [(5-chloroquinolin-8-yl)oxy]acetic acid
(2) (33 g, 139 mmol) in 4 M hydrochloric acid (300 mL) was refluxed (98–100 °C) for 4 h.
The reaction was monitored by TLC. The reaction mass was then cooled to room temperature,
diluted with water (500 mL) and basified to pH 9 with 10 % aqueous sodium hydroxide so-
lution at room temperature. The reaction mass was filtered and the obtained solid was washed
with water. Crystallization of the crude product from ethanol afforded 35g of the title com-
pound (3) on drying.
General procedure for the synthesis of compounds 4a–g
To a solution of compound 3 (1.5 g, 4.85 mmol) in DMF (45 mL) was added potassium
tert-butoxide (0.559 g, 5.82 mmol) in small portions at 0–5 °C. After completion of the addi-
tion, the temperature of the reaction mass was raised to 5–10°C and stirred at this temperature
for 15–20 min. The corresponding alkyl halide (5.82 mmol) was added into the reaction mass
in 5–10 min at 5–10 °C and stirred for 15 min. The reaction mass was then heated to 60 °C
and stirred at this temperature for 20–60 min; monitored by TLC. After complete conversion,
the reaction mass was cooled to room temperature and quenched with cold water (200 mL).
The obtained solid was filtered, washed with water and dried to yield the corresponding N-
alkyl derivatives 4a–g.
The corresponding alkyl halides used for the reactions were methyl iodide, ethyl iodide,
n-propyl bromide, n-butyl bromide, n-pentyl bromide, benzyl bromide and 4-bromobenzyl
bromide.
General procedure for the synthesis of compounds 4h–n
To a solution of compound 3 (1.5g, 4.85 mmol) in pyridine (15 mL) was added slowly
over 10–15 min the respective alkyl/aryl sulphonyl chloride or alkyl/aralkyl chloroformate
(5.82 mmol) at 0–5 °C. After completion of the addition, the temperature of the reaction mix-
ture was allowed to rise slowly to room temperature and stirred at this temperature for 30–40
min. The reaction was monitored by TLC. After complete conversion, the reaction mass was
quenched with water (45 mL) and 2 M HCl was added until the pH of the reaction mass was
neutral. The product was extracted twice with ethyl acetate, the combined ethyl acetate layer
was washed with water and dried with anhydrous sodium sulphate. The organic phase was
then concentrated partially under vacuum to reduce the volume to 15 mL. Then 20 mL tert-
-butylmethyl ether was added at room temperature and stirred for 15 min. The precipitated
solid was filtered and dried to obtain the corresponding N-alkylsulphonyl/alkoxycarbonyl
derivatives 4h–n. The crude compounds were crystallized from a hot acetone–water mixture.
Microbiological procedures for the activity study
For assessing their antibacterial activity, the compounds were cultured for 48 h against
two pathogenic bacterial strains, such as S. aureus MTCC-96 (Gram-positive) and S. typhimu-
rium MTCC-98 (Gram-negative). The minimum inhibitory concentrations (MIC) were deter-
mined as per the recommendations of the Clinical and Laboratory Standards Institute (CLSI,
www.clsi.org) on Muller–Hinton Agar containing serial twofold dilution of the drugs. MIC
was taken after 48 h incubation along with positive and negative controls at 37 °C. Dimethyl
sulphoxide was used as the solvent. Petri dishes with 100mm diameter were used.
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SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF NOVEL BENZIMIDAZOLES
1205
For the antifungal activity, all the compounds were tested with a similar procedure as
above against two different fungi: A. niger and C. albicans.
CONCLUSIONS
A series of novel substituted benzimidazole–quinoline derivatives was syn-
thesized by condensation of o-phenylenediamine with [(5-chloroquinolin-8-yl)-
oxy]acetic acid, followed by subsequent reactions of this compound with diffe-
rent electrophiles. All the compounds were subjected to biological screening and
they showed promising antibacterial activity against S. aureus (Gram-positive)
and S. typhimurium (Gram-negative), which were comparable to the activity of
known standard drugs. This proves the high therapeutic value of these com-
pounds and encourages further study to explore their biological potential. Some
of the compounds (4a, 4i, 4j and 4l) also exhibited good antifungal activity against
A. niger but the antifungal activities against C. albicans were disappointing.
SUPPLEMENTARY MATERIAL
Analytical and spectral data of the synthesized compounds are available electronically at
http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. One of the authors (R. B. Chaudhari) is thankful to Alchem Synthon
(P) Ltd., Ambernath, Mumbai (India) for providing the chemicals required for the research
work and The Principal, New Arts, Commerce and Science College, Ahmednagar, Maharash-
tra (India) for the use of the laboratory facilities. Thanks go to the Sophisticated Analytical
Instrumentation Facility (SAIF), Punjab University, Chandigarh for providing spectral ana-
lysis and the Microcare Laboratory Surat, Gujarat (An ISO 9001:2000 certified Lab) for the
biological screening of the compounds.
И З В О Д
СИНТЕЗА И АНТИБИКРОБНА АКТИВНОСТ НОВИХ N-СУПСТИТУИСАНИХ
8-(1-АЛКИЛ/АЛКИЛСУЛФОНИЛ/АЛКОКСИКАРБОНИЛ-БЕНЗИМИДАЗОЛ-2-
-ИЛМЕТОКСИ)-5-ХЛОРХИНОЛИНА
RAJU B. CHAUDHARI и SAHEBRAO S. RINDHE
PG Department of Chemistry; New Arts, Commerce and Science College,
Ahmednagar-414003, Maharashtra, India
У раду је приказана синтеза серије нових деривата 8-(1-алкил/алкилсулфонил/ал-
коксикарбонил-бензимидазол-2-илметокси)-5-хлорхинолина. Једињења су добијена конден-
зацијом о-фенилендиамина и [(5-хлорхинолин-8-ил)окси]сирћетне киселине, после чега је
уследила супституција на азоту различитим електрофилним реагенсима у присуству одгова-
рајуће базе чиме је добијена серија хетероцикличних једињења која садрже бензимидазолско
1
и хинолинско језгро. Структуре једињења потврђене су спектралним подацима – H-NMR,
13C-NMR, IC и масеним спектрима. Готово сва једињења показују значајну антибактеријску
активност према Salmonella typhimurium и Staphylococcus aureus. Нека од њих показују добру
антифунгалну активност према Aspergillus niger, али је антифунгална активност према
Candida albicans веома слаба.
(Примљено 8. јула 2010, ревидирано 7. јануара 2011)
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