Microwave-assisted synthesis of pyrido[1,2-a]benzimidazole derivatives of β-aryloxyquinoline and their antimicrobial and antituberculosis activities

Article abstract of DOI:10.1007/s00044-012-0322-5

A new series containing pyrido[1,2-a]benzimidazole derivatives of β-aryloxyquinoline has been synthesized via base catalyzed microwave-assisted multi-component cyclocondensation reaction. This methodology allowed us to achieve the desired products in good yields in very short time with the use of 10 mol% NaOH as a non-hazardous organic base. The chemical structures of compounds 6a-x were elucidated by ¹H NMR, ¹³C NMR, FT-IR, elemental analysis, and mass spectral data. The titled derivatives were tested against a panel of pathogenic strains of bacteria and fungi for antimicrobial activity and against Mycobacterium tuberculosis H37Rv for their antitubercular activity. The structural activity relationship study revealed that antimicrobial and antitubercular potency of the title compounds depends not only on the bicyclic heteroaromatic pharmacophore appended through ether linked aryl ring but also on the nature of the peripheral substituents and may also upon their spatial relationship and positional changes.

Full text of DOI:10.1007/s00044-012-0322-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0322-5
ORIGINAL RESEARCH
Microwave-assisted synthesis of pyrido[1,2-a]benzimidazole
derivatives of b-aryloxyquinoline and their antimicrobial
and antituberculosis activities
•
Chetan B. Sangani Hardik H. Jardosh
•
•
Manish P. Patel Ranjan G. Patel
Received: 21 August 2012 / Accepted: 25 October 2012
Ó Springer Science+Business Media New York 2012
Abstract A new series containing pyrido[1,2-a]benz-
imidazole derivatives of b-aryloxyquinoline has been
synthesized via base catalyzed microwave-assisted multi-
component cyclocondensation reaction. This methodology
allowed us to achieve the desired products in good yields
in very short time with the use of 10 mol% NaOH as a
non-hazardous organic base. The chemical structures of
of lives were lost during the last two centuries (WHO report,
2010). There is no universally effective vaccine against
infection caused by MTB (Russell et al., 2010); therefore, the
development of antitubercular drugs becomes thirsty area in
the medicinal chemistry research. Moreover, the problems
posed by multi-drug-resistant (MDR) microorganisms have
reachedanalarminglevelinmanycountriesaroundtheworld.
Some antimicrobial and antitubercular drugs were failed
during the chemotherapy against the infections caused by
MDR microorganism (Diekema et al., 2004; WHO report,
2008). These reports encompass the development of new and
effective antitubercular and antimicrobial drugs. In pursuit of
this goal, we have synthesized pyrido[1,2-a]benzimidazole
derivatives bearing b-aryloxyquinoline nucleus with the hope
that amalgamation of these two biopotent moiety into a single
scaffold may produce novel heterocyclic scaffold with
promising biological activity.
1
compounds 6a–x were elucidated by H NMR, 13C NMR,
FT-IR, elemental analysis, and mass spectral data. The
titled derivatives were tested against a panel of pathogenic
strains of bacteria and fungi for antimicrobial activity and
against Mycobacterium tuberculosis H37Rv for their anti-
tubercular activity. The structural activity relationship
study revealed that antimicrobial and antitubercular
potency of the title compounds depends not only on the
bicyclic heteroaromatic pharmacophore appended through
ether linked aryl ring but also on the nature of the
peripheral substituents and may also upon their spatial
relationship and positional changes.
Quinoline derivatives are found to possess wide range of
useful biological properties including antitubercular (Mital
et al., 2006), antibacterial (Kalluraya et al., 2008), anti-
fungal (Rana et al., 2008), antimalarial (Charris et al.,
2005; Dave et al., 2009), anti-inflammatory (Bava and
Kumar 2009), and anticancer activities (Shi et al., 2008).
Moreover, the presence of aryl ring appended via ether
linkage at b-position of quinoline moiety is found to be
highly active against MTB (H37Rv) and plays a vital role
in the development of new antituberculosis drugs (Mungra
et al., 2011; Upadhaya et al., 2009).
Keywords Pyrido[1,2-a]benzimidazole ꢀ
Aryloxyquinoline ꢀ Microwave-assisted synthesis ꢀ
Antimicrobial activity ꢀ Antitubercular activity
Introduction
Tuberculosis is mainly caused by Mycobacterium tubercu-
losis bacteria(MTB). Itisfound tobethe secondleadingkiller
disease from a single infectious agent because around billions
On the other hand, pyrido[1,2-a]benzimidazole deriva-
tives did not receive much attention until the past decades
(Panda et al., 2003), but from last few years they attracted
organic as well as medicinal chemist due to their diverse
syntheses and various biological activities, such as antitu-
bercular (Pieroni et al., 2011), antimicrobial (Rida et al.,
2006; Takemura et al., 2004; Rida et al., 1988), anti-HIV-1
C. B. Sangani ꢀ H. H. Jardosh ꢀ M. P. Patel (&) ꢀ R. G. Patel
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India
e-mail: patelmanish1069@yahoo.com
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Med Chem Res
(Rida et al., 2006), anticancer (Rida et al., 2006; El-Hawash
et al., 1999), antineoplastic (Badawey et al., 1995a, b; 1999),
antiviral (Kotovskaya et al., 2005), and antimalarial (Ndakala
et al., 2011).
hand, further increase in the amount of NaOH resulted into
the sticky mass which required ice-water work-up and gave
poor yield. The formation of products was continuously
checked by thin layer chromatography (TLC) at regular
time interval to optimize reaction time and it was found
that reaction was completed within 4 min. The above
results showed that the best results were obtained when the
reaction was carried out with 10.0 mol% of NaOH under
microwave irradiation at 280 W for 4 min.
Previously, pyrido[1,2-a]benzimidazoles have been pre-
pared using different synthetic approaches (Bogdanowicz-
Szwed and Czarny, 1993; Prostakov et al., 1983; Russell and
Van Nievelt, 1995; Sundberg and Ellis, 1982; Yan et al.,
2009; Algul et al., 2009; Dawood et al., 2010, 2011; Wu
et al., 2011). However, some shortcomings were observed in
these methods such as, longer reaction time, use of hazardous
organic base, drastic reaction conditions, and poor yield. To
overcome these drawbacks, we have adopted the microwave-
assisted organic synthesis (MAOS) approach and NaOH as
an eco-friendly base which facilitate to construct the title
derivatives with more efficacy in shorter reaction time.
In the light of the above-mentioned reports and in con-
tinuation of our efforts toward the synthesis of quinoline-
based biologically active heterocycles (Shah et al., 2012;
Jardosh and Patel, 2011, 2012; Mungra et al., 2011;
Makawana et al., 2012; Kathrotiya et al., 2012 ), an attempt
has been through to undertake the microwave-assisted
NaOH catalyzed synthesis of pyrido[1,2-a]benzimidazole
derivatives bearing b-aryloxyquinoline nucleus and evalu-
ated their antimicrobial and antitubercular activities.
The formation of compounds 6a–x may proceed via
two steps. (i) Initial formation of an intermediate heterylid-
enenitrile by Knoevenagel condensation of b-aryloxyquino-
line-3-carbaldehydes 3a–l with malononitrile 4 and (ii)
intermolecular cyclization, driven through the nucleophilic
attack of 2-cyanomethylbenzimidazole 5a,5b in basic reac-
tionconditiongives7 whichundergoesairoxidationtofurnish
pyrido[1,2-a]benzimidazole as the final product (Scheme 2).
The structures of newly synthesized compounds
1
6a–x were confirmed by H NMR, 13C NMR, FT-IR, ele-
mental analysis, and mass spectral data. The IR spectrum
of title compounds 6a–x showed absorption bands around
3,500–3,400 and 3,350–3,300 cm-1 correspond to asym-
metric and symmetric stretching of primary amino group,
bands around 2,250–2,190 cm-1 for –C:N stretching of
cyano group and 1,250–1,180 cm-1 for C–O–C stretching
1
of ether linkage. In H NMR spectrum of the compounds
6a–x, multiplets in the range of d 6.98–8.83 ppm appeared
for aromatic protons. Moreover, a singlet around d
2.32–2.59 and d 3.76–3.92 ppm stands for methyl and
methoxy protons, respectively. A distinctive broad singlet
in the range of d 8.75–8.97 appeared for the primary amine.
In the 13C NMR spectral data of the title compounds 6a–x,
the signal at around d 77.60–87.95 ppm is assigned to
carbon attached with carbonitrile while signals around d
115.10–158.60 ppm are attributed to all the aromatic car-
bons. Also, distinctive signals around d 20.88–21.85 and d
55.85–56.16 ppm stand for methyl and methoxy of
6a–x derivatives, respectively. The obtained elemental
analysis values are in good agreement with the theoretical
data. Furthermore, mass spectral studies of all the title
compounds showed molecular ion peak M?ꢀ corresponding
to their exact mass. All physical, analytical data, as well as
spectroscopic characterization data of the synthesized
compounds 6a–x are given in ‘‘Experimental’’ section.
Results and discussion
Chemistry
The required intermediates 2-chloroquinoline-3-carbalde-
hydes 1a–c were prepared by Vilsmeier-Haack reaction of
various substituted acetanilide (Meth-Cohn and Bramha,
1978). The synthetic precursors b-aryloxyquinoline-3-car-
baldehydes 3a–l were synthesized by nucleophilic displace-
ment of chloro group at C-2 position of 1a–c with various
phenols 2a–d by refluxing in dimethylformamide using anhy-
drous potassium carbonate as a base (Scheme 1) (Mungra
et al., 2011). Substituted pyrido[1,2-a]benzimidazole-2,4-
dicarbonitrile derivatives 6a–x have been synthesized effi-
ciently via microwave-assisted one-pot three-component
cyclocondensation of b-aryloxyquinoline-3-carbaldehydes
3a–l, malononitrile 4, and 2-cyanomethylbenzimidazole 5a,b
in ethanol containing 10 mol% of NaOH at280 W (Scheme 1).
The reaction was optimized by varying the mole ratio of
catalyst (NaOH). A mixture of respective b-arylox-
yquinoline-3-carbaldehyde, malononitrile, and 2-cyanom-
ethylbenzimidazole was subjected to microwave irradiation
(280 W) by varying mole ratio of NaOH 2.5, 5.0, 7.5, 10.0,
and 12.5 mol%. It was observed that when the amount of
NaOH was increased to 10.0 mol%, the reaction rate was
increased within shorter reaction time (4 min). On the other
Antimicrobial activity
Antimicrobial activity of the title compounds 6a–x was
carried out by broth microdilution method (NCCLS, 2002).
Mueller–Hinton broth was used as nutrient medium to
grow and dilute the compound suspension for the test
bacteria and Sabouraud Dextrose broth used for fungal
nutrition. The strains used for the activity were procured
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Med Chem Res
Scheme 1 Representative route
for the synthesis of compounds
3a–l and 6a–x
Scheme 2 Plausible
mechanistic pathway for the
compounds 6a–x
from [MTCC-Microbial Type Culture Collection] Institute
of Microbial Technology, Chandigarh. The compounds
6a–x were screened for their antibacterial activity against
Bacillus subtilis (MTCC 441), Clostridium tetani (MTCC
449), Streptococcus pneumoniae (MTCC 1936), Esche-
richia coli (MTCC 443), Salmonella typhi (MTCC 98), and
Vibrio cholerae (MTCC 3906) as well as for antifungal
activity against Aspergillus fumigatus (MTCC 3008) and
Candida albicans (MTCC 227). DMSO was used as dilu-
ents to get desired concentration of compounds to test upon
standard bacterial strains. Serial dilutions were prepared in
primary and secondary screening. The control tube con-
taining no antibiotic was immediately subcultured (before
inoculation) by spreading a loopful evenly over a quarter of
plate of medium suitable for the growth of the test organ-
ism and put for incubation at 37 °C overnight. The tubes
were then incubated overnight. The MIC of the control
organism was read to check the accuracy of the compound
concentrations. The MIC was defined as the lowest con-
centration of the antibiotic or test sample allowing no
visible growth. All the tubes not showing visible growth (in
the same manner as control tube described above) was
123

Med Chem Res
subcultured and incubated overnight at 37 °C. The amount
of growth from the control tube before incubation (which
represents the original inoculum) was compared. Subcul-
tures might show similar number of colonies indicating
bacteriostatic, a reduced number of colonies indicating a
partial or slow bactericidal activity, and no growth if the
whole inoculum has been killed. The test must include a
second set of the same dilutions inoculated with an
organism of known sensitivity. Each synthesized com-
pound was diluted obtaining 2,000 lg/mL concentration as
a stock solution. In primary screening, 500, 250, and
200 lg/mL concentrations of the synthesized compounds
were taken. The active synthesized compounds found in
this primary screening were further tested in a second set of
dilution against all microorganisms. The compounds found
active in primary screening were similarly diluted to obtain
100, 62.5, 50, and 25 lg/mL concentrations. The highest
dilution showing at least 99 % inhibition is taken as MIC.
In this study, ampicillin, ciprofloxacin, and norfloxacin
were used as standard antibacterial drugs, whereas griseo-
fulvin was used as standard antifungal drug.
ampicillin. Against V. cholerae compounds 6b, 6f, and 6t
(MIC = 100 lg/mL) were found to be equipotent to
ampicillin.
Exploration of antifungal screening data revealed that,
against fungiC. albicans, compound6o (MIC = 200 lg/mL)
was found to exhibit fabulous activity; compounds 6c, 6e, 6h,
and 6p (MIC = 250 lg/mL) showed remarkable activity,
while compounds 6d, 6i, 6j, 6m, 6n, 6q, 6r, 6w, and 6x
(MIC = 500 lg/mL) were found equally potent when com-
pared with griseofulvin. None of the synthesized compounds
was found to be active against A. fumigatus.
Antituberculosis activity
The encouraging results from the antimicrobial studies
prompted us to go for the preliminary screening of the title
compounds 6a–x for their in vitro antituberculosis activity
against M. tuberculosis H37Rv by using Lowenstein–Jensen
medium (conventional method) as described by Rattan
(2000). A primary screen was conducted at primary dilution
6.25 lg/ml against M. tuberculosis H37Rv, where
6.25 lg/ml of each test compound were added to liquid
Lowenstein–Jensen Medium and then media were sterilized
by inspissations method. A culture of M. tuberculosis
H37Rv growing on Lowenstein–Jensen Medium was har-
vested in 0.85 % saline in bijou bottles. DMSO was used as
vehicle to get desired concentration. These tubes were
then incubated at 37 °C for 24 h followed by streaking of M.
tuberculosis H37Rv (5 9 104 bacilli per tube). These tubes
were then incubated at 37 °C. Growth of bacilli was seen
after 12, 22, and finally 28 days of incubation. Tubes having
the compounds were compared with control tubes where
medium alone was incubated with M. tuberculosis H37Rv.
The concentration at which complete inhibition of colonies
occurred was taken as active concentration of test com-
pound. The standard strain M. tuberculosis H37Rv was
tested with known drug isoniazid and rifampicin. The
screening results are summarized as % inhibition relative to
standard drug isoniazid and rifampicin. Compounds
effecting \90 % inhibition in the primary screen were not
evaluated further. Compounds demonstrating at least 90 %
inhibition in the primary screen were re-tested at lower
concentration (MIC) in a Lowenstein–Jensen medium and
evaluated their MIC values.
The antibacterial screening data (Table 1) revealed that,
against Gram-positive bacteria B. subtilis, compounds 6a,
6f, and 6w (MIC = 100 lg/mL) were found to be more
potent than ampicillin and equipotent to norfloxacin.
Compounds 6g, 6s, and 6v (MIC = 125 lg/mL) were
found to have significant activity when compared with
ampicillin. Compounds 6e, 6j, 6l, 6m, and 6r
(MIC = 200 lg/mL) were found to possess better activity
than ampicillin, while compounds 6b, 6c, 6d, 6h, 6i, 6k,
6n, 6o, 6t, 6u, and 6x (MIC = 250 lg/mL) were found
equally potent to ampicillin. Against C. tetani, compound
6n (MIC = 62.5 lg/mL) showed fabulous activity when
compared with ampicillin and ciprofloxacin, while com-
pounds 6a, 6i, 6s, 6t, and 6x (MIC = 100 lg/mL) showed
significant activity compare to ampicillin and equivalent to
ciprofloxacin. Compounds 6j and 6r (MIC = 125 lg/mL)
as well as compounds 6d, 6k, 6l, 6o, 6v, and 6w
(MIC = 200 lg/mL) were found to be more potent than
ampicillin, while compounds 6b, 6c, 6e, 6h, 6m, 6p, 6q,
and 6u (MIC = 250 lg/mL) were found to be equipotent
to ampicillin. Against S. pneumoniae, Compound 6a
(MIC = 62.5 lg/mL) was found to have more efficacy,
while compounds 6g, 6p, 6q, 6v, and 6x were found to
have identical activity when compare with ampicillin.
Bold numbers indicates more or equally potent com-
pounds compare to standard drugs
The antimycobacterial activity results of the compounds
6a–x are shown in Table 2. Of the compounds screened for
antituberculosis activity, compounds 6p (R1 = H, R2 = F,
R3 = CH3), 6t (R1 = CH3, R2 = F, R3 = CH3), 6x
(R1 = OCH3, R2 = F, R3 = CH3), and 6h (R1 = CH3,
R2 = F, R3 = H) found to possess better activity against
M. tuberculosis H37Rv and exhibited highest % inhibition.
The MIC values of these compounds found to be 6.25,
12.5, 12.5, and 25 lg/mL respectively. In this set of
Against Gram-negative bacteria E coli, compounds 6e, 6n,
6p, and 6u (MIC = 62.5 lg/mL) showed remarkable
activity, while compounds 6b, 6f, 6m, 6o, and 6x (MIC =
100 lg/mL) were found to be equally potent when compared
with ampicillin. Against S. typhi compounds 6b, 6e, 6u,
and 6v (MIC = 100 lg/mL) showed equal potency with
123

Med Chem Res
Table 1 Antimicrobial activity (MIC, lg/mL) of compounds 6a-x
Compound
Gram-positive bacteria
Gram-negative bacteria
Ec. St.
Fungi
Af.
Bs. Ct.
Sp.
Vc.
Ca.
MTCC 441 MTCC 449 MTCC 1936 MTCC 443 MTCC 98 MTCC 3906 MTCC 3008 MTCC 227
6a (R1 = H, R2 = H, R3 = H)
100
250
250
250
200
100
125
250
250
200
250
200
200
250
250
500
500
200
125
250
250
125
100
250
250
200
250
500
500
250
100
125
200
200
250
62.5
200
250
250
125
100
100
250
200
200
100
250
100
50
62.5
125
200
125
200
250
100
200
250
500
500
500
250
200
250
100
100
250
125
200
250
100
200
100
100
50
250
100
125
200
62.5
100
250
200
250
125
125
200
100
62.5
100
62.5
250
200
250
200
62.5
200
200
100
100
25
250
100
200
250
100
125
200
250
200
250
200
500
200
200
125
125
250
250
250
200
100
100
250
200
100
25
200
100
125
250
200
100
200
250
200
250
125
200
500
200
250
500
200
125
200
100
250
125
125
200
100
25
500
1,000
[1,000
250
6b (R1 = H, R2 = CH3, R3 = H)
6c (R1 = H, R2 = OCH3, R3 = H)
6d (R1 = H, R2 = F, R3 = H)
250
500
500
500
6e (R1 = CH3, R2 = H, R3 = H)
6f (R1 = CH3, R2 = CH3, R3 = H)
6g (R1 = CH3, R2 = OCH3, R3 = H)
6h (R1 = CH3, R2 = F, R3 = H)
6i (R1 = OCH3, R2 = H, R3 = H)
6j (R1 = OCH3, R2 = CH3, R3 = H)
6k (R1 = OCH3, R2 = OCH3, R3 = H)
6l (R1 = OCH3, R2 = F, R3 = H)
6m (R1 = H, R2 = H, R3 = CH3)
6n (R1 = H, R2 = CH3, R3 = CH3)
6o (R1 = H, R2 = OCH3, R3 = CH3)
6p (R1 = H, R2 = F, R3 = CH3)
6q (R1 = CH3, R2 = H, R3 = CH3)
6r (R1 = CH3, R2 = CH3, R3 = CH3)
6s (R1 = CH3, R2 = OCH3, R3 = CH3)
6t (R1 = CH3, R2 = F, R3 = CH3)
6u (R1 = OCH3, R2 = H, R3 = CH3)
6v (R1 = OCH3, R2 = CH3, R3 = CH3)
1,000
[1,000
[1,000
500
250
1,000
1,000
250
1,000
[1,000
250
500
500
[1,000
[1,000
500
500
500
1,000
1,000
[1,000
[1,000
500
500
200
250
500
500
[1,000
[1,000
500
1,000
[1,000
1,000
1,000
500
[1,000
[1,000
1,000
–
6w (R1 = OCH3, R2 = OCH3, R3 = CH3) 100
6x (R1 = OCH3, R2 = F, R3 = CH3)
Ampicillin
250
250
50
500
–
Ciprofloxacin
–
–
Norfloxacin
100
–
10
10
10
10
–
–
Griseofulvin
–
–
–
–
–
100
500
Bold numbers indicate more or equally potent compounds compare to standard drugs
– not tested
Bs, Bacillus subtilis; Ct, Clostridium tetani; Sp, Streptococcus pneumoniae; Ec, Escherichia coli; St, Salmonella typhi; Vc, Vibrio cholerae; Af, Aspergillus
fumigatus; Ca, Candida albicans; MTCC, Microbial Type Culture Collection
heterocyclic compounds, compound 6p (R1 = H, R2 = F,
R3 = CH3) is appeared as the promising antimicrobial
member with significant antitubercular activity.
C. tetani and showed better activity to that of ampicillin and
ciprofloxacin, e.g., compounds 6n, 6r, 6s, 6t, 6v, 6w, and 6x.
Compounds having H/CH3 at quinoline ring and CH3 at
benzimidazole ring enhance the antibacterial effectiveness
against S. pneumoniae. Against E. coli, compounds with CH3
group at quinoline and benzimidazole ring found to have more
potential than the other compounds, e.g., 6e, 6n, 6p, and 6u.
Compounds containing CH3 group at quinoline, aryloxy, and
benzimidazole rings found to have more potential to inhibit the
growth of S. typhi, e.g., compounds 6b, 6e, 6u, and 6v. In case
of V. cholerae, compounds having CH3 group at quinoline and
aryloxy rings found to be equipotent to ampicillin, e.g., com-
pounds 6b, 6f, and 6t. Compounds with unsubstituted quino-
lineringand H/F at aryloxy ring showed morepotencycompare
to griseofulvin, e.g., compounds 6c, 6e, 6h, 6o, and 6p.
Structure–Activity Relationship (SAR) study
The exploration of the structure–activity relationship of
antimicrobial screening revealed that the unsubstituted
compound 6a shows significant activity against all the
Gram-positive bacteria. Against B. subtilis, compounds
having CH3 and OCH3 groups at para position of ether
linked aryl ring gives better results compare to other
members of the series, e.g., compounds 6f, 6w, 6g, 6s, and
6v. Compounds with unsubstituted quinoline ring and CH3
at benzimidazole ring effectively inhibits the growth of
123

Med Chem Res
Organic solvents were purified by standard methods
(Furniss, 2004) and stored over molecular sieves. The
microwave-assisted reactions are conducted in a ‘‘RAGA’s
Modified Electromagnetic Microwave System’’ whereby
microwaves are generated by magnetron at a frequency of
2,450 MHz having an adjustable output power levels, i.e.,
10 levels from 140 to 700 W and with an individual sensor
for temperature control (fiber optic is used as a individual
sensor for temperature control) with attachment of reflux
condenser with constant stirring (thus avoiding the risk of
high-pressure development). All melting points were taken
in open capillaries and are uncorrected. Thin-layer chro-
matography (TLC, on aluminum plates coated with silica
gel 60 F254, 0.25 mm thickness, Merck) was used for
monitoring the progress of all reactions, purity, and
homogeneity of the synthesized compounds. Elemental
analysis (% C, H, N) was carried out by Perkin-Elmer 2400
series-II elemental analyzer and all compounds are
within 0.4 % of theory specified. The FT-IR spectra
were recorded using potassium bromide disc on a Shima-
dzu FT-IR 8401 spectrophotometer and only the charac-
teristic peaks are reported in cm-1. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6 on a Bruker Avance
400F (MHz) spectrometer using TMS as an internal stan-
dard at 400 and 100 MHz, respectively. Chemical shifts are
reported in parts per million (ppm). Mass spectra were
scanned on a Shimadzu LCMS 2010 spectrometer.
Table 2 Antimycobacterial activity of the compounds 6a–x
Compound
Primary screen (6.25 lg/mL)
% Inhibition
Actual MIC lg/mL
6a
80
52
24
75
19
32
62
94
46
58
79
86
49
12
64
99
71
58
25
97
78
10
70
96
99
98
–
6b
–
6c
–
6d
–
6e
–
6f
–
6g
–
6h
25
–
6i
6j
–
6k
–
6l
–
6m
–
6n
–
6o
–
6p
6.25
–
6q
6r
–
6s
–
6t
12.5
–
6u
6v
–
6w
–
6x
12.5
0.2
40
General procedure for the synthesis
Isoniazid
Rifampicin
of pyrido-[1,2-a]benzimidazole derivatives 6a–x
Bold numbers indicate [90 % inhibition
In a 50-mL round-bottomed flask, b-aryloxyquinoline-
3-carbaldehyde 3a–l (3 mmol), malononitrile 4 (3 mmol),
2-cyanomethyl-benzimidazole 5a,b (3 mmol), and NaOH
(10 mol%) in ethanol (15 mL) were thoroughly mixed and
subjected to microwave irradiation at 280 W (40 % of
output power) for 4 min. After the completion of reaction
(evidenced by TLC—Hexane::Ethyl acetate::4:6), the
mixture was allowed to stir at room temperature for
10–15 min, the solid mass separated was filtered, washed
well with ethanol (10 mL), dried and purified by leaching
in equal volume ratio of chloroform and methanol (40 mL)
to obtain pure solid sample. Analytical, physical, and
spectroscopic characterization data of synthesized com-
pounds 6a–x are mentioned below.
On the other hand, the evaluation of the structure–activity
relationship of antitubercular activity exposed that com-
pounds having F group at ether linked aryl ring appended to
quinoline and CH3 group at benzimidazole unit found to
exhibit more potency against M. tuberculosis H37Rv, e.g.,
compounds 6h, 6p, 6t, and 6x except compound.
The above-mentioned results shows that electronic influ-
ence of both the OCH3 (electron-donating) group and F
(electron-withdrawing) group affects the antimicrobial activ-
ity in some extent, while only F group influences the antitu-
bercular activity of the tested compounds. On the other hand,
effect of lipophilic CH3 group becomes more dominant com-
pare to hydrophilic OCH3 group to enhance the antimicrobial
and antitubercular effectiveness of the tested compounds.
1-Amino-3-(2-phenoxyquinolin-3-yl)pyrido
[1,2-a]benzimidazole-2,4-dicarbonitrile (6a)
Yield 87 %; m.p. 240–241 °C; IR (KBr, cm-1): 3,455 and
3,315 (asym. and sym. str. of –NH2), 2,215 (–C:N str.),
1,215 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 7.00 (d, 2H, J = 8.4 Hz, H-20,24), 7.12 (m, 3H,
Experimental
All reactions were performed with commercially available
reagents and they were used without further purification.
123

Med Chem Res
H-21,22,23), 7.41 (t, 1H, J1 = 7.6, J2 = 8.0, H-9), 7.52
(m, 2H, H-8,14), 7.68 (d, 1H, J = 8.0 Hz, H-13), 7.75 (t,
1H, J1 = 7.2, J2 = 8.0, H-15), 7.87 (d, 1H, J = 8.0 Hz,
H-10), 8.08 (d, 1H, J = 8.0 Hz, H-7), 8.59 (d, 1H,
J = 8.4 Hz, H-16), 8.67 (s, 1H, H-12), 8.80 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 77.68 (C–CN),
87.79 (C–CN), 115.15, 115.91, 119.11, 120.03, 123.37,
124.09, 125.19, 127.02, 127.22, 127.65, 128.54, 132.72,
134.02, 135.60, 141.13, 144.88, 145.61, 146.76, 147.01,
148.71, 152.19, 154.48, 156.91, 158.58, (Ar–C); Anal.
Calcd. for C28H16N6O (452.47 g/mol): C 74.33, H 3.56, N
18.57 % Found: C 74.15, H 3.49, N 18.53 %; MS (m/z):
452.2 (M?).
148.80, 151.15, 152.51, 158.00 (Ar–C); Anal. Calcd. for
C29H18N6O2 (482.49 g/mol): C 72.19, H 3.76, N 17.42 %
Found: C 72.32, H 4.00, N 17.55 %; MS (m/z): 482.7
(M?).
1-Amino-3-[2-(4-fluorophenoxy)quinolin-3-yl]pyrido
[1,2-a]benzimidazole-2,4-dicarbonitrile (6d)
Yield 75 %; m.p. 254–255 °C; IR (KBr, cm-1): 3,425 and
3,340 (asym. and sym. str. of –NH2), 2,210 (–C:N str.),
1,225 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 7.22 (d, 2H, J = 8.4 Hz, H-23,21), 7.30 (d, 2H,
J = 8.4 Hz, H-20,24), 7.49 (t, 1H, J1 = 7.6, J2 = 8.0,
H-9), 7.61 (m, 2H, H-8,14), 7.74 (d, 1H, J = 8.0 Hz,
H-13), 7.79 (t, 1H, J1 = 7.2, J2 = 8.0, H-15), 7.93 (d, 1H,
J = 8.0 Hz, H-10), 8.15 (d, 1H, J = 8.0 Hz, H-7), 8.66 (d,
1H, J = 8.4 Hz, H-16), 8.75 (s, 1H, H-12), 8.88 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 77.95 (C–CN),
87.93 (C–CN), 115.28, 116.03, 116.41, 119.62, 120.17,
122.20, 122.94, 125.30, 126.22, 127.13, 127.44, 128.77,
129.05, 130.49, 132.06, 134.84, 141.76, 145.01, 146.60,
147.45, 148.80, 151.37, 152.50, 157.95 (Ar–C); Anal.
Calcd. for C28H15FN6O (470.46 g/mol): C 71.48, H 3.21, N
17.86 % Found: C 71.44, H 3.37, N 17.94 %; MS (m/z):
470.7 (M?).
1-Amino-3-[2-(4-methylphenoxy)quinolin-3-yl]pyrido
[1,2-a]benzimidazole-2,4-dicarbonitrile (6b)
Yield 82 %; m.p. 233–235 °C; IR (KBr, cm-1): 3,430 and
3,330 (asym. and sym. str. of –NH2), 2,205 (–C:N str.),
1,195 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.34, (s, 3H, CH3, C-22), 7.18 (d, 2H, J = 8.4 Hz,
H-23,21), 7.26 (d, 2H, J = 8.0 Hz, H-20,24), 7.44 (t, 1H,
J1 = 7.6, J2 = 8.0, H-9), 7.58 (m, 2H, H-8,14), 7.70 (d,
1H, J = 8.0 Hz, H-13), 7.77 (t, 1H, J1 = 7.2, J2 = 8.0,
H-15), 7.90 (d, 1H, J = 8.0 Hz, H-10), 8.11 (d, 1H,
J = 8.0 Hz, H-7), 8.63 (d, 1H, J = 8.4 Hz, H-16), 8.72 (s,
1H, H-12), 8.85 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) d: 20.92 (CH3), 78.10 (C–CN), 87.84 (C–CN),
115.49, 115.98, 116.39, 119.53, 120.18, 122.18, 122.68,
125.20, 126.19, 127.10, 127.40, 128.85, 128.96, 130.48,
132.06, 134.87, 141.81, 145.03, 146.56, 147.40, 148.79,
151.15, 152.49, 158.24 (Ar–C); Anal. Calcd. for
C29H18N6O (466.49 g/mol): C 74.67, H 3.89, N 18.02 %
Found: C 74.42, H 4.04, N 17.95 %; MS (m/z): 466.1
(M?).
1-Amino-3-[2-(4-phenoxy)-6-methylquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6e)
Yield 89 % m.p. 261–263 °C; IR (KBr, cm-1): 3,450 and
3,335 (asym. and sym. str. of –NH2), 2,205 (–C:N str.),
1,205 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.37 (s, 3H, CH3, C-14), 7.15 (d, 2H, J = 8.4 Hz,
H-20,24), 7.26 (m, 3H, H-21,22,23), 7.56 (t, 1H, J1 = 7.6,
J2 = 7.6, H-9), 7.72 (m, 3H, H-13,8,15), 7.89 (d, 1H,
J = 8.0 Hz, H-16), 7.98 (d, 1H, J = 8.0 Hz, H-10), 8.64
(s, 1H, H-12), 8.79 (d, 1H, J = 8.0, H-7), 8.97 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 21.33 (CH3),
78.25 (C–CN), 87.84 (C–CN), 115.60, 115.83, 116.32,
119.21, 119.94, 122.53, 123.40, 125.14, 126.98, 127.89,
129.12, 134.04, 135.58, 141.18, 145.02, 145.18, 146.80,
147.60, 148.89, 152.60, 154.78, 157.03, 157.84, 158.08
(Ar–C); Anal. Calcd. for C29H18N6O2 (466.49 g/mol): C
74.67, H 3.89, N 18.02 % Found: C 74.59, H 4.01, N
17.89 %; MS (m/z): 466.4 (M?).
1-Amino-3-[2-(4-methoxyphenoxy)quinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6c)
Yield 79 %; m.p. 277–279 °C; IR (KBr, cm-1): 3,400 and
3,320 (asym. and sym. str. of –NH2), 2,200 (–C : N str.),
1,200 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 3.77 (s, 3H, OCH3, C-22), 7.09 (d, 2H, J = 8.4 Hz,
H-23,21), 7.20 (d, 2H, J = 8.0 Hz, H-20,24), 7.41 (t, 1H,
J1 = 7.6, J2 = 8.0, H-9), 7.54 (m, 2H, H-8,14), 7.69 (d,
1H, J = 8.0 Hz, H-13), 7.75 (t, 1H, J1 = 7.2, J2 = 8.0,
H-15), 7.88 (d, 1H, J = 8.0 Hz, H-10), 8.09 (d, 1H,
J = 8.0 Hz, H-7), 8.57 (d, 1H, J = 8.4 Hz, H-16), 8.62 (s,
1H, H-12), 8.77 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) d: 55.87 (OCH3), 78.03 (C–CN), 87.77
(C–CN), 115.04, 115.94, 116.55, 119.42, 120.21, 122.20,
122.71, 125.22, 126.21, 127.11, 127.25, 129.05, 129.01,
130.52, 132.11, 134.88, 141.92, 144.92, 146.55, 147.43,
1-Amino-3-[2-(4-methylphenoxy)-6-methylquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6f)
Yield 83 %; m.p. 243–245 °C; IR (KBr, cm-1): 3,470 and
3,315 (asym. and sym. str. of –NH2), 2,195 (–C:N str.),
1,220 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.32, (s, 3H, CH3, C-22), 2.53, (s, 3H, CH3, C-14), 7.02
123

Med Chem Res
1-Amino-3-[2-(4-phenoxy)-6-methoxyquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6i)
(d, 2H, J = 8.4 Hz, H-23,21), 7.24 (d, 2H, J = 8.4 Hz,
H-20,24), 7.48 (t, 1H, J1 = 7.6, J2 = 7.6, H-9), 7.61 (m,
3H, H-13,8,15), 7.86 (d, 1H, J = 8.0 Hz, H-16), 7.93 (d,
1H, J = 8.0 Hz, H-10), 8.61 (s, 1H, H-12), 8.72 (d, 1H,
J = 8.0, H-7), 8.87 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) d: 20.93 (CH3), 21.30 (CH3), 78.20 (C–CN),
87.93 (C–CN), 115.11, 115.66, 116.31, 119.99, 120.06,
122.73, 123.41, 125.14, 127.20, 127.82, 129.11, 133.84,
135.61, 141.38, 144.87, 145.17, 146.71, 147.60, 149.00,
152.61, 154.75, 157.01, 158.00, 158.60 (Ar–C); Anal.
Calcd. for C30H20N6O (480.52 g/mol): C 74.99, H 4.20, N
17.49 % Found: C 75.09, H 4.12, N 17.31 %; MS (m/z):
480.3 (M?).
Yield 85 %; m.p. 237–238 °C; IR (KBr, cm-1): 3,420 and
3,345 (asym. and sym. str. of –NH2), 2,190 (–C:N str.),
1,190 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 3.80 (s, 3H, OCH3, C-14), 7.20 (d, 2H, J = 8.4 Hz,
H-20,24), 7.32 (m, 3H, H-21,22,23), 7.61 (t, 1H, J1 = 7.6,
J2 = 7.6, H-9), 7.77 (m, 3H, H-13,8,15), 7.86 (d, 1H,
J = 8.0 Hz, H-16), 7.98 (d, 1H, J = 8.0 Hz, H-10), 8.62
(s, 1H, H-12), 8.81 (d, 1H, J = 8.0, H-7), 8.92 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 56.03 (OCH3),
78.08 (C–CN), 87.75 (C–CN), 115.31, 115.71, 116.05,
119.42, 120.10, 122.70, 123.29, 125.32, 127.23, 127.74,
128.91, 133.98, 135.60, 141.33, 144.90, 145.13, 146.69,
147.63, 149.03, 152.43, 154.71, 156.93, 157.94, 158.25
(Ar–C); Anal. Calcd. for C29H18N6O2 (482.49 g/mol): C
72.19, H 3.76, N 17.42 % Found: C 72.23, H 3.65, N
17.58 %; MS (m/z): 482.6 (M?).
1-Amino-3-[2-(4-methoxyphenoxy)-6-methylquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6g)
Yield 81 %; m.p. 273–275 °C; IR (KBr, cm-1): 3,475 and
3,325 (asym. and sym. str. of –NH2), 2,225 (–C:N str.),
1,240 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d
2.52 (s, 3H, CH3, C-14), 3.78 (s, 3H, OCH3, C-22), 7.00 (d,
2H, J = 8.4 Hz, H-23,21), 7.21 (d, 2H, J = 8.4 Hz,
H-20,24), 7.45 (t, 1H, J1 = 7.6, J2 = 7.6, H-9), 7.62 (m, 3H,
H-13,8,15), 7.87 (d, 1H, J = 8.0 Hz, H-16), 7.90 (d, 1H,
J = 8.0 Hz, H-10), 8.58 (s, 1H, H-12), 8.64 (d, 1H, J = 8.0,
H-7), 8.82 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6)
d: 21.33 (CH3), 55.89 (OCH3), 78.15 (C–CN), 87.89
(C–CN), 115.08, 115.65, 116.01, 119.58, 120.04, 122.72,
123.32, 125.13, 127.18, 127.75, 129.05, 133.99, 135.60,
141.08, 144.94, 145.09, 146.79, 147.54, 148.99, 152.58,
154.72, 156.97, 157.95, 158.48 (Ar–C); Anal. Calcd. for
C30H20N6O2 (496.52 g/mol): C 72.57, H 4.06, N 16.93 %
Found: C 72.59, H 4.12, N 17.01 %; MS (m/z): 496.6 (M?).
1-Amino-3-[2-(4-methylphenoxy)-6-methoxyquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6j)
Yield 80 %; m.p. 269–270 °C; IR (KBr, cm-1): 3,400 and
3,310 (asym. and sym. str. of –NH2), 2,205 (–C:N str.),
1,225 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d
2.34 (s, 3H, CH3, C-22), 3.92 (s, 3H, OCH3, C-14), 7.14 (d,
2H, J = 8.4 Hz, H-23,21), 7.27 (d, 2H, J = 8.4 Hz,
H-20,24), 7.51 (t, 1H, J1 = 7.6, J2 = 7.6, H-9), 7.67 (m, 3H,
H-13,8,15), 7.85 (d, 1H, J = 8.0 Hz, H-16), 7.94 (d, 1H,
J = 8.0 Hz, H-10), 8.57 (s, 1H, H-12), 8.62 (d, 1H, J = 8.0,
H-7), 8.78 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6)
d: 20.88 (CH3), 56.12, (OCH3), 77.65 (C–CN), 87.89
(C–CN), 115.20, 115.60, 115.99, 119.48, 119.95, 122.70,
123.30, 125.10, 126.98, 127.80, 129.02, 133.88, 135.61,
140.99, 144.95, 145.07, 146.80, 147.60, 149.02, 152.60,
154.69, 157.01, 157.90, 157.90 (Ar–C); Anal. Calcd. for
C30H20N6O2 (496.52 g/mol): C 72.57, H 4.06, N 16.93 %
Found: C 72.39, H 3.92, N 17.11 %; MS (m/z): 496.2 (M?).
1-Amino-3-[2-(4-fluorophenoxy)-6-methylquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6h)
Yield 78 %; m.p. 265–267 °C; IR (KBr, cm-1): 3,450 and
3,320 (asym. and sym. str. of –NH2), 2,210 (–C:N str.),
1,250 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.38 (s, 3H, CH3, C-22), 7.02 (d, 2H, J = 8.4 Hz,
H-23,21), 7.27 (d, 2H, J = 8.4 Hz, H-20,24), 7.50 (t, 1H,
J1 = 7.6, J2 = 7.6, H-9), 7.65 (m, 3H, H-13,8,15), 7.88 (d,
1H, J = 8.0 Hz, H-16), 7.91 (d, 1H, J = 8.0 Hz, H-10),
8.61 (s, 1H, H-12), 8.72 (d, 1H, J = 8.0, H-7), 8.90 (br s,
2H, NH2); 13C NMR (100 MHz, DMSO-d6) d: 21.34
(CH3), 78.06 (C–CN), 87.90 (C–CN), 115.24, 115.73,
116.06, 119.60, 120.01, 122.62, 123.30, 125.16, 127.19,
127.82, 128.95, 134.01, 135.59, 141.07, 144.88, 145.14,
146.80, 147.55, 148.92, 152.44, 154.80, 157.02, 157.91,
158.38 (Ar–C); Anal. Calcd. for C29H17FN6O (484.48 g/
mol): C 71.89, H 3.54, N 17.35 % Found: C 72.14, H 3.70,
N 17.19 %; MS (m/z): 484.2 (M?).
1-Amino-3-[2-(4-methoxyphenoxy)-6-methoxyquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6k)
Yield 77 %; m.p. 270–272 °C; IR (KBr, cm-1): 3,440 and
3,350 (asym. and sym. str. of –NH2), 2,200 (–C:N str.),
1,200 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d
3.78 (s, 3H, OCH3, C-22), 3.85 (s, 3H, OCH3, C-14), 6.98 (d,
2H, J = 8.4 Hz, H-23,21), 7.14 (d, 2H, J = 8.4 Hz,
H-20,24), 7.42 (t, 1H, J1 = 7.6, J2 = 7.6, H-9), 7.58 (m, 3H,
H-13,8,15), 7.86 (d, 1H, J = 8.0 Hz, H-16), 7.96 (d, 1H,
J = 8.0 Hz, H-10), 8.59 (s, 1H, H-12), 8.65 (d, 1H, J = 8.0,
H-7), 8.84 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6)
d: 55.85 (OCH3), 55.95 (OCH3), 78.08 (C–CN), 87.88
123

Med Chem Res
(C–CN), 115.40, 115.70, 116.13, 119.32, 120.14, 122.80,
123.20, 125.10, 127.19, 127.80, 129.17, 133.89, 135.61,
141.03, 145.02, 145.21, 146.89, 147.55, 149.03, 152.61,
154.74, 157.02, 157.90, 157.99 (Ar–C); Anal. Calcd. for
C30H20N6O3 (512.52 g/mol): C 70.30, H 3.93, N 16.40 %
Found: C 70.45, H 4.17, N 16.52 %; MS (m/z): 512.5 (M?).
1,180 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
1
d H NMR (400 MHz, DMSO-d6): d 2.34 (s, 3H, CH3,
C-22), 2.58 (s, 3H, CH3, C-8), 7.00 (d, 2H, J = 8.4 Hz,
H-23,21), 7.19 (d, 1H, J = 8.8 Hz, H-20), 7.26 (d, 1H,
J = 8.8 Hz, H-24), 7.41 (d, 1H, J = 8.0 Hz, H-9), 7.57 (m,
2H, H-14,13), 7.74 (t, 1H, J1 = 7.2, J2 = 8.0, H-15), 7.82
(d, 1H, J = 8.0 Hz, H-10), 7.91 (s, 1H, H-7), 8.53 (d, 1H,
J = 8.4 Hz, H-16), 8.68 (s, 1H, H-12), 8.84 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 20.92 (CH3),
21.81 (CH3), 77.84 (C–CN), 87.80 (C–CN), 115.00,
115.88, 116.40, 119.43, 120.34, 122.30, 122.70, 125.19,
125.99, 127.11, 127.44, 128.80, 129.01, 130.40, 132.07,
134.90, 141.80, 144.98, 146.60, 147.32, 148.80, 151.16,
152.51, 157.92 (Ar–C); Anal. Calcd. for C30H20N6O
(480.52 g/mol): C 74.99, H 4.20, N 17.49 % Found: C
75.12, H 3.94, N 17.29 %; MS (m/z): 480.8 (M?ꢀ).
1-Amino-3-[2-(4-fluorophenoxy)-6-methoxyquinolin-3-
yl]pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (6l)
Yield 76 %; m.p. 260–261 °C; IR (KBr, cm-1): 3,435 and
3,300 (asym. and sym. str. of –NH2), 2,180 (–C:N str.),
1,220 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 3.82 (s, 3H, OCH3, C-14), 7.12 (d, 2H, J = 8.4 Hz,
H-23,21), 7.25 (d, 2H, J = 8.4 Hz, H-20,24), 7.53 (t, 1H,
J1 = 7.6, J2 = 7.6, H-9), 7.68 (m, 3H, H-13,8,15), 7.87 (d,
1H, J = 8.0 Hz, H-16), 7.95 (d, 1H, J = 8.0 Hz, H-10),
8.57 (s, 1H, H-12), 8.64 (d, 1H, J = 8.0, H-7), 8.80 (br s,
2H, NH2); 13C NMR (100 MHz, DMSO-d6) d: 55.00
(OCH3), 77.60 (C–CN), 87.80 (C–CN), 115.55, 115.78,
116.19, 119.56, 120.05, 122.74, 123.40, 125.17, 127.27,
127.64, 129.11, 133.88, 135.77, 141.12, 144.89, 145.19,
146.81, 147.60, 149.01, 152.61, 154.73, 156.95, 157.99,
158.07 (Ar–C); Anal. Calcd. for C29H17FN6O2 (500.48 g/
mol): C 69.59, H 3.42, N 16.79 % Found: C 69.67, H 3.28,
N 17.03 %; MS (m/z): 500.1 (M?ꢀ).
1-Amino-3-[2-(4-methoxyphenoxy)quinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6o)
Yield 81 %; m.p. 269–271 °C; IR (KBr, cm-1): 3,400 and
3,330 (asym. and sym. str. of –NH2), 2,200 (–C:N str.),
1,245 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
1
d H NMR (400 MHz, DMSO-d6): d 2.56 (s, 3H, CH3,
C-8), 3.76 (s, 3H, OCH3, C-22), 7.15 (d, 2H, J = 8.4 Hz,
H-23,21), 7.23 (d, 1H, J = 8.8 Hz, H-20), 7.33 (d, 1H,
J = 8.8 Hz, H-24), 7.45 (d, 1H, J = 8.0 Hz, H-9), 7.56 (m,
2H, H-14,13), 7.75 (t, 1H, J1 = 7.2, J2 = 8.0, H-15), 7.84
(d, 1H, J = 8.0 Hz, H-10), 7.95 (s, 1H, H-7), 8.61 (d, 1H,
J = 8.4 Hz, H-16), 8.75 (s, 1H, H-12), 8.94 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 21.75 (CH3),
55.90, (OCH3), 78.12 (C–CN), 87.77 (C–CN), 115.43,
115.94, 116.42, 119.50, 120.23, 122.17, 122.70, 125.21,
126.16, 126.91, 127.42, 128.90, 129.02, 130.59, 132.03,
134.88, 141.84, 145.00, 146.60, 147.38, 148.81, 151.19,
152.66, 158.39 (Ar–C); Anal. Calcd. for C30H20N6O2
(496.52 g/mol): C 72.57, H 4.06, N 16.93 % Found: C
72.61, H 4.19, N 17.13 %; MS (m/z): 496.7 (M?ꢀ).
1-Amino-3-[2-(4-phenoxy)quinolin-3-yl]-8-
methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6m)
Yield 88 %; m.p. 233–235 °C; IR (KBr, cm-1): 3,420 and
3,340(asym.andsym. str.of–NH2),2,220(–C:Nstr.),1,230
1
1
(C–O–C ether str.); H NMR (400 MHz, DMSO-d6): d H
NMR (400 MHz, DMSO-d6): d 2.57 (s, 3H, CH3, C-8), 7.18
(d, 2H, J = 8.4 Hz, H-20,24), 7.25 (m, 3H, H-21,22,23), 7.51
(d, 1H, J = 8.0 Hz, H-9), 7.64 (m, 2H, H-14,13), 7.75 (t, 1H,
J1 = 7.2, J2 = 8.0, H-15), 7.82 (d, 1H, J = 8.0 Hz, H-10),
7.94 (s, 1H, H-7), 8.51 (d, 1H, J = 8.4 Hz, H-16), 8.62 (s, 1H,
H-12), 8.75 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6)
d: 21.78 (CH3), 78.21 (C–CN), 87.94 (C–CN), 115.22, 115.83,
116.38, 119.54, 120.15, 122.09, 122.70, 125.22, 126.20,
127.11, 127.52, 128.90, 129.01, 130.52, 132.11, 134.90,
141.85, 145.13, 146.60, 147.42, 148.80, 151.14, 152.50, 158.50
(Ar–C); Anal. Calcd. for C29H18N6O (466.49 g/mol): C 74.67,
H 3.89, N 18.02 % Found: C 74.45, H 4.06, N 17.84 %; MS
(m/z): 466.5 (M?ꢀ).
1-Amino-3-[2-(4-fluorophenoxy)quinolin-3-yl]-8-
methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6p)
Yield 80 %; m.p. 237–239 °C; IR (KBr, cm-1): 3,445 and
3,310 (asym. and sym. str. of –NH2), 2,185 (–C:N str.),
1,200 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
1-Amino-3-[2-(4-methylphenoxy)quinolin-3-yl]-8-
methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6n)
1
d H NMR (400 MHz, DMSO-d6): d 2.57 (s, 3H, CH3,
C-8), 7.09 (d, 2H, J = 8.4 Hz, H-23,21), 7.25 (d, 1H,
J = 8.8 Hz, H-20), 7.38 (d, 1H, J = 8.8 Hz, H-24), 7.47
(d, 1H, J = 8.0 Hz, H-9), 7.55 (m, 2H, H-14,13), 7.76 (t,
1H, J1 = 7.2, J2 = 8.0, H-15), 7.87 (d, 1H, J = 8.0 Hz,
Yield 84 %; m.p. 257–259 °C; IR (KBr, cm-1): 3,455 and
3,320 (asym. and sym. str. of –NH2), 2,215 (–C:N str.),
123

Med Chem Res
H-10), 7.96 (s, 1H, H-7), 8.51 (d, 1H, J = 8.4 Hz, H-16),
8.66 (s, 1H, H-12), 8.81 (br s, 2H, NH2); 13C NMR
(100 MHz, DMSO-d6) d: 21.84 (CH3), 78.10 (C–CN),
87.95 (C–CN), 115.03, 116.00, 116.33, 119.50, 120.01,
122.22, 122.80, 125.21, 126.20, 127.11, 127.45, 128.90,
129.00, 130.50, 132.06, 134.88, 141.79, 145.04, 146.43,
147.39, 148.80, 151.16, 152.90, 158.48 (Ar–C); Anal.
Calcd. for C29H17FN6O (484.48 g/mol): C 71.89, H 3.54, N
17.35 % Found: C 71.75, H 4.71, N 17.42 %; MS (m/z):
484.4 (M?ꢀ).
(494.55 g/mol): C 75.29, H 4.48, N 16.99 % Found: C 75.38,
H 4.30, N 17.17 %; MS (m/z): 494.6 (M?ꢀ).
1-Amino-3-[2-(4-methoxyphenoxy)-6-methylquinolin-
3-yl]-8-methylpyrido[1,2-a]benzimidazole-2,
4-dicarbonitrile (6s)
Yield 78 %; m.p. 251–253 °C; IR (KBr, cm-1): 3,470 and
3,320(asym.andsym. str.of–NH2),2,220(–C:Nstr.),1,245
(C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d 2.53
(s, 3H, CH3, C-8), 2.56 (s, 3H, CH3, C-14), 3.78 (s, 3H, OCH3,
C-22), 7.01 (d, 2H, J = 8.4 Hz, H-23,21), 7.21 (d, 1H,
J = 8.8 Hz, H-20), 7.27 (d, 1H, J = 8.8 Hz, H-24), 7.43 (d,
1H, J = 8.0 Hz, H-9), 7.61 (s, 1H, H-13), 7.70 (d, 1H,
J = 8.4 Hz, H-15), 7.77 (d, 1H, J = 8.0 Hz, H-10), 7.86 (s,
1H, H-7), 8.49 (d, 1H, J = 8.0 Hz, H-16), 8.58 (s, 1H, H-12),
8.77 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) d:
21.31 (CH3), 21.78 (CH3), 55.87 (OCH3), 77.68 (C–CN),
87.79 (C–CN), 115.04, 116.01, 119.09, 120.01, 123.33,
124.15, 125.13, 126.95, 127.13, 127.72, 128.53, 132.66,
133.96, 135.59, 141.10, 144.91, 145.50, 146.75, 147.00,
148.69, 152.21, 154.48, 156.95, 157.95, (Ar–C); Anal. Calcd.
for C31H22N6O2 (510.55 g/mol): C 72.93, H 4.34, N 16.46 %
Found: C 73.04, H 4.32, N 16.51 %; MS (m/z): 510.2 (M?).
1-Amino-3-[2-(4-phenoxy)-6-methylquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6q)
Yield 87 %; m.p. 246–248 °C; IR (KBr, cm-1): 3,410 and
3,325 (asym. and sym. str. of –NH2), 2,195 (–C:N str.),
1,235 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d
2.53 (s, 3H, CH3, C-8), 2.56 (s, 3H, CH3, C-14), 7.16 (d, 2H,
J = 8.4 Hz, H-20,24), 7.28 (m, 3H, H-21,22,23), 7.46 (d,
1H, J = 8.0 Hz, H-9), 7.63 (s, 1H, H-13), 7.73 (d, 1H,
J = 8.4 Hz, H-15), 7.79 (d, 1H, J = 8.0 Hz, H-10), 7.89 (s,
1H, H-7), 8.51 (d, 1H, J = 8.0 Hz, H-16), 8.68 (s, 1H, H-12),
8.87 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) d:
21.32 (CH3), 21.78 (CH3), 55.87 (OCH3), 78.13 (C–CN),
87.84 (C–CN), 115.50, 115.95, 118.89, 120.04, 123.30,
124.10, 125.09, 127.00, 127.24, 127.70, 128.50, 132.65,
134.06, 135.44, 141.33, 145.01, 145.63, 146.70, 147.08,
148.70, 152.66, 154.52, 157.35, 158.09, (Ar–C); Anal.
Calcd. for C30H20N6O (480.52 g/mol): C 74.99, H 4.20, N
17.49 % Found: C 74.83, H 4.33, N 17.52 %; MS (m/z):
480.5 (M?ꢀ).
1-Amino-3-[2-(4-fluorophenoxy)-6-methylquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6t)
Yield 75 %; m.p. 275–277 °C; IR (KBr, cm-1): 3,465 and
3,345 (asym. and sym. str. of –NH2), 2,225 (–C:N str.),
1,230 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
1
d H NMR (400 MHz, DMSO-d6): d 2.50 (s, 3H, CH3,
C-8), 2.58 (s, 3H, CH3, C-14), 6.99 (d, 2H, J = 8.4 Hz,
H-23,21), 7.18 (d, 1H, J = 8.8 Hz, H-20), 7.25 (d, 1H,
J = 8.8 Hz, H-24), 7.40 (d, 1H, J = 8.0 Hz, H-9), 7.57 (s,
1H, H-13), 7.69 (d, 1H, J = 8.4 Hz, H-15), 7.75 (d, 1H,
J = 8.0 Hz, H-10), 7.85 (s, 1H, H-7), 8.47 (d, 1H,
J = 8.0 Hz, H-16), 8.65 (s, 1H, H-12), 8.79 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) d: 21.33 (CH3),
21.80 (CH3), 77.64 (C–CN), 87.89 (C–CN), 115.08,
116.04, 119.06, 120.02, 123.23, 124.12, 124.93, 127.05,
127.09, 127.92, 128.83, 132.46, 134.07, 135.79, 141.17,
144.81, 145.56, 146.77, 147.07, 148.59, 152.29, 154.38,
157.11, 158.60, (Ar–C); Anal. Calcd. for C30H19FN6O
(498.51 g/mol): C 72.28, H 3.84, N 16.86 % Found: C
72.44, H 3.72, N 17.01 %; MS (m/z): 498.1 (M?ꢀ).
1-Amino-3-[2-(4-methylphenoxy)-6-methylquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6r)
Yield 83 %; m.p. 244–245 °C; IR (KBr, cm-1): 3,480 and
3,310 (asym. and sym. str. of –NH2), 2,190 (–C:N str.),
1,210 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6): d
1H NMR (400 MHz, DMSO-d6): d 2.33 (s, 3H, CH3, C-22),
2.52 (s, 3H, CH3, C-8), 2.59 (s, 3H, CH3, C-14), 7.08 (d, 2H,
J = 8.4 Hz, H-23,21), 7.26 (d, 1H, J = 8.8 Hz, H-20), 7.34
(d, 1H, J = 8.8 Hz, H-24), 7.49 (d, 1H, J = 8.0 Hz, H-9),
7.65 (s, 1H, H-13), 7.70 (d, 1H, J = 8.4 Hz, H-15), 7.78 (d,
1H, J = 8.0 Hz, H-10), 7.87 (s, 1H, H-7), 8.54 (d, 1H,
J = 8.0 Hz, H-16), 8.68 (s, 1H, H-12), 8.83 (br s, 2H, NH2);
13C NMR (100 MHz, DMSO-d6) d: 20.94 (CH3), 21.31
(CH3), 21.85 (CH3), 78.25 (C–CN), 87.89 (C–CN), 115.37,
116.02, 118.99, 120.08, 123.30, 124.20, 125.17, 126.90,
127.21, 127.80, 128.60, 132.70, 133.95, 135.60, 141.13,
144.77, 145.51, 146.80, 147.03, 148.65, 152.20, 154.50,
156.90, 157.96, (Ar–C); Anal. Calcd. for C31H22N6O
1-Amino-3-[2-(4-phenoxy)-6-methoxyquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6u)
Yield 86 %; m.p. 275–276 °C, IR (KBr, cm-1): 3,410 and
3,340 (asym. and sym. str. of –NH2), 2,210 (–C:N str.),
123

Med Chem Res
1,185 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.56 (s, 3H, CH3, C-8), 3.90 (s, 3H, OCH3, C-14), 7.12 (d,
2H, J = 8.4 Hz, H-20,24), 7.21 (m, 3H, H-21,22,23), 7.40
(d, 1H, J = 8.0 Hz, H-9), 7.58 (s, 1H, H-13), 7.68 (d, 1H,
J = 8.4 Hz, H-15), 7.75 (d, 1H, J = 8.0 Hz, H-10), 7.84 (s,
1H, H-7), 8.53 (d, 1H, J = 8.0 Hz, H-16), 8.67 (s, 1H,
H-12), 8.82 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-
d6) d: 21.80 (CH3), 56.10 (OCH3), 77.73 (C–CN), 87.80
(C–CN), 115.07, 116.05, 119.19, 120.21, 123.53, 124.25,
125.17, 127.05, 127.34, 127.82, 128.63, 132.72, 134.11,
135.75, 141.33, 144.97, 145.60, 146.75, 147.09, 148.59,
152.11, 154.58, 156.87, 157.18, (Ar–C); Anal. Calcd. for
C30H20N6O2 (496.52 g/mol): C 72.57, H 4.06, N 16.93 %
Found: C 72.51, H 4.26, N 16.84 %; MS (m/z): 496.3 (M?ꢀ).
78.00 (C–CN), 87.92 (C–CN), 115.08, 115.90, 119.16,
120.05, 123.24, 124.17, 125.18, 127.12, 127.22, 127.68,
128.86, 132.73, 133.78, 135.60, 141.17, 144.99, 145.54,
146.70, 147.06, 148.70, 152.20, 154.50, 157.24, 158.55,
(Ar–C); Anal. Calcd. for C31H22N6O3 (526.54 g/mol): C
70.71, H 4.21, N 15.96 % Found: C 70.55, H 4.33, N
16.03 %; MS (m/z): 526.6 (M?ꢀ).
1-Amino-3-[2-(4-fluorophenoxy)-6-methoxyquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6x)
Yield 77 %; m.p. 255–256 °C; IR (KBr, cm-1): 3,460 and
3,330 (asym. and sym. str. of –NH2), 2,210 (–C:N str.),
1,240 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.55 (s, 3H, CH3, C-8), 3.82 (s, 3H, OCH3, C-14), 7.04
(d, 2H, J = 8.4 Hz, H-23,21), 7.23 (d, 1H, J = 8.8 Hz,
H-20), 7.29 (d, 1H, J = 8.8 Hz, H-24), 7.42 (d, 1H,
J = 8.0 Hz, H-9), 7.60 (s, 1H, H-13), 7.71 (d, 1H,
J = 8.4 Hz, H-15), 7.79 (d, 1H, J = 8.0 Hz, H-10), 7.87
(s, 1H, H-7), 8.51 (d, 1H, J = 8.0 Hz, H-16), 8.65 (s, 1H,
H-12), 8.95 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-
d6) d: 21.77 (CH3), 56.05 (OCH3), 78.15 (C–CN), 87.83
(C–CN), 115.23, 116.09, 119.11, 119.98, 123.24, 124.26,
125.32, 126.98, 127.34, 127.68, 128.60, 132.59, 133.90,
135.61, 141.23, 144.77, 144.99, 146.81, 147.05, 148.72,
152.20, 155.97, 157.44, 158.04, (Ar–C); Anal. Calcd. for
C30H19FN6O2 (514.51 g/mol): C 70.03, H 3.72, N 16.33 %
Found: C 69.95, H 3.63, N 16.50 %; MS (m/z): 514.3
(M?ꢀ).
1-Amino-3-[2-(4-methylphenoxy)-6-methoxyquinolin-3-yl]-
8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6v)
Yield 82 %; m.p. 250–252 °C; IR (KBr, cm-1): 3,440 and
3,325 (asym. and sym. str. of –NH2), 2,200 (–C:N str.),
1,200 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.34 (s, 3H, CH3, C-22), 2.56 (s, 3H, CH3, C-8), 3.92 (s,
3H, OCH3, C-14), 7.11 (d, 2H, J = 8.4 Hz, H-23,21), 7.28
(d, 1H, J = 8.8 Hz, H-20), 7.32 (d, 1H, J = 8.8 Hz, H-24),
7.48 (d, 1H, J = 8.0 Hz, H-9), 7.62 (s, 1H, H-13), 7.72 (d,
1H, J = 8.4 Hz, H-15), 7.79 (d, 1H, J = 8.0 Hz, H-10),
7.88 (s, 1H, H-7), 8.54 (d, 1H, J = 8.0 Hz, H-16), 8.73 (s,
1H, H-12), 8.92 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) d: 20.91 (CH3), 21.85 (CH3), 56.16 (OCH3),
78.15 (C–CN), 87.84 (C–CN), 115.49, 116.03, 118.99,
120.18, 123.16, 124.20, 125.16, 126.90, 127.05, 127.68,
128.50, 132.70, 133.94, 135.60, 141.11, 144.77, 145.54,
146.80, 147.01, 148.70, 152.20, 154.50, 156.90, 158.24,
(Ar–C); Anal. Calcd. for C31H22N6O2 (510.55 g/mol): C
72.93, H 4.34, N 16.46 % Found: C 73.08, H 4.29, N
16.54 %; MS (m/z): 510.2 (M?ꢀ).
Conclusion
A series of some new pyrido[1,2-a]benzimidazole deriva-
tives 6a–x containing b-aryloxyquinoline moiety has been
synthesized via microwave-assisted one-pot multicompo-
nent reaction in the presence of non-hazardous base
(NaOH). This synthetic strategy allows the construction of
relatively complicated pyridine frameworks equipped with
a benzimidazole unit and introduction of substituted b-a-
ryloxyquinolines at the fourth positions of pyridine with
fascinating yield in short time. From the appraisal of the
antimicrobial activity data, it can be concluded that com-
pounds 6a, 6e, 6n, 6p, and 6u having excellent antibacte-
rial property, while compounds 6o and 6p showed better
antifungal property. Evaluation of antitubercular activity
shows that compounds 6t and 6x found to have better
antitubercular activity and compound 6p is appeared as the
promising antimicrobial member with significant antitu-
bercular activity. From the SAR study, it is commendable
to mention that the antimicrobial and antitubercular activ-
ities of the title compounds depends not only on the
1-Amino-3-[2-(4-methoxyphenoxy)-6-methoxyquinolin-3-
yl]-8-methylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile
(6w)
Yield 80 %; m.p. 279–280 °C; IR (KBr, cm-1): 3,405 and
3,320 (asym. and sym. str. of –NH2), 2,200 (–C:N str.),
1,235 (C–O–C ether str.); 1H NMR (400 MHz, DMSO-d6):
d 2.57 (s, 3H, CH3, C-8), 3.78 (s, 3H, OCH3, C-22), 3.83 (s,
3H, OCH3, C-14), 7.01 (d, 2H, J = 8.4 Hz, H-23,21), 7.22
(d, 1H, J = 8.8 Hz, H-20), 7.28 (d, 1H, J = 8.8 Hz, H-24),
7.42 (d, 1H, J = 8.0 Hz, H-9), 7.60 (s, 1H, H-13), 7.69 (d,
1H, J = 8.4 Hz, H-15), 7.78 (d, 1H, J = 8.0 Hz, H-10),
7.92 (s, 1H, H-7), 8.64 (d, 1H, J = 8.0 Hz, H-16), 8.71 (s,
1H, H-12), 8.85 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) d: 21.83 (CH3), 55.89 (OCH3), 55.98 (OCH3),
123

Med Chem Res
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bicyclic heteroaromatic pharmacophore appended through
ether linked aryl ring but also on the nature of the
peripheral substituents and may also upon their spatial
relationship and positional changes. This study highlights
the identification of new molecules as good antimicrobial
and antitubercular agents which can be of interest for fur-
ther detailed pre-clinical investigations.
Acknowledgments The authors are thankful to Department of
Chemistry, Sardar Patel University for providing research facilities and
NMR facility. We are also thankful to Vaibhav Analytical Laboratory,
Ahmedabad for the FT-IR and Sophisticated Instrumentation Centre
for Applied Research and Training (SICART), Vallabh Vidyanagar for
elemental analysis. As well as Oxygen Healthcare Research Pvt. Ltd.,
Ahmedabad for providing mass spectrometry facilities and Microcare
Laboratory, Surat for antimicrobial screening of the compounds
reported herein. One of the authors is grateful to UGC, New Delhi for a
Research Fellowship in Sciences for Meritorious Students.
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