Sequential synthesis of amino-1,4-naphthoquinone-appended triazoles and triazole-chromene hybrids and their antimycobacterial evaluation

Article abstract of DOI:10.1016/j.ejmech.2014.08.009

A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et₃N/CuI in water. Aminonaphthoquinone- appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2, 3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC₅₀ = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC₅₀ < 1.56 μM).

Full text of DOI:10.1016/j.ejmech.2014.08.009

European Journal of Medicinal Chemistry 85 (2014) 737e746
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Sequential synthesis of amino-1,4-naphthoquinone-appended
triazoles and triazole-chromene hybrids and their antimycobacterial
evaluation
Balasubramanian Devi Bala a, Sivasubramanian Muthusaravanan a, Tan Soo Choon b,
,
, *
Mohamed Ashraf Ali b c, Subbu Perumal a
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India
b Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
c New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan 301030, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-
appended triazoles was accomplished via a sequential three-component reaction of substituted N-
propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-
dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended imi-
nochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-
appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity
against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-
yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active
Received 24 March 2014
Received in revised form
1 August 2014
Accepted 4 August 2014
Available online 5 August 2014
Keywords:
Three-component reactions
N-Propargylaminonaphthoquinones
Click reaction triazole-naphthoquinone
hybrid
one with IC50 ¼ 1.87
m
M, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine
M).
(20 times) and equipotent as the drug ethambutol (IC50 < 1.56
m
© 2014 Elsevier Masson SAS. All rights reserved.
Mycobacterium tuberculosis
1. Introduction
of the most prevailing click reactions. 1,2,3-Triazoles have gained
tremendous attention as they find utility as agrochemicals, dyes,
photographic materials and photostabilizers [6]. Triazoles are also
attractive as important heterocyclic pharmacophore for developing
several therapeutic agents, including anti-HIV [7], antimicrobial,
antifungal [8], antiviral [9], anticancer [10], antitubercular [8,11]
Tuberculosis (TB), a contagious and potentially fatal disease
caused by Mycobacterium tuberculosis (MTB), has become an
important world-wide public health problem with one-third of the
world's population infected by the TB bacillus. Annually about 3.1
million deaths are reported and there are about 9 million new cases
added each year [1]. In the last five decades, only a few drugs have
been accepted by the Food and Drug Administration (FDA) to treat
TB because of the complications associated with the discovery and
clinical testing of new candidates [2]. Hence there is a continuing
need for the development of potent new antitubercular agents that
effectively combat TB with low toxicity profiles and short therapy
duration is accorded a great importance [3].
antiallergic [12], antibiotic [13], selective
b3-adrenergic receptor
agonists [14] and Src-kinase inhibitors [15]. Hence the synthesis of
triazole-conjugated compounds accessed through click reaction
continues to attract the attention of chemists, in a bid to identify
molecules with enhanced pharmacological properties [16].
Naphthoquinones are recognized for their ability to modify DNA
and thus belong to an essential class of natural products with
widespread biological applications [17]. They are well known for
their antifungal [18], antiinflammatory [19], antiallergic [20],
molluscicidal [21], antiplasmodial [22], leishmanicidal [23] and
antitumour activities [24]. Buckle et al. [25] reported the synthesis
of naphtho[2,3-d]-v-triazoles and their antiallergic activity. 4,9-
Dihydro-4,9-dioxo-lH-naphtho[2,3-d]-v-triazoles have ability to
inhibit the IgE-mediated passive cutaneous anaphylaxis (PCA) re-
action in rats and hence constitute a potent class of antiallergic
compounds [25]. 1,2,3-Triazolic para-naphthoquinones were
Development of new methodologies for the efficient synthesis
of heterocycles with promising medicinal properties is of great
importance to organic chemists [4]. 1,2,3-Triazoles derived from
Huisgen's 1,3-dipolar cycloaddition [5] of azides and alkynes is one
* Corresponding author.
E-mail address: subbu.perum@gmail.com (S. Perumal).
http://dx.doi.org/10.1016/j.ejmech.2014.08.009
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

738
B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
evaluated against the infective bloodstream form of Trypanosoma
cruzi, the etiological agent of Chagas disease and found to be more
active than the anti-T. cruzi drug benznidazole [26].1-Alkyl-1H- and
2-alkyl-2H-naphtho-[2,3-d]triazole-4,9-diones display high po-
tency and selectivity against Gram positive (Gþ) pathogens
including methicillin-resistant Staphylococcus aureus (MRSA) [27]
(Fig. 1).
The biological significance of triazoles and 1,4-naphthoquinones
as well as their hybrids alluded to above prompted us to report now
a facile three-component sequential synthesis of hitherto unreported
Scheme 1. Two- and three-component sequential synthesis of 1,2,3-
triazolylmethylamino-1,4-naphthoquinones 7c.
functionalized
1,2,3-triazolylmethylamino-1,4-naphthoquinones
4e9 from the reaction of N-propargylaminonaphthoquinones,
alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide
(Scheme 1). The synthesized triazole-naphthoquinone hybrids were
screened for in vitro antimycobacterial activity against M. tuberculosis
Table 1
Optimization of reaction conditions for the synthesis of 1,2,3-triazolylmethylamino-
1,4-naphthoquinones 7c.a
H37Rv. This work stems as a part of our research programme recently
Entry
Two-component reaction
Solvent
Catalyst
Yield of 7c (%)b
launched on (i) the synthesis of novel naphthoquinone based het-
erocyclic systems [28,29] and (ii) screening of the synthesized com-
pounds to discover novel antitubercular lead candidates [30].
1
2
3
4
5
6
7
8
9
Toluene
rt, 1 h
rt, 1 h
rt, 40 min
rt, 30 min
rt, 2 h
rt, 2 h
rt, 3 h
rt, 30 min
rt, grinding, 1 min
84
74
70
81
71
34
-
96
90
Dichloroethane
Dichloromethane
Nitromethane
THF
DMF
DMSO
2. Results and discussion
2.1. Chemistry
c
Water
N-Propargylaminonaphthoquinones were synthesized by our
earlier method [29]. For optimization, initially we examined the
model two-component reaction of 2-((4-chlorophenyl)(prop-2-
ynyl)amino)naphthalene-1,4-dione and benzyl azide (Scheme 1)
in toluene at ambient temperature in the presence of CuI/Et3N,
which furnished the expected triazole, 7c in 84% yield in 1 h
(Table 1). This reaction in nitromethane solvent afforded 81% of 7c
in 30 min, whilst it proceeded less efficiently in dichloroethane,
dichloromethane, THF and DMF, affording the product in lower
yields of 74%, 70%, 71%, 34% respectively (Table 1). In DMSO, the
reaction failed to give the product. To our delight, we found that the
reaction either under solvent-free conditions or in water proceeded
very well and afforded an excellent yield of 7c, 90% and 96%
respectively (Table 1).
d
–
Three-component reaction
10
11
12
–
–
–
d (one pot)
rt, grinding, 10 min
70 ꢀC, 10 min
70 ꢀC, 2 min then rt,
grinding 1 min
39
47
52
d (one pot)
d (sequential)e
13
14
15
Water (one pot)
Water (one pot)
Water (sequential)e
rt, grinding, 7 min
44
71
96
70 ꢀC, 5 min
70 ꢀC, 2 min then rt,
grinding 1 min
a
All the reactions were performed in the presence of 5 mol% of CuI and Et3N
(1 mmol).
b
c
Yield after filtration through a pad of silica gel.
Reaction failed to occur.
Solvent-free reaction.
These reactions performed first at 70 ꢀC for 2 min and then 1 added and ground
d
e
at rt for 1 min.
Further, we also examined the efficacy of the three-component
reaction in a one-pot manner under neat conditions as well as in
water. In our preliminary experiment, equimolar amounts of 2-((4-
chlorophenyl)(prop-2-ynyl)amino)naphthalene-1,4-dione, benzyl
bromide and sodium azide (each 1 mmol) (Scheme 1) were taken
together with the catalyst CuI (5 mol %) and base Et3N (1 mmol) and
the mixture ground at room temperature. After completion of the
reaction under solvent-free conditions and in water, we have ob-
tained only 39% and 44% of triazole 7c respectively (Table 1), whilst
the reaction under these conditions at 70 ꢀC afforded 47% and 71%
of triazole (Table 1) respectively. To our delight, we found that the
triazole 7c was obtained in near quantitative yield by performing
the reaction sequentially in water at 70 ꢀC. In this method,
equimolar amounts of benzyl bromide and sodium azide (each
1 mmol) together with 1 ml of water were taken in a reaction vial
and heated for 2 min at 70 ꢀC. To this reaction mixture, 2-((4-
chlorophenyl)(prop-2-ynyl)amino)naphthalene-1,4-dione
(1 mmol) was added and the reaction mixture ground for additional
1 min in the presence of CuI/Et3N at ambient temperature. After
completion of the reaction (TLC), the reddish brown solid formed
was separated and purified by filtration through a short pad of silica
gel using a mixture of n-hexaneeethyl acetate to obtain pure
compound 7c in near quantitative yield, 96% (Table 1).
Fig. 1. Structures of previously reported 1,2,3-triazole linked/fused-1,4-
naphthoquinones [25e27].
Scheme 2. Sequential three-component synthesis of 1,2,3-triazolylmethylamino-1,4-
naphthoquinones 4e9.

B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
739
Encouraged by the efficiency of the reaction protocol described
above, the substrate scope was probed next with a variety of
substituted alkyl bromides/2-bromonaphthalene-1,4-dione, so-
dium azide and substituted N-propargylaminonaphthoquinones
(Scheme 2), which afforded a library of functionalized 1,2,3-
triazolylmethylamino-1,4-naphthoquinones (Table 2). In the case
of allyl bromide, the reaction was found to be more facile, the initial
grinding for 2 min in water and subsequent reaction with N-
propargylaminonaphthoquinones in the presence of CuI/Et3N
occurred efficiently at room temperature affording the product, in
contrast to heating at 70 ꢀC required for the first step in the case of
other organic halides.
The
structure
of
1,2,3-triazolylmethylamino-1,4-
naphthoquinones 4e9 was deduced from elemental analysis and
one- and two-dimensional NMR spectroscopic and mass spectral
data and elemental analysis. As a representative case, the structural
assignment of 5a is described below (Figs. 2 and 3). The 1H NMR
spectrum of 5a has two singlets at 5.11 and 5.17 ppm, each
Table 2
Sequential three-component synthesis of 1,2,3-triazolylmethylamino-1,4-naphthoquinones 4e9.

740
B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
Fig. 2. 1H and 13C assignments of compound 5a.
Fig. 4. 1H and 13C NMR assignments of compound 12a.
component sequential reaction of 2-(prop-2-ynyl(p-tolyl)amino)
naphthalene-1,4-dione, bromoacetonitrile and sodium azide in
presence of CuI/Et3N in water (Scheme 2). Subsequently, 1,2,3-
triazolylacetonitriles 4, without isolation, were treated with sali-
cylaldehyde and Et3N and the reaction at room temperature for
24 h afforded 12a in 54% yield. To our delight, the transformation of
intermediate 4 to 12 occurred more efficiently under microwave
irradiation at 60 ꢀC in 3 min furnishing 89% of 12a. Employing these
reaction conditions, nine compounds in series 12 could be obtained
in moderate to good yields, which discloses the generality of this
protocol.
The structure of 12 was deduced from elemental analysis and
one- and two-dimensional NMR spectroscopic and mass data. As a
representative case, the structural assignment of 12a is described in
Figs. 4 and 5. The 1H NMR spectrum of 12a has a 2H singlet
appearing at 5.28 ppm readily assignable to the hydrogens of the
methylene group. These methylene hydrogens and a 1H singlet at
8.60 ppm due to H-50 show HMB correlations with C-40, whilst H-400
of the chromene ring gives another singlet at 8.56 ppm. The other
protons of chromene ring appear as two-proton multiplets in the
regions 7.37e7.44 and 7.61e7.68 ppm. The other protons are
assigned correspondingly.
A plausible mechanism for the formation of 12 is described
below. The initially formed 1,2,3-triazolylacetonitrile 4 via click
reaction, in the presence of base undergoes aldol condensation
with salicyaldehyde affording the intermediate 13 (Scheme 4).
Subsequent intramolecular annulation of intermediate 13 and
concomitant dehydration furnishes aminonaphthoquinone
appended iminochromene-triazole hybrid heterocycle.
Fig. 3. Selected HMB correlations of compound 5a.
accounting for two protons assignable to the hydrogens of the two
methylene groups, other than that of ethyl group, which were
distinguished by the fact that the former gives a HMB correlation
with C-2 of the naphthoquinone ring, whilst the latter gives a HMB
correlation with the ester carbonyl (Fig. 3). Among the two singlets
at 6.07 and 7.69 ppm each integrating for one proton, the first one
shows HMB correlations with C-1 and C-4 carbonyls of naph-
thoquinone ring assigning it to H-3, whilst that at 7.69 ppm was due
to H-50 of the triazole ring. The two doublets of doublets occurring
at 7.91 and 7.99 (1H, J ¼ 7.5, 1.4 Hz) ppm are due to H-5 and H-8 and
the two triplets of doublets at 7.61 and 7.66 ppm (1H, J ¼ 7.5, 1.4 Hz)
have been assigned to H-6 and H-7. The chemical shifts of the hy-
drogens and C,HeCOSY correlations enabled the assignment of the
hydrogen-bearing carbons.
As triazolylcoumarins [31], 2-iminochromenes [32] and todda-
coumaquinone (coumarin-naphthoquinone dimer) [33] are known
to possess significant biological activities, we have now synthesized
the
amino-1,4-naphthoquinone-appended
iminochromene-
2.2. In vitro antimycobacterial activity
triazole hybrid heterocycles 12 (Scheme 3) adopting the method
of Quain et al. [34] Initially, the 1,2,3-triazolylacetonitriles 4
required for this synthesis were obtained from the three-
The thirty eight-compound library was subjected to High
Throughput Screen (HTS) for in vitro antimycobacterial activity
Scheme 3. Sequential one pot synthesis of aminonaphthoquinone appended iminochromene-triazole hybrid heterocycle 12.

B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
741
potent than the ethambutol. The compound, 2-(((1-benzyl-1H-
1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naph-
thalene-1,4-dione (7d) emerged as the most active one with
IC50 ¼ 1.87
mM, being more potent than the anti-TB drugs, cyclo-
serine (6 times), pyrimethamine (20 times) and equipotent as the
drug ethambutol (IC50 < 1.56).
These results also demonstrate that the naphthoquinone-
triazoles with fluorine and chlorine in aniline part are more
active than the other compounds, while the presence of a CF3 at
para-position of aniline conferred maximum activity. Similarly, the
presence of two chlorines in the phenyl rings also enhances the
activity. However, all the compounds were less active than isoni-
azid and amikacin.
Fig. 5. Selected HMB correlations of compound 12a.
3. Conclusion
against M. tuberculosis H37Rv using an assay adapted from the
microdilution AlamarBlue (AB) broth assay reported by Collins and
Franzblau [35]. Five standard drugs were used as references
together with the synthesized compound for the assay. Data were
analysed using the IDBS Activity Base software and the dose
response result was analysed using a four parameter logistic fit to
the data (Excel Fit equation (205)) with the maximum and mini-
mum locked at 100 and 0. From these curves, IC50 and IC90 values
were calculated. The MIC is the minimum concentration of the
compound required to inhibit 90% of bacterial growth and the MIC
In conclusion, we have developed a facile synthesis of a library of
hitherto unreported functionalized 1,2,3-triazolylmethylamino-1,4-
naphthoquinones via a sequential three-component reaction of N-
propargylaminonaphthoquinones with variously substituted alkyl
bromides/2-bromonaphthalene-1,4-dione and sodium azide in the
presence of Et3N/CuI in water. Formation of organic azide and its
concomitant reaction with alkyne take place efficiently in one-pot
and the reaction protocol is experimentally simple. A series of
aminonaphthoquinone-appended iminochromene-triazole hybrid
heterocycles have also been synthesized. All the triazole-
naphthoquinone hybrids were screened for their in vitro activity
against M. tuberculosis H37Rv (MTB). Among them, 2-(((1-benzyl-
1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)na-
phthalene-1,4-dione (7d) emerged to be the most active one with
values (mM) of the synthesized compounds and five standard
antitubercular drugs are presented in Table 3.
All the naphthoquinone-triazole hybrids 4e9 and 12 that
showed IC50 < 35 and IC90 < 55 were more potent than the standard
drug pyrimethamine (IC50 ¼ 37.35 and IC90 ¼ 74.96). From the IC50
values, fourteen compounds 4a, 4ce4e, 5ae5c, 6b, 6e, 7d, 7g, 9c,
12b and 12h were found to be more active than cycloserine
(IC50 ¼ 12.47) and the IC90 values show that nineteen compounds
4be4e, 5ae5c, 6b, 6e, 7c, 7d, 7g, 8a, 8c, 9c, 12b, 12h and 12i were
more active than the standard drug ethambutol (IC90 ¼ 32.79) and
six compounds 4a, 5c, 6e, 7d, 7g and 12h were more potent than
cycloserine (IC90 ¼ 13.49).
IC50 ¼ 1.87
mM, being more potent than the anti-TB drugs, cyclo-
serine (6 times), pyrimethamine (20 times) and equipotent as the
drug ethambutol (IC50 < 1.56 mM).
4. Experimental section
The MIC values show that ten compounds 4e, 5b, 5c, 6b, 6e, 7c,
7g, 9c, 12b and 12h possess activity equal to that of cycloserine
(MIC ¼ 25.00). Compound 4a (MIC ¼ 15.00) showed a potency
equal to ethambutol (MIC ¼ 12.50) and 7d (MIC ¼ 10.00) was more
4.1. Chemistry
Melting points were measured in open capillary tubes and are
uncorrected. The 1H NMR, 13C NMR, DEPT, H,HeCOSY and
Scheme 4. Mechanism for the synthesis of aminonaphthoquinone appended iminochromene-triazole hybrid heterocycle 12.

742
B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
Table 3
C
21H14FN5O2: C, 65.11; H, 3.64; N,18.08%. Found C, 65.23; H, 3.57; N,
Screening of triazole-naphthoquinone hybrids against Mycobacterium tuberculosis.a
17.97%.
S. no Comp IC50
M)
IC90
M)
MIC
M)
S. no Comp IC50
M)
IC90
M)
MIC
M)
(
m
(
m
(
m
(
m
(
m
(
m
4.1.1.2. 2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(3-methoxy-
phenyl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile
(4b).
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
2.81
6.13
15.00 20
50.00 21
50.00 22
50.00 23
25.00 24
50.00 25
25.00 26
25.00 27
50.00 28
50.00 29
50.00 30
50.00 31
25.00 32
50.00 33
50.00 34
25.00 35
7c
7d
7e
7f
7g
8a
8b
8c
9a
2.58 15.06
1.87 4.60
24.95 36.38
15.30 44.31
25.00
10.00
50.00
50.00
25.00
50.00
50.00
50.00
50.00
50.00
25.00
50.00
25.00
50.00
50.00
Red semi-solid; Yield: 91%; 1H NMR (300 MHz, CDCl3) dH: 3.78 (s,
3H), 5.19 (s, 2H), 5.30 (s, 2H), 6.10 (s, 1H), 6.74e6.84 (m, 3H), 7.30 (t,
1H, J ¼ 7.8 Hz), 7.63 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.70 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.79 (s, 1H), 7.94 (dd, 1H, J ¼ 7.5, 1.5 Hz), 8.01 (dd, 1H, J ¼ 7.5,
1.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 37.5, 49.6, 55.4, 111.9, 112.3,
112.5,113.7, 118.0, 123.1, 125.5,126.6,130.6, 132.2, 132.3, 132.6,134.1,
145.3,146.5,151.3,160.8,182.9,183.6. Anal. Calcd. for C22H17N5O3: C,
66.16; H, 4.29; N, 17.53%. Found C, 66.23; H, 4.18; N, 17.63%.
16.30 25.50
10.64 19.83
11.19 25.90
9.95 21.87
11.91 27.93
8.46 16.42
5.38
9.97
14.00 28.89
19.11 37.92
13.28 27.86
28.57 37.72
19.20 46.50
7.20 16.50
23.87 47.60
8.57 17.72
18.57 37.72
27.20 36.50
3.28
7.86
9
17.20 36.50
18.57 27.72
18.28 36.50
21.58 45.06
5.87 14.60
24.95 36.38
15.30 34.31
6.38 11.97
10
11
12
13
14
15
16
17
18
19
9b
9c
12a
12b
12c
12d
12e
12g
12h
12i
4.1.1.3. 2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(o-tolyl)-
amino)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile (4c). Red solid;
Yield: 93%; m.p 106e108 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 2.10 (s,
3H), 5.03 (br s, 2H), 5.33 (s, 2H), 5.67 (s, 1H), 7.06e7.09 (m, 1H),
7.23e7.29 (m, 3H), 7.61 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.68 (td, 1H, J ¼ 7.5,
1.2 Hz), 7.94e7.99 (m, 3H). 13C NMR (75 MHz, CDCl3) dC: 17.5, 37.4,
49.1, 110.5, 112.6, 123.6, 125.4, 126.5, 127.3, 127.8, 128.3, 131.8, 132.2,
132.3, 132.4, 134.1, 134.7, 143.1, 145.2, 150.6, 183.2, 183.4. Anal. Calcd.
for C22H17N5O2: C, 68.92; H, 4.47; N,18.27%. Found C, 69.01; H, 4.59;
N, 18.16%.
21.58 55.06 100.00
21.87 44.60 100.00
25.52 55.44 100.00 36
17.00 38.89 50.00 37
28.71 47.92 100.00 38
7a
7b
3.18
9.86
25.00
50.00
18.57 27.72
Drugs
Amikacin
0.07 0.08
12.47 13.49
<1.56 32.79
0.16
25.00
12.50
0.31
Cycloserine
Ethambutol
Isoniazid
0.18
0.29
Pyrimethamine
37.35 74.96 100.00
a
Compound 12f was not screened against MTB.
4.1.1.4. 2-(4-(((2-chlorophenyl)(1,4-dioxo-1,4-dihydronaphthalen-2-yl)
amino)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile (4d). Orange solid;
Yield: 91%; m.p 119e121 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.12 (s,
2H), 5.34 (s, 2H), 5.91 (s, 1H), 7.27e7.34 (m, 3H), 7.46e7.50 (m, 1H),
7.63 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.67 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.93e7.95 (m,
2H), 8.00e8.03 (m, 1H). 13C NMR (75 MHz, CDCl3) dC: 37.5, 49.1, 111.5,
112.5, 123.6, 125.5, 126.6, 128.4, 128.9, 129.0, 130.9, 131.5, 132.0, 132.2,
132.6, 134.1, 142.1, 144.6, 150.1, 182.3, 183.7. Anal. Calcd. for
C,HeCOSY, HMBC were recorded on a Bruker (Avance) 300 MHz
NMR instrument using TMS as internal standard and CDCl3 as
solvent. Standard Bruker software was used throughout. Chemical
shifts are given in parts per million (d-scale) and the coupling
constants are given in Hertz. Silica gel-G plates (Merck) were used
for TLC analysis with a mixture of petroleum ether (60e80 ꢀC) and
ethyl acetate as eluent. Elemental analyses were performed on a
Perkin Elmer 2400 Series II Elemental CHNS analyzer. Mass spectra
were recorded in LCQ Fleet mass spectrometer, Thermo Fisher In-
struments Limited, US. Electrospray ionization mass spectrometry
(ESI-MS) analysis was performed in the positive ion mode on a
liquid chromatography ion trap. Microwave reactions have been
carried out in a Biotage Microwave synthesizer.
C21H14ClN5O2: C, 62.46; H, 3.49; N,17.34%. Found C, 62.38; H, 3.38; N,
17.43%.
4.1.1.5. 2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(phenyl)-
amino)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile (4e). Red solid;
Yield: 94%; m.p 114e116 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.22 (s,
2H), 5.30 (s, 2H), 6.07 (s, 1H), 7.17e7.20 (m, 2H), 7.29e7.32 (m, 1H),
7.39e7.44 (m, 2H), 7.64 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.70 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.78 (s, 1H), 7.95 (dd, 1H, J ¼ 7.5, 1.5 Hz), 8.02 (dd, 1H, J ¼ 7.5,
1.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 37.3, 49.5, 112.7, 113.2, 123.2,
123.5, 125.8, 126.4, 126.7, 129.7, 132.1, 132.2, 132.4, 133.8, 144.7,
145.4, 151.2, 182.6, 183.3. ESI-MS: m/z. Calcd.: 369.12; Found: 370.17
(MþH)þ, 392.17 (MþNa)þ. Anal. Calcd. for C21H15N5O2: C, 68.28; H,
4.09; N, 18.96%. Found, C, 68.34; H, 4.19; N, 18.89%.
4.1.1. General procedure for the synthesis of 1,2,3-triazolylmethy-
lamino-1,4-naphthoquinones 4e9
A mixture of substituted bromide 2 and sodium azide 3 (each
1 mmol) together with 1 ml of water was taken in a reaction vial
and heated for 2 min at 70 ꢀC. To this reaction mixture, N-prop-
argylaminonaphthoquinone 1 (1 mmol) was added and the reac-
tion mixture ground for additional 1 min in the presence of CuI
(5 mol%) and Et3N (1 mmol) at ambient temperature. After
completion of the reaction (TLC), the product was extracted with
ethyl acetate and washed with water (2 ꢁ 20 mL), the organic layer
separated and dried over anhydrous sodium sulphate and the sol-
vent was removed under reduced pressure. The resulting crude
product was purified by filtration through a short pad of silica gel
using 7:3 n-hexaneeethyl acetate to obtain pure compounds 4e9.
4.1.1.6. Ethyl2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(p-tolyl)-
amino)methyl)-1H-1,2,3-triazol-1-yl)acetate (5a). Red solid; Yield:
96%; m.p 114e116 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 1.25 (t, 3H,
J ¼ 7.2 Hz), 2.35 (s, 3H), 4.22 (q, 2H, J ¼ 7.2 Hz), 5.11 (s, 2H), 5.18 (s,
2H), 6.07 (s, 1H), 7.05 (d, 2H, J ¼ 8.4 Hz), 7.18 (d, 2H, J ¼ 8.4 Hz), 7.61
(td, 1H, J ¼ 7.5, 1.4 Hz), 7.66 (td, 1H, J ¼ 7.5, 1.4 Hz), 7.69 (s, 1H), 7.91
(dd, 1H, J ¼ 7.5, 1.4 Hz), 7.99 (dd, 1H, J ¼ 7.5, 1.4 Hz). 13C NMR
(75 MHz, CDCl3) dC: 13.9, 21.0, 50.0, 50.8, 62.2, 112.6, 124.0, 125.4,
125.9, 126.5, 130.4, 132.3, 132.4, 132.5, 133.8, 136.7, 143.0, 144.1,
151.5, 166.0, 183.0, 183.3. ESI-MS: m/z. Calcd.: 430.16; Found: 431.25
(MþH)þ, 453.25 (MþNa)þ. Anal. Calcd. for C24H22N4O4: C, 66.97; H,
5.15; N, 13.02%. Found C, 66.90; H, 5.05; N, 13.14%.
4.1.1.1. 2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(4-fluoro-
phenyl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile
(4a).
Red solid; Yield: 90%; m.p 106e108 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 1H NMR (300 MHz, CDCl3) dH: 5.16 (s, 2H), 5.34 (s, 2H), 6.00 (s,
1H), 7.07e7.12 (m, 2H), 7.16e7.21 (m, 2H), 7.62 (td, 1H, J ¼ 7.5,
1.2 Hz), 7.69 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.85 (s, 1H), 7.92 (dd, 1H, J ¼ 7.5,
4.1.1.7. Ethyl2-(4-(((4-bromophenyl)(1,4-dioxo-1,4-dihydronaphthal-
en-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetate (5b). Red solid;
Yield: 95%; m.p 148e150 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 1.27 (t,
3H, J ¼ 7.2 Hz), 4.23 (q, 2H, J ¼ 7.2 Hz), 5.12 (s, 2H), 5.14 (s, 2H), 6.22
1.2 Hz), 7.98 (dd, 1H, J ¼ 7.5, 1.2 Hz). 13C NMR (75 MHz, CDCl3) dC
:
37.5, 49.8, 112.4, 113.0, 116.9, 123.1, 125.5, 126.6, 128.0, 132.1, 132.2,
132.6, 134.1, 141.3, 145.1, 151.2, 161.2, 182.9, 183.5. Anal. Calcd. for

B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
743
(s, 1H), 7.08 (d, 2H, J ¼ 8.4 Hz), 7.49 (d, 2H, J ¼ 8.4 Hz), 7.62 (td, 1H,
J ¼ 7.5, 1.5 Hz), 7.65 (s, 1H), 7.69 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.92 (dd, 1H,
J ¼ 7.5,1.5 Hz), 8.01 (dd,1H, J ¼ 7.5,1.5 Hz). 13C NMR (75 MHz, CDCl3)
dC: 13.9, 49.6, 50.8, 62.3, 114.1, 119.9, 124.0, 125.4, 126.5, 127.5, 132.2,
132.3, 132.5, 132.8, 133.9, 143.4, 144.9, 150.9, 165.9, 182.4, 183.4.
Anal. Calcd. for C23H19BrN4O4: C, 55.77; H, 3.87; N, 11.31%. Found C,
55.90; H, 3.78; N, 11.25%.
120.1,122.3,125.5,126.5,127.1,129.8,131.0,132.0,132.1,132.2,132.6,
134.0, 143.3, 144.4, 150.9, 182.5, 183.5. ESI-MS: m/z. Calcd.: 404.10;
Found: 405.17 (MþH)þ, 427.17 (MþNa)þ. Anal. Calcd. for
C
22H17ClN4O2: C, 65.27; H, 4.23; N, 13.84%. Found C, 65.37; H, 4.29;
N, 13.71%.
4.1.1.13. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(4-fluorophenyl)-
amino)naphthalene-1,4-dione (6b). Red solid; Yield: 92%; m.p
4.1.1.8. Ethyl2-(4-(((4-chlorophenyl)(1,4-dioxo-1,4-dihydronaph-tha-
112e114 ꢀC; 1H NMR (300 MHz, CDCl3) dH
: 4.94 (dt, 2H,
len-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetate
(5c). Red
J ¼ 6.0,1.2 Hz), 5.14 (s, 2H), 5.24 (dq,1H, J ¼ 17.1, 0.9 Hz), 5.33 (dq,1H,
J ¼ 10.2, 0.9 Hz), 5.91e6.04 (m, 1H), 6.07 (s, 1H), 7.04e7.11 (m, 2H),
7.14e7.20 (m, 2H), 7.52 (s, 1H), 7.62 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.70 (td,
1H, J ¼ 7.5, 1.5 Hz), 7.93 (dd, 1H, J ¼ 7.5, 1.5 Hz), 8.02 (dd, 1H J ¼ 7.5,
1.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 50.0, 52.6, 112.8, 116.6, 120.0,
120.1,122.4,125.4,126.5,127.9,131.0,132.3,132.4,133.9,141.7,143.5,
151.3, 161.0, 182.7, 183.4. Anal. Calcd. for C22H17FN4O2: C, 68.03; H,
4.41; N, 14.43%. Found C, 68.09; H, 4.30; N, 14.52%.
solid; Yield: 92%; m.p 150e152 ꢀC; 1H NMR (300 MHz, CDCl3) dH
:
1.27 (t, 3H, J ¼ 7.2 Hz), 4.23 (q, 2H, J ¼ 7.2 Hz), 5.12 (s, 2H), 5.15 (s,
2H), 6.20 (s, 1H), 7.08 (d, 2H, J ¼ 8.7 Hz), 7.49 (d, 2H, J ¼ 8.7 Hz), 7.63
(td, 1H, J ¼ 7.5, 1.5 Hz), 7.65 (s, 1H), 7.70 (td, 1H, J ¼ 7.5, 1.5 Hz),
7.91e7.94 (m, 1H), 8.01e8.04 (m, 1H). 13C NMR (75 MHz, CDCl3) dC
:
13.9, 49.7, 50.7, 62.3, 113.7, 124.0, 125.4, 126.5, 127.1, 129.8, 132.0,
132.1, 132.2, 132.5, 133.9, 143.4, 144.2, 150.8, 166.0, 182.4, 183.4.
Anal. Calcd. for C23H19ClN4O4: C, 61.27; H, 4.25; N, 12.43%. Found C,
61.36; H, 4.19; N, 12.35%.
4.1.1.14. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(3-
methoxyphenyl)amino)naphthalene-1,4-dione (6c). Red solid; Yield:
89%; m.p 119e121 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 3.78 (s, 3H),
4.93 (dt, 2H, J ¼ 6.0,1.2 Hz), 5.17 (s, 2H), 5.22 (dq,1H, J ¼ 17.1, 0.9 Hz),
5.31 (dq, 1H, J ¼ 10.2, 0.9 Hz), 5.90e6.04 (m, 1H), 6.16 (s, 1H),
6.73e6.82 (m, 3H), 7.25e7.30 (m, 1H), 7.48 (s, 1H), 7.62 (td, 1H,
J ¼ 7.5, 1.4 Hz), 7.69 (td, 1H, J ¼ 7.5, 1.4 Hz), 7.94 (dd, 1H, J ¼ 7.5,
4.1.1.9. Ethyl2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(4-fluoro-
phenyl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetate (5d). Red solid;
Yield: 90%; m.p 113e115 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 1.27 (t,
3H, J ¼ 7.2 Hz), 4.24 (q, 2H, J ¼ 7.2 Hz), 5.12 (s, 2H), 5.16 (s, 2H), 6.06
(s, 1H), 7.05e7.12 (m, 2H), 7.15e7.20 (m, 2H), 7.62 (td, 1H, J ¼ 7.5,
1.2 Hz), 7.66e7.72 (m, 2H), 7.92 (dd, 1H, J ¼ 7.5, 1.2 Hz), 8.01 (dd, 1H,
J ¼ 7.5, 1.2 Hz). 13C NMR (75 MHz, CDCl3) dC: 13.9, 50.0, 50.8, 62.3,
112.7, 116.7, 124.2, 125.4, 126.5, 128.0, 132.2, 132.3, 132.5, 134.0,
141.5, 143.7, 151.2, 161.0, 166.0, 182.7, 183.4. ESI-MS: m/z. Calcd.:
434.14; Found: 435.17 (MþH)þ, 457.17 (MþNa)þ. Anal. Calcd. for
1.4 Hz), 8.02 (dd, 1H J ¼ 7.5, 1.4 Hz). 13C NMR (75 MHz, CDCl3) dC
:
49.9, 52.6, 55.3, 111.8, 112.2, 113.4, 118.1, 120.0, 122.3, 125.5, 126.5,
130.4, 131.1, 132.3, 132.4, 132.5, 133.9, 143.8, 146.8, 151.4, 160.6,
182.8, 183.5. Anal. Calcd. for C23H20N4O3: C, 68.99; H, 5.03; N,
13.99%. Found C, 69.07; H, 5.15; N, 13.92%.
C
23H19FN4O4: C, 63.59; H, 4.41; N, 12.90%. Found, C, 63.47; H, 4.48;
N, 12.99%.
4.1.1.15. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(o-tolyl)amino)-
naphthalene-1,4-dione (6d). Red solid; Yield: 91%; m.p 91e92 ꢀC;
1H NMR (300 MHz, CDCl3) dH: 2.11 (s, 3H), 4.93e5.96 (m, 4H), 5.23
(d, 1H, J ¼ 17.1 Hz), 5.32 (d, 1H, J ¼ 10.2 Hz), 5.72 (s, 1H), 5.91e6.05
(m, 1H), 7.07e7.10 (m, 1H), 7.22e7.27 (m, 3H), 7.63e7.71 (m, 3H),
7.96e8.02 (m, 2H). 13C NMR (75 MHz, CDCl3) dC: 17.5, 49.3, 52.6,
110.3,120.0,122.8,125.4,126.4,127.3,127.6,128.1,131.4,131.6,132.2,
132.3, 132.5, 134.0, 134.7, 143.3, 143.9, 150.8, 183.3, 183.4. Anal.
Calcd. for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57%. Found C, 71.79;
H, 5.15; N, 14.70%.
4.1.1.10. Ethyl2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(3-
meth-oxyphenyl)amino)methyl)-1H-1,2,3-triazol-1-yl)acetate (5e).
Red solid; Yield: 88%; m.p 84e86 ꢀC; 1H NMR (300 MHz, CDCl3) dH
:
1.26 (t, 3H, J ¼ 7.2 Hz), 3.78 (s, 3H), 4.23 (q, 2H, J ¼ 7.2 Hz), 5.11 (s,
2H), 5.20 (s, 2H), 6.15 (s, 1H), 6.73e6.83 (m, 3H), 7.27e7.31 (m, 1H),
7.62 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.65 (s, 1H), 7.69 (td, 1H, J ¼ 7.5, 1.2 Hz),
7.94 (dd, 1H, J ¼ 7.5, 1.2 Hz), 8.02 (dd, 1H J ¼ 7.5, 1.2 Hz). 13C NMR
(75 MHz, CDCl3) dC: 13.9, 49.9, 50.8, 55.3, 62.3, 111.8, 112.3, 113.4,
118.1, 124.0, 125.5, 126.6, 130.4, 132.3, 132.4, 132.5, 133.9, 144.1,
146.8,151.4,160.7,166.0,182.8,183.5. Anal. Calcd. for C24H22N4O5: C,
64.57; H, 4.97; N, 12.55%. Found C, 64.46; H, 4.91; N, 12.67%.
4.1.1.16. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(2-chlorophenyl)-
amino)naphthalene-1,4-dione (6e). Red solid; Yield: 92%; m.p
103e105 ꢀC; 1H NMR (300 MHz, CDCl3) dH
: 4.95 (dt, 2H,
4.1.1.11. E thyl2-(4-(((2-chlorophenyl)(1, 4-dio xo-1, 4-
dihydronaphthal-en-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ace-
J ¼ 6.0,1.2 Hz), 5.09 (s, 2H), 5.24 (dq, 1H, J ¼ 17.1, 0.9 Hz), 5.34 (dq,
1H, J ¼ 10.2, 0.9 Hz), 5.92e6.05 (m, 2H), 7.25e7.31 (m, 3H),
7.44e7.48 (m, 1H), 7.62 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.64 (s, 1H), 7.70 (td,
1H, J ¼ 7.5, 1.2 Hz), 7.93 (dd, 1H, J ¼ 7.5, 1.2 Hz), 8.03 (dd, 1H J ¼ 7.5,
1.2 Hz). 13C NMR (75 MHz, CDCl3) dC: 49.4, 52.7, 111.2, 120.1, 122.8,
125.5, 126.5, 128.3, 128.7, 129.1, 130.7, 131.1, 131.5, 132.1, 132.3, 132.5,
134.0, 142.5, 143.1, 150.3, 182.3, 183.7. Anal. Calcd. for C22H17ClN4O2:
C, 65.27; H, 4.23; N, 13.84%. Found C, 65.16; H, 4.16; N, 13.94%.
tate (5f). Red semi-solid; Yield: 91%; 1H NMR (300 MHz, CDCl3) dH
:
1.27 (t, 3H, J ¼ 7.2 Hz), 4.24 (q, 2H, J ¼ 7.2 Hz),5.11 (s, 2H), 5.14 (s,
2H), 6.00 (s, 1H), 7.26e7.32 (m, 3H), 7.45e7.48 (m, 1H), 7.60 (td, 1H,
J ¼ 7.5, 1.2 Hz), 7.68 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.82 (s, 1H), 7.92 (d, 1H,
J ¼ 7.5 Hz), 8.01 (d,1H, J ¼ 7.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 13.8,
49.0, 50.7, 62.2, 111.0, 124.5, 125.3, 126.4, 128.1, 128.6, 129.0, 130.5,
131.3, 131.9, 132.1, 132.3, 133.8, 142.3, 143.1, 150.1, 166.0, 182.0, 183.5.
Anal. Calcd. for C23H19ClN4O4: C, 61.27; H, 4.25; N, 12.43%. Found C,
61.18; H, 4.36; N, 12.36%.
4.1.1.17. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(phenyl)amino)
naphthalene-1,4-dione (6f). Red semi-solid; Yield: 90%; 1H NMR
(300 MHz, CDCl3) dH: 4.92 (dt, 2H, J ¼ 6.0,1.2 Hz), 5.18 (s, 2H),
5.20e5.25 (m, 1H), 5.31 (dq, 1H, J ¼ 10.2, 0.9 Hz), 5.90e6.03 (m, 1H),
6.14 (s, 1H), 7.16e7.19 (m, 2H), 7.24e7.29 (m, 1H), 7.36e7.41 (m, 2H),
7.49 (s, 1H), 7.62 (td, 1H, J ¼ 7.5, 1.4 Hz), 7.69 (td, 1H, J ¼ 7.5, 1.4 Hz),
7.92 (dd, 1H, J ¼ 7.5, 1.4 Hz), 8.02 (dd, 1H J ¼ 7.5, 1.4 Hz). 13C NMR
(75 MHz, CDCl3) dC: 49.9, 52.5, 113.1, 119.9, 122.3, 125.3, 125.8, 126.5,
126.6, 129.7, 131.0, 132.2, 132.3, 132.4, 133.8, 143.7, 145.6, 151.3,
182.7, 183.4. Anal. Calcd. for C22H18N4O2: C, 71.34; H, 4.90; N,15.13%.
Found C, 71.22; H, 4.97; N, 15.04%.
4.1.1.12. 2-(((1-Allyl-1H-1,2,3-triazol-4-yl)methyl)(4-chlorophenyl)-
amino)naphthalene-1,4-dione (6a). Red solid; Yield: 94%; m.p
148e150 ꢀC; 1H NMR (300 MHz, CDCl3) dH
: 4.93 (dt, 2H,
J ¼ 6.0,1.2 Hz), 5.12 (s, 2H), 5.24 (dq, 1H, J ¼ 16.8, 0.9 Hz), 5.32 (dq,
1H, J ¼ 10.2, 0.9 Hz), 5.91e6.04 (m, 1H), 6.19 (s, 1H), 7.13 (d, 2H,
J ¼ 8.7 Hz), 7.34 (d, 2H, J ¼ 8.7 Hz), 7.49 (s, 1H), 7.62 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.70 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.91 (dd, 1H, J ¼ 7.5, 1.5 Hz), 8.02
(dd,1H J ¼ 7.5,1.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 49.8, 52.6,113.8,

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B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
4.1.1.18. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(p-tolyl)amino)
naphthalene-1,4-dione (7a). Red solid; Yield: 96%; m.p 146e148 ꢀC;
1H NMR (300 MHz, CDCl3) dH: 2.34 (s, 3H), 5.14 (s, 2H), 5.48 (s, 2H),
6.06 (s, 1H), 7.01 (d, 2H, J ¼ 8.4 Hz), 7.15 (d, 2H, J ¼ 8.4 Hz), 7.17e7.20
(m, 2H), 7.31e7.34 (m, 3H), 7.39 (s, 1H), 7.59 (td, 1H, J ¼ 7.5, 1.2 Hz),
7.67 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.89 (dd, 1H, J ¼ 7.5, 1.2 Hz), 8.00 (dd, 1H,
J ¼ 7.5, 1.2 Hz). 13C NMR (75 MHz, CDCl3) dC: 21.0, 50.0, 53.9, 112.5,
122.6, 125.3, 125.8, 126.4, 127.6, 128.5, 128.9, 130.3, 132.3, 133.8,
134.6, 136.6, 142.9, 144.0, 151.4, 182.9, 183.3. Anal. Calcd. for
J ¼ 7.5, 1.4 Hz). 13C NMR (75 MHz, CDCl3) dC: 49.2, 54.1, 111.3, 123.0,
125.5, 126.5, 127.3, 128.2, 128.6, 129.0, 129.2, 130.6, 131.5, 132.0,
132.3, 132.4, 133.9, 134.5, 142.3, 143.3, 150.2, 182.2, 183.6. Anal.
Calcd. for C26H19ClN4O2: C, 68.65; H, 4.21; N, 12.32%. Found C,
68.78; H, 4.11; N, 12.26%.
4.1.1.24. 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(2,4-dichloro-
phenyl)amino)naphthalene-1,4-dione (7g). Red solid; Yield: 89%;
m.p 77e79 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.00 (s, 2H), 5.49 (s,
2H), 6.06 (s, 1H), 7.17e7.23 (m, 4H), 7.32e7.42 (m, 4H), 7.49 (s, 1H),
7.60 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.68 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.88 (dd, 1H,
J ¼ 7.5,1.2 Hz), 8.01 (dd,1H, J ¼ 7.5,1.2 Hz). 13C NMR (75 MHz, CDCl3)
dC: 48.8, 54.0, 111.5, 122.9, 125.4, 126.4, 127.6, 128.3, 128.6, 128.9,
130.0, 130.2, 131.8, 132.0, 132.3, 132.4, 133.4, 133.9, 134.4, 141.1,
142.6,149.8,181.8,183.5. Anal. Calcd. for C26H18Cl2N4O2: C, 63.81; H,
3.71; N, 11.45%. Found C, 63.90; H, 3.60; N, 11.37%.
C
27H22N4O2: C, 74.64; H, 5.10; N, 12.89%. Found C, 74.56; H, 5.23; N,
12.96%.
4.1.1.19. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-
bromophenyl)-amino)naphthalene-1,4-dione (7b). Red solid; Yield:
94%; m.p 148e150 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.08 (s, 2H),
5.47 (s, 2H), 6.20 (s, 1H), 7.02 (d, 2H, J ¼ 8.7 Hz), 7.18e7.35 (m, 6H),
7.45 (d, 2H, J ¼ 8.7 Hz), 7.59e7.72 (m, 2H), 7.88 (d, 1H, J ¼ 7.2 Hz),
8.01 (d, 1H, J ¼ 7.2 Hz).13C NMR (75 MHz, CDCl3) dC: 49.7, 54.1, 114.4,
120.0, 122.6, 125.6, 126.6, 127.5, 127.8, 128.7, 129.1, 132.2, 132.6,
132.8, 134.0, 134.4, 143.5, 144.8, 151.0, 182.5, 183.6. Anal. Calcd. for
4.1.1.25. 2-((4-fluorophenyl)((1-(2-oxo-2-phenylethyl)-1H-1,2,3-
triazol-4-yl)methyl)amino)naphthalene-1,4-dione (8a). Red solid;
Yield: 93%; m.p 137e139 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.17 (s,
2H), 5.82 (s, 2H), 6.09 (s, 1H), 7.04e7.10 (m, 2H), 7.16e7.21 (m, 2H),
7.48e7.53 (m, 2H), 7.57e7.69 (m, 3H), 7.71 (s, 1H), 7.88e8.00 (m,
4H). 13C NMR (75 MHz, CDCl3) dC: 50.1, 55.4, 112.6, 116.7, 124.7,
125.4, 126.6, 128.0, 128.1, 129.1, 132.2, 132.3, 132.4, 133.8, 133.9,
134.5, 141.6, 143.6, 151.2, 161.1, 182.8, 183.5, 190.1. Anal. Calcd. for
C
26H19BrN4O2: C, 62.54; H, 3.84; N, 11.22%. Found C, 62.45; H, 3.95;
N, 11.28%.
4.1.1.20. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-
chlorophenyl)amino)naphthalene-1,4-dione (7c). Red solid; Yield:
94%; m.p 140e142 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.09 (s, 2H),
5.48 (s, 2H), 6.18 (s, 1H), 7.09 (d, 2H, J ¼ 8.7 Hz), 7.15e7.18 (m, 2H),
7.28e7.36 (m, 6H), 7.62 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.70 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.87e7.90 (m, 1H), 8.01e8.04 (m, 1H). 13C NMR (75 MHz,
CDCl3) dC: 49.7, 54.1, 113.9, 122.6, 125.5, 126.6, 127.2, 127.7, 128.7,
129.0, 129.8, 132.1, 132.2, 132.3, 132.6, 134.0, 134.4, 143.5, 144.3,
151.0, 182.5, 183.5. ESI-MS: m/z. Calcd.: 454.12; Found: 455.25
(MþH)þ, 477.25 (MþNa)þ. Anal. Calcd. for C26H19ClN4O2: C, 68.65;
H, 4.21; N, 12.32%. Found C, 68.73; H, 4.33; N, 12.21%.
C27H19FN4O3: C, 69.52; H, 4.11; N,12.01%. Found C, 69.59; H, 4.01; N,
12.14%.
4.1.1.26. 2-(((1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazol-4-yl)meth-
yl)(o-tolyl)amino)naphthalene-1,4-dione (8b). Red solid; Yield: 90%;
m.p 164e166 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 2.12 (s, 3H), 5.26 (br
s, 2H), 5.74 (s, 1H), 5.83 (s, 2H), 7.09e7.12 (m, 1H), 7.22e7.27 (m,
3H), 7.51 (t, 2H, J ¼ 7.8 Hz), 7.58e7.70 (m, 3H), 7.82 (s, 1H),
7.95e8.01 (m, 4H). 13C NMR (75 MHz, CDCl3) dC: 17.6, 49.4, 55.4,
110.2, 125.1, 125.4, 126.5, 127.4, 127.7, 128.0, 128.1, 129.1, 131.7, 132.2,
132.4, 132.5, 133.8, 133.9, 134.5, 134.9, 143.1, 144.2, 150.8, 183.4,1
190.1. ESI-MS: m/z. Calcd.: 462.17; Found: 463.25 (MþH)þ, 485.33
(MþNa)þ. Anal. Calcd. for C28H22N4O3: C, 72.71; H, 4.79; N, 12.11%.
Found C, 72.60; H, 4.72; N, 12.20%.
4.1.1.21. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoro-
methyl)phenyl)amino)naphthalene-1,4-dione (7d). Red solid; Yield:
90%; m.p 188e190 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.11 (s, 2H),
5.47 (s, 2H), 6.37 (s, 1H), 7.14e7.18 (m, 2H), 7.25 (d, 2H, J ¼ 7.2 Hz),
7.31e7.34 (m, 4H), 7.57 (d, 2H, J ¼ 8.4 Hz), 7.63 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.71 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.89 (dd, 1H, J ¼ 7.5, 1.5 Hz), 8.03
(dd, 1H, J ¼ 7.5, 1.5 Hz). 13C NMR (75 MHz, CDCl3) dC: 49.5, 54.2,
116.4, 122.4, 123.9 (1JC,F ¼ 270.4 Hz, CF3), 125.3, 125.7, 126.7, 127.7
(2JC,F ¼ 32.5 Hz), 127.8, 128.7, 129.1, 132.2, 132.3, 132.8, 134.1, 134.5,
144.3, 149.1, 150.9, 182.2, 183.6. Anal. Calcd. for C27H19F3N4O2: C,
66.39; H, 3.92; N, 11.47%. Found C, 66.29; H, 3.99; N, 11.56%.
4.1.1.27. 2-((2,4-dichlorophenyl)((1-(2-oxo-2-phenylethyl)-1H-1,2,3-
triazol-4-yl)methylamino)naphthalene-1,4-dione (8c). Red semi-
solid; Yield: 88%; 1H NMR (300 MHz, CDCl3) dH: 5.06 (s, 2H), 5.84
(s, 2H), 6.11 (s, 1H), 7.22e7.29 (m, 2H), 7.45e7.54 (m, 3H), 7.57e7.70
(m, 3H), 7.80 (s, 1H), 7.89 (d, 1H, J ¼ 7.5 Hz), 7.94e8.00 (m, 3H). 13
C
NMR (75 MHz, CDCl3) dC: 49.0, 55.5, 111.4, 125.0, 125.5, 126.6, 128.0,
128.5, 129.1, 130.2, 130.4, 131.9, 132.2, 132.4, 132.5, 133.6, 133.8,
134.0, 134.5, 141.3, 142.7, 149.9, 182.0, 183.7, 190.0. Anal. Calcd. for
4.1.1.22. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(3-
methoxyphenyl)amino)naphthalene-1,4-dione (7e). Red solid; Yield:
C
27H18Cl2N4O3: C, 62.68; H, 3.51; N,10.83%. Found, C, 62.59; H, 3.63;
91%; m.p 123e125 ꢀC; 1H NMR (300 MHz, CDCl3) dH 1H NMR
:
N, 10.89%.
(300 MHz, CDCl3) dH: 3.73 (s, 3H), 5.14 (s, 2H), 5.47 (s, 2H), 6.13 (s,
1H), 6.70e6.79 (m, 3H), 7.14e7.33 (m, 6H), 7.40 (s, 1H), 7.59 (td, 1H,
J ¼ 7.5, 1.2 Hz), 7.67 (td, 1H, J ¼ 7.5, 1.2 Hz), 7.88 (dd, 1H, J ¼ 7.5,
4.1.1.28. 2-(4-(((1,4-dioxo-1,4-dihydronaphthalen-2-yl)(p-tolyl)-
amino)methyl)-1H-1,2,3-triazol-1-yl)naphthalene-1,4-dione
(9a).
1.2 Hz), 8.00 (d, 1H, J ¼ 7.5, 1.2 Hz). 13C NMR (75 MHz, CDCl3) dC
:
Red solid; Yield: 75%; m.p 227e229 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 2.35 (s, 3H), 5.27 (s, 2H), 6.12 (s, 1H), 6.48 (s, 1H), 7.13 (d, 2H,
J ¼ 8.1 Hz), 7.20 (d, 2H, J ¼ 8.1 Hz), 7.56e7.79 (m, 4H), 7.93 (d, 1H,
J ¼ 7.5 Hz), 7.98 (d,1H, J ¼ 7.5 Hz), 8.07 (d,1H, J ¼ 7.5 Hz), 8.14 (d, 1H,
J ¼ 7.5 Hz), 8.67 (s, 1H). 13C NMR (75 MHz, CDCl3) dC: 21.1, 50.1, 112.5,
125.4, 126.6, 126.1, 126.5, 126.7, 127.0, 129.5, 130.6, 132.1, 132.4,
132.5, 132.9, 133.9, 135.5, 136.9, 141.1, 142.5, 143.2, 151.5, 175.6,
180.5, 182.9, 183.6. Anal. Calcd. for C30H20N4O4: C, 71.99; H, 4.03; N,
11.19%. Found C, 72.05; H, 4.13; N, 11.06%.
49.8, 54.0, 55.3, 111.8, 112.3, 113.4, 118.2, 122.6, 125.4, 126.5, 127.7,
128.6, 129.0, 130.3, 132.2, 132.3, 132.4, 133.9, 134.5, 144.0, 146.7,
151.4, 160.6, 182.8, 183.5. Anal. Calcd. for C27H22N4O3: C, 71.99; H,
4.92; N, 12.44%. Found C, 72.08; H, 4.81; N, 12.36%.
4.1.1.23. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)(2-
chlorophenyl)amino)naphthalene-1,4-dione (7f). Yellow solid; Yield:
95%; m.p 107e109 ꢀC; 1H NMR (300 MHz, CDCl3) dH 1H NMR
:
(300 MHz, CDCl3) dH: 5.08 (s, 2H), 5.47 (s, 2H), 6.20 (s,1H), 7.17e7.28
(m, 5H), 7.33e7.43 (m, 4H), 7.53 (s, 1H), 7.60 (td, 1H, J ¼ 7.5, 1.4 Hz),
7.69 (td, 1H, J ¼ 7.5, 1.4 Hz), 7.90 (dd, 1H, J ¼ 7.5, 1.4 Hz), 8.02 (dd, 1H,
1
Two carbonyls are merged together.

B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
745
4.1.1.29. 2-((4-bromophenyl)((1-(1,4-dioxo-1,4-dihydronaphthalen-
2-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)naphthalene-1,4-dione
(9b). Red solid; Yield: 80%; m.p 248e250 ꢀC; 1H NMR2 (300 MHz,
4.1.2.3. 2-(((1-(2-imino-2H-chromen-3-yl)-1H-1,2,3-triazol-4-yl)-
methyl)(3-methoxyphenyl)amino)naphthalene-1,4-dione (12c).
Red solid; Yield: 77%; m.p 201e203 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 3.80 (s, 3H), 5.29 (s, 2H), 6.17 (s, 1H), 6.82e6.85 (m, 3H), 7.31 (t,
1H, J ¼ 7.8 Hz), 7.38e7.44 (m, 2H), 7.60e7.71 (m, 4H), 7.96e8.03 (m,
2H), 8.56 (s, 1H), 8.59 (s, 1H). 13C NMR (75 MHz, CDCl3) dC: 49.8,
55.4, 112.0, 112.6, 11.35, 116.7, 118.0, 118.3, 122.9, 123.8, 125.5, 125.6,
126.7, 128.9, 130.6, 132.3, 132.4, 132.5, 132.8, 133.2, 133.9, 144.1,
146.7, 151.4, 152.6, 155.7, 160.8, 182.8, 183.7. Anal. Calcd. for
CDCl3) dH:
1H NMR (300 MHz, CDCl3) dH: 5.24 (s, 2H), 6.27 (s, 1H),
6.51 (s, 1H), 7.16 (d, 2H, J ¼ 8.7 Hz), 7.53 (d, 2H, J ¼ 8.7 Hz), 7.51e7.73
(m, 3H), 7.81 (t, 1H, J ¼ 7.5 Hz), 7.95 (d, 1H, J ¼ 7.4 Hz), 8.03 (d, 1H,
J ¼ 7.8 Hz), 8.11 (d,1H, J ¼ 7.4 Hz), 8.18 (d,1H, J ¼ 7.8 Hz), 8.70 (s,1H).
Anal. Calcd. for C29H17BrN4O4: C, 61.61; H, 3.03; N, 9.91%. Found C,
61.52; H, 2.91; N, 9.98%.
C29H21N5O4: C, 69.18; H, 4.20; N, 13.91%. Found C, 69.26; H, 4.07; N,
13.82%.
4.1.1.30. 2-((4-chlorophenyl)((1-(1,4-dioxo-1,4-dihydronaphthalen-
2-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)naphthalene-1,4-dione
(9c). Red solid; Yield: 77%; m.p 223e225 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 5.24 (s, 2H), 6.26 (s, 1H), 6.49 (s, 1H), 7.21 (d, 2H,
J ¼ 8.7 Hz), 7.38 (d, 2H, J ¼ 8.7 Hz), 7.59e7.71 (m, 3H), 7.79 (t, 1H,
J ¼ 7.5 Hz), 7.94 (d,1H, J ¼ 7.5 Hz), 8.01 (d,1H, J ¼ 7.5 Hz), 8.10 (d,1H,
J ¼ 7.5 Hz), 8.16 (d, 1H, J ¼ 7.5 Hz), 8.69 (s, 1H). 13C NMR (75 MHz,
CDCl3) dC: 49.9, 112.4, 113.8, 125.4, 125.5, 126.5, 126.7, 127.0, 127.3,
129.5, 130.0, 132.0, 132.2, 132.3, 132.6, 132.9, 134.0, 135.5, 141.1,
141.9, 144.4, 151.0, 175.6, 180.4, 182.4, 183.7. Anal. Calcd. for
4.1.2.4. 2-((2-chlorophenyl)((1-(2-imino-2H-chromen-3-yl)-1H-
1,2,3-triazol-4-yl)methyl)amino)naphthalene-1,4-dione
(12d).
Yellow solid; Yield: 93%; m.p 163e165 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 5.19 (s, 2H), 6.06 (s, 1H), 7.27e7.42 (m, 5H), 7.47e7.50 (m,
1H), 7.57e7.69 (m, 4H), 7.93 (d, 1H, J ¼ 7.5 Hz), 8.00 (d, 1H,
J ¼ 7.2 Hz), 8.55 (s, 1H), 8.69 (s, 1H). 13C NMR (75 MHz, CDCl3) dC
:
49.1, 111.3, 116.6, 117.9, 122.8, 124.0, 125.4, 125.5, 126.6, 128.2, 128.7,
128.9, 129.2, 130.7, 131.6, 132.0, 132.2, 132.4, 132.7, 133.2, 133.8,
142.3, 143.2, 150.1, 152.5, 155.6, 182.0, 183.6. ESI-MS: m/z. Calcd.:
507.11; Found: 509.18 (Mþ2H)þ. Anal. Calcd. for C28H18ClN5O3: C,
66.21; H, 3.57; N, 13.79%. Found C, 66.35; H, 3.67; N, 13.70%.
C
29H17ClN4O4: C, 66.86; H, 3.29; N, 10.76%. Found C, 66.78; H, 3.40;
N, 10.70%.
4.1.2. General procedure for the synthesis of aminonaphthoquinone
appended iminochromene-triazole hybrid heterocycle 12
4.1.2.5. 2-((2,4-dimethylphenyl)((1-(2-imino-2H-chromen-3-yl)-1H-
1,2,3-triazol-4-yl)methyl)amino)naphthalene-1,4-dione
(12e).
1,2,3-Triazolylacetonitrile
4 was synthesized according the
Red solid; Yield: 82%; m.p 213e215 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 2.13 (s, 3H), 2.33 (s, 3H), 5.03 (s, 1H), 5.48 (s, 1H), 5.73 (s, 1H),
7.04e7.10 (m, 3H), 7.37e7.45 (m, 2H), 7.60e7.71 (m, 4H), 7.99e8.02
(m, 2H), 8.57 (s, 1H), 8.70 (s, 1H). 13C NMR (75 MHz, CDCl3) dC: 17.5,
20.9, 49.2, 110.4, 116.6, 118.0, 123.0, 124.1, 125.3, 125.4, 126.5, 127.1,
128.3, 128.8, 132.1, 132.4, 132.6, 133.0, 133.8, 134.4, 137.9, 140.8,
144.2, 150.9, 152.6, 155.6, 183.2, 183.3. Anal. Calcd. for C30H23N5O3:
C, 71.84; H, 4.62; N, 13.96%. Found C, 71.91; H, 4.50; N, 14.06%.
procedure described above. This intermediate 4 in situ without
isolation was treated with salicyaldehyde (1 mmol) and Et3N
(1 mmol) in a vial and subjected to microwave irradiation at 100 W,
60 ꢀC and 1 bar pressure. After a period of 1e2 min, the tempera-
ture reached a plateau, 60 ꢀC, and remained constant. After
completion of the reaction (TLC), the reaction mixture obtained was
extracted with ethyl acetate and washed with water (2 ꢁ 20 mL).
The organic layer was separated, dried over anhydrous sodium
sulphate, the solvent removed under reduced pressure and purified
by filtration through a short pad of silica gel using 8:2 n-hex-
aneeethyl acetate to obtain pure 12.
4.1.2.6. 2-(((1-(2-imino-2H-chromen-3-yl)-1H-1,2,3-triazol-4-yl)-
methyl)(phenyl)amino)naphthalene-1,4-dione
(12f). Red
solid;
Yield: 79%; m.p 214e216 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 5.30 (s,
2H), 6.15 (s, 1H), 7.24e7.32 (m, 3H), 7.37e7.44 (m, 4H), 7.60e7.71
(m, 4H), 7.96 (dd, 1H, J ¼ 7.5, 0.9 Hz), 8.01 (dd, 1H, J ¼ 7.5, 0.9 Hz),
8.56 (s, 1H), 8.59 (s, 1H). 13C NMR (75 MHz, CDCl3) dC: 49.9, 113.3,
116.7, 118.0, 122.9, 123.7, 125.4, 125.5, 126.2, 126.7, 127.0, 128.9,
129.9, 132.3, 132.4, 132.5, 132.8, 133.2, 133.9, 144.0, 145.6, 151.4,
152.6, 155.6, 182.8, 183.6. Anal. Calcd. for C28H19N5O3: C, 71.03; H,
4.04; N, 14.79%. Found C, 70.96; H, 4.15; N, 14.71%.
4.1.2.1. 2-(((1-(2-imino-2H-chromen-3-yl)-1H-1,2,3-triazol-4-yl)
methyl)(p-tolyl)amino)naphthalene-1,4-dione (12a). Red solid;
Yield: 89%; m.p 183e185 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 2.35 (s,
3H), 5.23 (s, 2H), 6.10 (s, 1H), 7.13 (d, 2H, J ¼ 7.5 Hz), 7.21 (d, 2H,
J ¼ 7.5 Hz), 7.37e7.44 (m, 2H), 7.61e7.68 (m, 4H), 7.96 (d, 1H,
J ¼ 7.5 Hz), 8.01 (d, 1H, J ¼ 7.2 Hz), 8.56 (s, 1H), 8.60 (s, 1H). 13C NMR
(75 MHz, CDCl3) dC: 21.0, 50.0, 112.8, 116.7, 118.1, 123.0, 123.8, 125.4,
125.5, 126.1, 126.7, 128.9, 130.6, 132.4, 132.5, 132.7, 133.1, 133.8,
136.9, 143.1, 144.2, 151.6, 152.7, 155.6, 183.0, 183.5. Anal. Calcd. for
4.1.2.7. 2-(((1-(6-bromo-2-imino-2H-chromen-3-yl)-1H-1,2,3-
triazol-4-yl)methyl)(p-tolyl)amino)naphthalene-1,4-dione
(12g).
Red solid; Yield: 81%; m.p 221e223 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 1H NMR (300 MHz, CDCl3) dH: 2.36 (s, 3H), 5.27 (s, 2H), 6.08 (s,
1H), 7.12 (d, 2H, J ¼ 7.5 Hz), 7.21 (d, 2H, J ¼ 7.5 Hz), 7.31 (d, 1H,
J ¼ 8.7 Hz), 7.59e7.79 (m, 4H), 7.95 (d, 1H, J ¼ 7.5 Hz), 8.00 (d, 1H,
C
29H21N5O3: C, 71.45; H, 4.34; N, 14.37%. Found C, 71.56; H, 4.48; N,
14.29%.
4.1.2.2. 2-((4-fluorophenyl)((1-(2-imino-2H-chromen-3-yl)-1H-
J ¼ 7.5 Hz), 8.49 (s, 1H), 8.61 (s, 1H). 13C NMR (75 MHz, CDCl3) dC
:
1,2,3-triazol-4-yl)methyl)aminonaphthalene-1,4-dione
(12b).
Yellow solid; Yield: 76%; m.p 231e233 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 5.26 (s, 2H), 6.09 (s, 1H), 7.08e7.14 (m, 2H), 7.23e7.27 (m,
2H), 7.38e7.45 (m, 2H), 7.63e7.72 (m, 4H), 7.96 (d, 1H, J ¼ 7.2 Hz),
8.01 (d, 1H, J ¼ 7.5 Hz), 8.57 (s, 1H), 8.63 (s, 1H). 13C NMR (75 MHz,
CDCl3) dC: 49.9, 113.1, 116.6, 116.9, 118.0, 122.9, 123.7, 125.5, 126.6,
128.2, 128.8, 132.2, 132.3, 132.4, 132.7, 133.1, 133.9, 141.6, 143.8,
151.3, 152.6, 155.6, 161.1, 182.7, 183.5. Anal. Calcd. for C28H18FN5O3:
C, 68.43; H, 3.69; N, 14.25%. Found C, 68.30; H, 3.75; N, 14.34%.
21.0, 49.9, 112.7, 118.2, 118.3, 119.6, 123.7, 125.4, 126.3, 126.7, 130.6,
131.0, 131.5, 132.3, 132.4, 133.9,135.4, 137.0, 142.9, 144.3, 151.3, 151.5,
155.0, 183.0, 183.6. Anal. Calcd. for C29H20BrN5O3: C, 61.49; H, 3.56;
N, 12.36%. Found C, 61.43; H, 3.65; N, 12.23%.
4.1.2.8. 2-(((1-(6-chloro-2-imino-2H-chromen-3-yl)-1H-1,2,3-
triazol-4-yl)methyl)(4-fluorophenyl)amino)naphthalene-1,4-dione
(12h). Yellow solid; Yield: 88%; m.p 240e242 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 5.25 (s, 2H), 6.07 (s, 1H), 7.08e7.13 (m, 2H),
7.22e7.27 (m, 2H), 7.39 (d,1H, J ¼ 7.5 Hz), 7.56e7.71 (m, 4H), 7.95 (d,
1H, J ¼ 7.2 Hz), 8.00 (d, 1H, J ¼ 7.2 Hz), 8.50 (s, 1H), 8.63 (s, 1H). 13
C
2
Due to poor solubility of this compound we have taken only the 1H NMR
spectrum.
NMR (75 MHz, CDCl3) dC: 49.9, 113.2, 116.7, 118.1, 119.1, 123.8, 125.5,

746
B. Devi Bala et al. / European Journal of Medicinal Chemistry 85 (2014) 737e746
126.7,128.0,128.2,131.1, 131.6, 132.3,132.6, 132.7, 134.0,141.6, 144.0,
150.9, 151.3, 155.1, 155.6, 161.2, 182.8, 183.6. Anal. Calcd. for
Appendix A. Supplementary data
C
28H17ClFN5O3: C, 63.95; H, 3.26; N, 13.32%. Found C, 64.07; H, 3.18;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.08.009.
N, 13.19%.
4.1.2.9. 2-(((1-(2-imino-6-methyl-2H-chromen-3-yl)-1H-1,2,3-
triazol-4-yl)methyl)(phenyl)amino)naphthalene-1,4-dione
(12i).
References
Red solid; Yield: 90%; m.p 202e204 ꢀC; 1H NMR (300 MHz, CDCl3)
dH: 2.44 (s, 3H), 5.29 (s, 2H), 6.16 (s, 1H), 7.25e7.32 (m, 4H),
7.39e7.44 (m, 4H), 7.61 (td, 1H, J ¼ 7.5, 1.5 Hz), 7.68 (td, 1H, J ¼ 7.5,
1.5 Hz), 7.95 (d, 1H, J ¼ 7.5 Hz), 8.01 (d, 1H, J ¼ 7.5 Hz), 8.50 (s, 1H),
8.58 (s, 1H). 13C NMR (75 MHz, CDCl3) dC: 20.8, 49.9, 113.3, 116.4,
117.7, 122.8, 123.7, 125.5, 126.2, 127.7, 126.9, 128.6, 129.9, 132.3,
132.4, 132.5, 133.3, 133.9, 135.5, 143.9, 145.7, 150.8, 151.4, 155.8,
182.8, 183.6. Anal. Calcd. for C29H21N5O3: C, 71.45; H, 4.34; N,
14.37%. Found C, 71.39; H, 4.21; N, 14.45%.
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