Molecular iodine catalyzed synthesis of tetrazolo[1,5-a]-quinoline based imidazoles as a new class of antimicrobial and antituberculosis agents

Article abstract of DOI:10.1016/j.cclet.2012.11.007

A series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 6a-l have been synthesized by a reaction of tetrazolo[1,5-a]quinoline-4-carbaldehyde 3a-d, benzil 4, aromatic amine 5a-c and ammonium acetate in the presence of io

Full text of DOI:10.1016/j.cclet.2012.11.007

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1367–1370
www.elsevier.com/locate/cclet
Molecular iodine catalyzed synthesis of tetrazolo[1,5-a]-quinoline
based imidazoles as a new class of antimicrobial
and antituberculosis agents
*
Divyesh C. Mungra, Harshad G. Kathrotiya , Niraj K. Ladani,
Manish P. Patel, Ranjan G. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, India
Received 7 September 2012
Available online 1 December 2012
Abstract
A series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 6a–l have been synthesized by a
reaction of tetrazolo[1,5-a]quinoline-4-carbaldehyde 3a–d, benzil 4, aromatic amine 5a–c and ammonium acetate in the presence
of iodine through one-pot multi-component reaction (MCR) approach. All the derivatives were screened for antimicrobial and
antituberculosis activities and results worth further investigations.
# 2012 Harshad G. Kathrotiya. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Tetrazolo[1,5-a]quinoline; Imidazole; MCR; Iodine; Antimicrobial activity; Antituberculosis activity
The imidazole ring system is considered to be one of the most imperative heterocyclic substructures found in a large
number of natural products and pharmacologically active compounds. An examination of literature revealed that
imidazole and their analogues usually possess diverse biological activities like antimicrobial, antioxidant, anti-
hemolytic, cytotoxic [1], antimycobacterial [2], etc. On the other hand, the quinoline derivatives are also well known
for their various types of biological activities such as antimicrobial [3], antiproliferative [4], antimycobacterial [5],
anticancer [6], anti-HIV [7], anticoccidial [8], insecticidal [9], antidyslipidemic and antioxidative [10].
The tetrazole group has considered analogous to carboxylic group [11] as a pharmacophore. Several substituted
tetrazoles show pronounced activities including antimicrobial, antimycobacterial, antiproliferative, anticancer and
multi-drug resistance, etc. [12]. The most prominent pharmaceutical application of tetrazoles is as angiotensin II
receptor antagonists for the treatment of high-blood pressure [13]. The fusion of quinoline to the tetrazole ring is
known to increase the biological activity [14]. In particular, tetrazolo[1,5-a]quinoline-4-carbaldehyde serves as a key
synthetic intermediate for the synthesis of novel medicinally valuable compounds [15]. Encouraged by their potential
clinical applications and in continuation of our previous investigations on biopotent heterocycles [16], our efforts are
focused to design and synthesize more biologically potent heterocyclic systems via combination of diverse
therapeutically active moieties quinoline, tetrazole and imidazole together in a single scaffold.
* Corresponding author.
E-mail address: harshad_kathrotiya@yahoo.com (H.G. Kathrotiya).
1001-8417/$ – see front matter # 2012 Harshad G. Kathrotiya. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.

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D.C. Mungra et al. / Chinese Chemical Letters 23 (2012) 1367–1370
Scheme 1. General synthetic route for the synthesis of title compounds 6a–l.
Various methods for the synthesis of multi-substituted imidazole derivatives involving different catalysts including
AlCl3, FeCl3, Yb(OTf)3, NdCl3, LaCl3 [17], ZrOCl2Á8H2O [18], BF3ÁSiO2, zeolite [19], NaH2PO4 [20], cyclic
phosphoric acid [21], SiO2 [22], etc. are available but not a single report has been found where tetrazolo[1,5-
a]quinoline-4-carbaldehyde is used for the synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives using I2 as
catalyst. Also, the most suitable protocol for the synthesis of functionalized organic compounds would be a one-pot
reaction due to the fact that the synthesis can be performed without the isolation of the intermediates, without
discharging any functional groups and within shorter reaction time [23]. Thus, in a view to obtain more biologically
potent heterocyclic system, containing both therapeutically active moieties quinoline and imidazole, we report herein
the synthesis of novel imidazole analogues bearing tetrazolo[1,5-a]quinoline nucleus via MCR approach.
The imidazoles 6a–l were synthesized using iodine catalyst with good yield (76–85%). While optimizing, the yield
was very poor without catalyst. Presence of iodine in the reaction revealed good yield. Moreover, equivalence
optimization for best yield concluded to use just 10% of iodine in reaction. The key intermediate, tetrazolo[1,5-
a]quinoline-4-carbaldehyde 3a–d were synthesized by refluxing 2-chloroquinoline-3-carbaldehyde 2a–d, sodium
azide and acetic acid in ethanol according to our literature procedure [24]. 2-Chloroquinoline-3-carbaldehydes 2a–d
were synthesized according to literature procedure [25]. In present study, 1,2,4,5-tetrasubstituted imidazole
derivatives 6a–l have been synthesized by a reaction of tetrazolo[1,5-a]quinoline-4-carbaldehyde 3a–d, benzil 4,
aromatic amine 5a–c, ammonium acetate in the presence of iodine (Scheme 1).
Molecular iodine is capable of binding with the carbonyl oxygen increasing the reactivity of the parent carbonyl
compound. Iodine facilitates the formation of the diimine intermediate, which under mild acid catalysis of I2
condenses further with the carbonyl carbon of the 1,2-diketone and subsequent elimination of water affords imidazoles
6a–l (Scheme 2).
The structures of all the new synthesized compounds were established by 1H NMR, 13C NMR, FTIR, mass and
elemental analysis. The physicochemical and spectral properties of molecules of interests, compound 6h and 6l are
Scheme 2. Plausible mechanistic pathway for the synthesis of title compounds 6a–l.

D.C. Mungra et al. / Chinese Chemical Letters 23 (2012) 1367–1370
1369
Table 1
Antimicrobial and antituberculosis activities of title compounds (6a–l).
Compd.
R1
R2
Minimum inhibitory concentration (MIC, mg/mL)
Gram-positive
bacteria
Gram-negative
bacteria
Fungal species
Antituberculosis activity
S.P.
B.S.
S.T.
E.C.
A.F.
C.A.
% inhibition
M. tb H37Rv
6a
6b
6c
6d
6e
6f
H
CH3
H
250
200
250
200
200
500
100
125
500
100
250
250
125
100
250
250
200
250
200
250
>1000
>1000
1000
500
500
>1000
500
200
500
1000
1000
250
500
500
>1000
250
–
80
33
42
97
58
95
40
99
17
45
81
98
–
–
–
H
OCH3
H
–
Cl
H
62.5
62.5
100
–
H
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
200
250
250
100
100
1000
100
CH3
125
–
6g
6h
6i
OCH3
62.5
>1000
>1000
>1000
1000
1000
>1000
–
Cl
25
250
100
250
50
100
10
50
50
–
62.5
62.5
62.5
25
–
H
125
250
200
100
250
100
50
50
–
250
100
125
125
100
125
100
100
10
25
50
–
6j
CH3
–
6k
6l
OCH3
–
Cl
62.5
62.5
–
Ampicillin
Norfloxacin
Ciprofloxacin
Chloramphenicol
Griseofulvin
Nystatin
Refampicin
Isoniazid
100
10
25
50
–
–
–
–
–
–
–
–
–
–
–
–
–
100
500
100
–
–
–
–
–
–
–
100
–
–
–
–
–
–
–
98
99
40
0.20
–
–
–
–
–
–
S.P., Streptococcus pneumoniae; B.S., Bacillus subtilis; S.T., Salmonella typhi; E.C., Escherichia coli; A.F., Aspergillus fumigatus; C.A., Candida
albicans; M. tb H37Rv, Mycobacterium tuberculosis H37Rv; ‘–’ represents ‘not tested’.
presented in Ref. [26]. The target compounds were evaluated for their in vitro antimicrobial activity using broth
microdilution method according to National Committee for Clinical Laboratory Standards (NCCLS) [27].
The examination of antimicrobial activity data, it has been observed that compounds 6d, 6g, 6h and 6l showed
excellent activity against gram positive bacteria S. pneumonia compared to reference drugs. In case of inhibiting
Bacillus subtilis, compounds 6d, 6g, 6h and 6l were found to highly potent upon comparison with standard antibiotics.
Towards Salmonella typhi, compounds 6d and 6l have shown outstanding inhibitory effect, while compounds 6d and
6h displayed strong inhibition against Escherichia coli as compared to the standard drugs. Antifungal study revealed
that all the synthesized derivatives have poor activity against Aspergillus fumigatus except 6f. In comparison with
standard fungicidal griseofulvin, compounds 6d, 6h and 6l were found to posses better inhibitory results towards
Candida albicans. The encouraging results from the antimicrobial studies impelled us to go for preliminary screening
of synthesized compounds against Mycobacterium tuberculosis H37Rv, which is summarized in Table 1. In vitro
antituberculosis activity of all the newly synthesized compounds against M. tuberculosis H37Rv strain was determined
by using Lowenstein–Jensen medium (conventional method) as described by Rattan [28]. Four compounds those
exhibited highest % inhibition were again screened to get their MIC values (Table 1). Majority of the compounds
displayed poor activity while compounds 6h and 6l showed best activity against M. tuberculosis H37Rv.
The structure–activity relationship (SAR) study indicates that a change in the substituent might also affect the
antimicrobial activity of title compounds 6a–l. It is interesting to point out, those compounds 6d, 6h and 6l carrying
electron negative groups on quinoline ring displayed excellent antimicrobial activity along with antituberculosis
activity against majority of tested bacterial, fungal and tubercular strains.
Reviewing and comparing the activity data, it is worthy to mention that the compounds 6h and 6l emerged as the
promising antimicrobial member with better antitubercular activity. Iodine catalyzed multi component reaction is
proven synthetically useful to synthesize biologically active hybrid heterocyclic derivatives which is really non tedious
and effective way to prepare active molecule’s library against infectious disease. For full characterization, general
procedure for the synthesis of title compounds and method for determination of in vitro biological activity see
supporting information.

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D.C. Mungra et al. / Chinese Chemical Letters 23 (2012) 1367–1370
Acknowledgment
The authors are grateful to the Department of Chemistry, SP University, India for providing laboratory facilities.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.11.007.
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745 (C–Cl str.); 1H NMR (400 MHz, CDCl3): d 2.35 (s, 3H, CH3), 6.80–8.55 (m, 18H, Ar–H); 13C NMR (100 MHz, CDCl3): d 21.07 (CH3),
116.90, 117.23, 123.62, 126.90, 127.75, 128.10, 128.53, 128.66, 129.04, 129.30, 129.69, 130.42, 130.85, 131.32, 131.92, 132.40, 133.43,
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4.27, N 16.50 (%). 6l: Yield 80%; mp 264–65 8C; MS m/z: 529.9 [M+H]+; IR (KBr, cmÀ1): 3010 (Ar. C–H str.), 1590 (C C str.), 1610 (C
N
str.), 740 (C–Cl str.), 1250 and 1040 (C–O–C asym. and sym. str. of –OCH3); 1H NMR (400 MHz, CDCl3): d 3.67 (s, 3H, OCH3), 6.62–8.59 (m,
18H, Ar–H); 13C NMR (100 MHz, CDCl3): d 55.25 (OCH3), 113.97, 118.29, 124.78, 127.02, 127.35, 128.16, 128.53, 128.58, 128.94, 129.20,
129.64, 130.21, 131.01, 131.93, 132.51, 133.26, 133.40, 133.97, 134.18, 138.52, 140.85, 143.47, 146.30, 159.37 (Ar–C); Anal. Calcd. for
C
31H21ClN6O: C 70.38, H 4.00, N 15.88 (%); Found: C 70.51, H 3.72, N 16.02 (%).
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