Synthesis and antimicrobial activity of tetrazolo[1,5-a]-quinoline-4- carbonitrile derivatives

Article abstract of DOI:10.1007/s00706-010-0324-2

A series of new tetrazolo[1,5-a]quinoline-4-carbonitrile derivatives were synthesized for the first time via tetrazolo[1,5-a]quinoline derivatives. Elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data were used to elucidate the structures of all newly synthesized compounds. In vitro antimicrobial activities of synthesized compounds were investigated against Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, and two fungi, Candida albicans and Aspergillus niger, in comparison with standard drugs. Some of the tested compounds showed significant antimicrobial activity. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-010-0324-2

Monatsh Chem (2010) 141:787–791
DOI 10.1007/s00706-010-0324-2
ORIGINAL PAPER
Synthesis and antimicrobial activity of tetrazolo[1,5-a]-
quinoline-4-carbonitrile derivatives
•
Amol H. Kategaonkar Vilas B. Labade
•
Pravin V. Shinde Atul H. Kategaonkar
•
•
•
Bapurao B. Shingate Murlidhar S. Shingare
Received: 23 December 2009 / Accepted: 2 May 2010 / Published online: 3 June 2010
Ó Springer-Verlag 2010
Abstract A series of new tetrazolo[1,5-a]quinoline-4-
carbonitrile derivatives were synthesized for the first time
via tetrazolo[1,5-a]quinoline derivatives. Elemental anal-
is considered as a carboxylic group pharmacore, possesses
a wide range of biological activities. Several substituted
tetrazoles have been shown to possess anticonvulsant [3],
anti-inflammatory [4], CNS dispersant [5], antimicrobial
[6], anti-AIDS [7], and antifertility activity [8, 9].
1
ysis, IR, H NMR, 13C NMR, and mass spectral data were
used to elucidate the structures of all newly synthesized
compounds. In vitro antimicrobial activities of synthesized
compounds were investigated against Gram-positive
Bacillus subtilis, Gram-negative Escherichia coli, and two
fungi, Candida albicans and Aspergillus niger, in com-
parison with standard drugs. Some of the tested compounds
showed significant antimicrobial activity.
Nitriles are of particular interest in preparative organic
chemistry due to their rich chemistry [10–14]. They are
useful precursors for the synthesis of amines, carboxylic
acids, amides, ketones, and heterocyclic compounds such
as tetrazoles [15–17], thiazoles [18, 19], oxazoles [20, 21],
2-oxazolines [22], and 1,2-diarylimidazoles [23]. It has
also been well documented that the cyano group itself is
present in HIV protease inhibitors, 5-lypoxygenase inhib-
itors, and many other significant bioactive molecules [12,
13]. They are usually prepared by nucleophilic substitution
with the cyanide anion or by regenerating the cyano group
via oxidation, rearrangement, or elimination [14]. The
conversion of aldehydes into nitriles is a useful transfor-
mation [24, 25] and a topic of current interest to organic
chemists. To develop our ongoing research work [26–29],
we have synthesized the title compounds.
Keywords Tetrazolo[1,5-a]quinoline Á Nitrile Á
Antibacterial Á Antifungal
Introduction
Quinolines and their derivatives are important constituents
of pharmacologically active synthetic compounds. The
quinoline nucleus also occurs in the structure of numerous
naturally occurring alkaloids which have been associated
with a broad spectrum of biological activities [1, 2]. The
fusion of quinoline to the tetrazole ring is known to
increase the biological activity. The tetrazole group, which
Results and discussion
Chemistry
A. H. Kategaonkar Á V. B. Labade Á P. V. Shinde Á
B. B. Shingate Á M. S. Shingare (&)
In the present article, we report straightforward and con-
venient syntheses of new nitrile derivatives containing the
highly bioactive tetrazole moiety. The key intermediate
tetrazoloquinoline derivatives 2a–2i were prepared by the
reaction of 2-chloroquinoline-3-carbaldehyde derivatives
1a–1i with sodium azide in dimethyl sulfoxide (DMSO)/
AcOH mixture [30, 31]. We synthesized title com-
pounds 3a–3i by the reaction of tetrazoloquinoline
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad,
Maharashtra 431 004, India
e-mail: prof_msshingare@rediffmail.com
A. H. Kategaonkar
Pharmacology Laboratory, Maharashtra Institute of Pharmacy,
Pune, Maharashtra 411 038, India
123

788
A. H. Kategaonkar et al.
Scheme 1
N
R1
R2
R1
R2
R1
R2
C
N
O
b
O
a
N
Cl
N
N
N
N
R3
R3
N
R3
N
N
1a 1i
-
2a 2i
-
3a 3i
-
a) R1 = R2 = R3 = H;
b) R2 = R3 = H; R1 = Me;
c) R1 = R3 = H; R2 = Me; d) R1 = R2 = H; R3 = Me;
e) R2 = R3 = H; R1 = OMe; f) R1 = R3 = H; R2 = OMe;
g) R1 = R2 = H; R3 = OMe; h) R2 = R3 = H; R1 = OEt;
i) R1 = R2 = H; R3 = Et.
derivatives 2a–2i, hydroxylamine hydrochloride, and for-
mic acid under reflux in moderate to good yields (74–87%)
as outlined in Scheme 1. The structures of compounds 3a–
3i were confirmed by using analytical and spectral data. IR
spectra of 3a–3i showed an intense band in the region of
2,224–2,241 cm-1 of the m(C:N) stretch, which confirms
the formation of the desired compounds.
Table 1 Antibacterial and antifungal activity of compounds 3a–3i
Compound
B. subtilis
ZIa (MIC)b
E. coli
ZI (MIC)
C. albicans
ZI (MIC)
A. niger
ZI (MIC)
3a
14.0 (15)
12.4 (25)
16.0 (10)
14.0 (15)
15.0 (15)
12.0 (10)
18.0 (10)
14.0 (10)
12.0 (10)
16.8 (10)
NT
13.0 (15)
13.2 (15)
13.0 (15)
13.0 (15)
12.8 (15)
12.6 (10)
14.0 (10)
14.6 (10)
12.0 (10)
16.7 (10)
NT
12.0 (10)
12.0 (15)
13.0 (10)
12.0 (15)
13.0 (15)
14.0 (10)
12.0 (15)
12.0 (15)
14 (10)
15.0 (10)
12.0 (20)
13.0 (15)
12.0 (15)
11.0 (25)
16.0 (15)
15.0 (10)
13.0 (15)
14.7 (20)
NT
3b
3c
3d
3e
Biological assays
3f
3g
The antimicrobial activity of the synthesized compounds
was screened by the agar cup plate method against a panel
of human pathogenic microorganisms: one Gram-positive
strain (Bacillus subtilis NCIM 2250) and one-Gram nega-
tive strain (Escherichia coli ATCC 25922) were used for
the antibacterial assay, whereas Candida albicans MTCC
277 and Aspergillus niger NCIM 545 were used for the
antifungal assay. Microorganisms were maintained at
37 °C on Mueller–Hinton (MH) agar slants. MH agar and
Czapek–Dox broth were used to evaluate antibacterial and
antifungal activity. All compounds were dissolved in
DMSO in the required concentrations. Commercial anti-
biotics such as streptomycin (strept.) and griseofluvin
(gris.) in DMSO served as reference standards to compare
inhibition of growth. The plates containing bacterial
organism were incubated at 37 0.5 °C and plates con-
taining fungal organism were incubated at 28 0.5 °C for
48 h. The zone of inhibition was calculated by measuring
the diameter of the zone of inhibition of bacterial and
fungal growth around the disc. An average of three inde-
pendent determinations was recorded.
3h
3i
Strept.
Gris.
a
NTc
17.1 (10)
16.6 (10)
Zone of inhibition in mm
b
c
Minimum inhibitory concentration in lg/cm3
Not tested
plate that failed to show any visible macroscopic growth
was considered as its MIC. The MIC determination was
performed in triplicate for each organism and the experi-
ment was repeated where necessary.
In vitro antibacterial and antifungal activity was screened
by considering the zone of growth inhibition. The synthe-
sized compounds 3a–3i were screened with their different
concentrations with standard antibiotics such as streptomy-
cin (10 lg/cm3) and griseofluvin (10 lg/cm3; Table 1). The
results showed that most of our designed compounds had
moderate antibacterial and antifungal activities in between
10 and 25 lg/cm3 MIC values against standard antibiotics in
vitro as shown in Table 1. Compounds 3c (R1 = R3 = H,
R2 = Me), 3e (R2 = R3 = H, R1 = OMe), and 3g
(R1 = R2 = H, R3 = OMe) have a zone of inhibition (16.0,
15.0, and 18.0 mm) comparable to that of the standard
streptomycin (16.8 mm) against Bacillus subtilis. The data
indicate that a change in the substituent might also affect the
antibacterial activity of title compounds 3a–3i. Comparison
of biological activities among 3a–3i shows functional
The minimum inhibitory concentrations (MICs) of the
samples were determined by the cup plate method on MH
agar plates according to National Committee for Clinical
Laboratory Standards (NCCLS) (M7-A5 January 2000).
Thus MH agar containing the concentrations 0 (control), 1,
2, 3, 5, 10, 15, 20, 30, and 40 lg/cm3 MH were melted and
poured into Petri dishes. The plates were incubated at
37 °C, examined after 24 h, and incubated further for 72 h,
where necessary. The lowest concentration of the drug in a
123

Synthesis and antimicrobial activity
789
groups as R1/R3 = OMe or R2 = Me to be potentially more
active than R1/R = Me, R2 = OMe, R1 = OEt, or R3 = Et
against Bacillus subtilis.
(q, 2H, J = 6.0 Hz, O–CH2–CH3), 7.70–7.82 (m, 2H,
Ar–H), 8.57 (s, 1H, Ar–H), 8.70 (s, 1H, Ar–H), 10.75 (s,
1H, CHO) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 14.4, 64.2, 113.7, 116.5, 118.3, 122.5, 125.3, 126.4,
143.1, 146.3, 151.3, 178.4 ppm; MS: m/z = 243 [M ? 1].
In antifungal assays, compounds 3a (R1 = R2 = R3 =
H), 3f (R1 = R3 = H, R2 = OMe), and 3g (R1 = R2 = H,
R3 = OMe) showed 15.0, 16.0, and 15.0 mm zones of
inhibition, respectively, against Aspergillus niger, which
might be an indication that the functional groups R2/
R3 = OMe and R1 = R2 = R3 = H impart the antifungal
potency of the respective compounds, which in each case is
comparable to that of standard griseofluvin (16.6 mm).
9-Ethyltetrazolo[1,5-a]quinoline-4-carbaldehyde
(2i, C12H10N4O)
ꢀ
Yield 79%; m.p.: 162–164 °C; IR (KBr): m = 3,123 (arom.
C–H), 2,843 (ald. C–H), 1,742 (ald. C=O), 1,541 (tetrazole
1
stretch), 1,458 (arom. C=C) cm-1; H NMR (200 MHz,
CDCl3): d = 1.36 (t, 3H, J = 8.0 Hz, CH2–CH3), 2.89 (q,
2H, J = 8.0 Hz, CH2–CH3), 7.59–7.78 (m, 2H, Ar–H),
8.52 (s, 1H, Ar–H), 8.64 (s, 1H, Ar–H), 10.54 (s, 1H, CHO)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 14.7, 28.3,
105.6, 115.9, 119.1, 124.3, 128.8, 130.5, 138.5, 144.3,
153.5, 179.1 ppm; MS: m/z = 227 [M ? 1].
Conclusion
In conclusion, we have synthesized new tetrazolo[1,5-a]-
quinoline-4-carbonitrile derivatives via tetrazolo[1,5-a]-
quinoline derivatives and evaluated their antimicrobial
activities. All compounds demonstrated potent inhibition
against all the strains tested. Furthermore, we also conclude
that compound 3g showed better antibacterial activity than
the standard streptomycin.
General procedure for the synthesis of compounds 3a–3i
A mixture of tetrazolo[1,5-a]quinoline-4-carbaldehyde (2,
10 mmol), hydroxylamine hydrochloride (13 mmol), and
25 cm3 formic acid was heated under reflux for 2–3 h. The
progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was
poured on crushed ice. The solid obtained was extracted
with EtOAc (2 9 50 cm3). The organic extract was washed
with water and brine. The solvent was removed under
reduced pressure to afford crude product 3, which was
purified by column chromatography on silica gel by using
hexane/EtOAc (8:2) as eluent.
Experimental
All chemicals and solvents were purchased from Merck
(Darmstadt, Germany), Spectrochem (Mumbai, India), and
S.D. Fine-chem. (Mumbai, India). Solvents were com-
mercially available materials of reagent grade. Melting
points were determined in open capillaries on Kumar’s
melting point apparatus (India). IR spectra were recorded
Tetrazolo[1,5-a]quinoline-4-carbonitrile (3a, C10H5N5)
ꢀ
1
Yield 85%; m.p.: 276–278 °C; IR (KBr): m = 3,066 (arom.
on JASCO FT-IR 4100 (Japan) using KBr discs. H NMR
C–H), 2,241 (C:N), 1,531 (tetrazole stretch), 1,460
spectra were recorded on Varian Mercury Plus (400), and
Bruker DRX-300 and AC200 NMR spectrometer. Mass
spectra were recorded on Single-Quadrupole Mass Detec-
tor 3100, Waters. Elemental analyses were performed on
CHNS analyzer Flash 1112, Thermo Finnigan, and results
agreed with calculated values. The progress of the reactions
was monitored by TLC on Merck silica plates.
(arom. C=C) cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 7.90 (t, 1H, J = 7.5 Hz, Ar–H), 8.09 (t, 1H,
J = 7.5 Hz, Ar–H), 8.32 (d, 1H, J = 8.1 Hz, Ar–H),
8.68 (d, 1H, J = 8.1 Hz, Ar–H), 9.18 (s, 1H, Ar–H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 97.4, 114.1,
116.2, 121.8, 128.2, 129.5, 136.2, 138.3, 142.8, 149.2 ppm;
MS: m/z = 196.1 [M ? 1].
General procedure for the synthesis of compounds 2a–2i
7-Methyltetrazolo[1,5-a]quinoline-4-carbonitrile
(3b, C11H7N5)
Compounds 2a–2i were prepared by reported methods
[30, 31].
ꢀ
Yield 78%; m.p.: 248–250 °C; IR (KBr): m = 3,054 (arom.
C–H), 2,239 (C:N), 1,524 (tetrazole stretch), 1,481
(arom. C=C) cm-1 1H NMR (300 MHz, DMSO-d6):
;
7-Ethoxytetrazolo[1,5-a]quinoline-4-carbaldehyde
(2h, C12H10N4O2)
d = 2.56 (s, 3H, Ar–CH3), 7.97 (d, 1H, J = 8.7 Hz, Ar–
H), 8.07 (s, 1H, Ar–H), 8.55 (d, 1H, J = 8.7 Hz, Ar–H),
9.07 (s, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 20.8, 97.1, 114.1, 116.3, 122.7, 129.5, 129.9, 136.0,
138.9, 143.0, 145.5 ppm; MS: m/z = 210.2 [M ? 1].
ꢀ
Yield 85%; m.p.: 100–102 °C; IR (KBr): m = 3,097 (arom.
C–H), 2,784 (ald. C–H), 1,727 (ald. C=O), 1,537 (tetrazole
1
stretch), 1,464 (arom. C=C) cm-1; H NMR (200 MHz,
CDCl3): d = 1.24 (t, 3H, J = 6.0 Hz, O–CH2–CH3), 3.68
123

790
A. H. Kategaonkar et al.
8-Methyltetrazolo[1,5-a]quinoline-4-carbonitrile
(3c, C11H7N5)
7-Ethoxytetrazolo[1,5-a]quinoline-4-carbonitrile
(3h, C12H9N5O)
ꢀ
ꢀ
Yield 87%; m.p.: 232–234 °C; IR (KBr): m = 3,084 (arom.
Yield 78%; m.p.: 298–300 °C; IR (KBr): m = 3,074 (arom.
C–H), 2,235 (C:N), 1,537 (tetrazole stretch), 1,467
C–H), 2,224 (C:N), 1,521 (tetrazole stretch), 1,478
(arom. C=C) cm-1
;
1H NMR (300 MHz, DMSO-d6):
(arom. C=C) cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 2.43 (s, 3H, Ar–CH3), 7.78 (d, 1H, J = 8.7 Hz, Ar–
H), 7.91 (s, 1H, Ar–H), 8.43 (d, 1H, J = 8.7 Hz, Ar–H),
9.16 (s, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 20.5, 97.4, 114.6, 116.1, 122.2, 129.8, 130.0, 136.3,
138.4, 144.1, 146.3 ppm; MS: m/z = 210.2 [M ? 1].
d = 1.35 (t, 3H, J = 6.9 Hz, Ar–OCH2–CH3), 4.34 (q, 2H,
J = 6.9 Hz, Ar–OCH2–CH3), 7.24–7.42 (m, 3H, Ar–H),
8.63 (s, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 14.6, 63.6, 106.2, 110.2, 116.1, 117.1, 118.2, 124.2,
138.8, 148.9, 153.8, 158.3 ppm; MS: m/z = 240.1
[M ? 1].
9-Methyltetrazolo[1,5-a]quinoline-4-carbonitrile
(3d, C11H7N5)
9-Ethyltetrazolo[1,5-a]quinoline-4-carbonitrile
(3i, C12H9N5)
ꢀ
Yield 74%; m.p.: 244–246 °C; IR (KBr): m = 3,097 (arom.
ꢀ
C–H), 2,239 (C:N), 1,528 (tetrazole stretch), 1,470
Yield 76%; m.p.: 178–180 °C; IR (KBr): m = 3,084 (arom.
(arom. C=C) cm-1
;
1H NMR (300 MHz, DMSO-d6):
C–H), 2,232 (C:N), 1,524 (tetrazole stretch), 1,465
d = 2.51 (s, 3H, Ar–CH3), 7.87 (s, 1H, Ar–H), 8.01 (d, 1H,
J = 8.7 Hz, Ar–H), 8.57 (d, 1H, J = 8.7 Hz, Ar–H), 9.04
(s, 1H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 20.1, 97.3, 114.1, 116.7, 123.1, 129.4, 129.9, 136.8,
138.3, 144.1, 147.1 ppm; MS: m/z = 210.2 [M ? 1].
(arom. C=C) cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 1.36 (t, 3H, J = 6.9 Hz, Ar–CH2–CH3), 3.55 (q, 2H,
J = 6.9 Hz, Ar–CH2–CH3), 7.24 (t, 1H, J = 9.1 Hz, Ar–
H), 7.55 (d, 1H, J = 7.2 Hz, Ar–H), 8.77 (s, 1H, Ar–H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 14.8, 27.9,
106.2, 116.4, 118.6, 124.6, 129.7, 130.7, 138.3, 144.9,
155.9, 159.8 ppm; MS: m/z = 224.1 [M ? 1].
7-Methoxytetrazolo[1,5-a]quinoline-4-carbonitrile
(3e, C11H7N5O)
ꢀ
Yield 85%; m.p.: 200–202 °C; IR (KBr): m = 3,072 (arom.
Acknowledgments The authors would like to thank the Head of the
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad for constant encouragement and providing
necessary facilities. AmHK also wishes to express his gratitude to the
University Grant Commission, New Delhi for providing the financial
support as a Rajiv Gandhi National Fellowship to carry out the
present work.
C–H), 2,240 (C:N), 1,551 (tetrazole stretch), 1,473
(arom. C = C) cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 3.94 (s, 3H, Ar–OMe), 7.69–7.76 (m, 2H, Ar–H), 8.55
(d, 1H, J = 9.0 Hz, Ar–H), 8.99 (s, 1H, Ar–H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 56.1, 97.5, 114.1, 116.7,
118.0, 123.9, 124.1, 125.8, 142.5, 145.0, 158.7 ppm; MS:
m/z = 226.2 [M ? 1].
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9-Methoxytetrazolo[1,5-a]quinoline-4-carbonitrile
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ꢀ
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