Synthesis and antimicrobial screening of novel 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives

Article abstract of DOI:10.1134/S1070363217090171

A series of novel 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized by a click chemistry approach. The structures of all the newly synthesized compounds were chara

Full text of DOI:10.1134/S1070363217090171

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 9, pp. 2011–2020. © Pleiades Publishing, Ltd., 2017.
Synthesis and Antimicrobial Screening of Novel
9
-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-
1
3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione Derivatives
a
a
a
A. Kishore Kumar , V. Sunitha , B. Shankar ,
b
b
a
T. Murali Krishna , Ch. Abraham Lincoln , and P. Jalapathi *
a
Department of Chemistry, University College of Science, Osmania University,
Saifabad, Hyderabad, 500004 Telangana, India
*
e-mail: pochampalli.ou.chemi@gmail.com
b
Department of Biotechnology, Chaitanya Postgraduate College (Autonomous),
Kishanpura, Hanamkonda, Warangal, Telangana, 506001 India
Received January 21, 2016
Abstract—A series of novel 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized by a click chemistry approach. The
1
13
structures of all the newly synthesized compounds were characterized by IR, MASS, H and C NMR spectral
data. The final analogues showed good to excellent antibacterial and antifungal activities in an agar well
diffusion assay. Compounds 6i and 6f were the most active against all the test bacterial and fungal strains.
Keywords: xanthene, 1,2,3-triazole, click chemistry, antibacterial activity, antifungal activity
DOI: 10.1134/S1070363217090171
INTRODUCTION
There is a mounting need to develop new anti-
triazoles have also been found to act as powerful
pharmacophores. Encouraged by the above-mentioned
features and aimed at searching for new, broad-
spectrum, and more potent antimicrobial compounds
which can advance the present chemotherapeutic
treatments, we made an attempt to conjugate these two
(xanthene and 1,2,3-triazole) important pharmaco-
phores under one construct. Herein we report the syn-
thesis of xanthenedione- and 1,2,3-triazole-based bis-
heterocycles and their significant antimicrobial activities.
bacterial agents for overcoming bacterial resistance to
antibiotic therapy. Xanthenes are among the most
widespread class of natural compounds. Its derivatives,
such as 1,8-dioxooctahydroxanthenes (xanthenediones),
have attracted the attention of organic chemists due to
their broad-range biological and therapeutic applica-
tions as antiviral [1], antimicrobial [2], anti-inflam-
matory [3], antiplasmodial [4], and anticanceragents
In our previous research on the synthesis of bio-
active heterocyclic compounds and their evaluation for
antimicrobial activity [22, 23], we obtained evidence
to show that the introduction of substituted aryl groups
increases antimicrobial activity by enhancing the
lipophilicity of molecules and thus facilitating their
penetration into cells. Taking this into account, in the
present study we made an attempt to synthesize
xanthene- and 1,4-disubstituted 1,2,3-triazole-based
analogs bearing differently substituted phenyl groups.
[
5, 6]. Furthermore, xanthenes derivatives have been
widely used as pH-sensitive fluorescent materials
7, 8] and dyes [9], including laser dyes [10, 11]. Thus,
[
the synthesis of various xanthene derivatives is of great
importance.
Similarly, 1,2,3-triazoles and their analogs have
occupied significant role in organic and medicinal
chemistry due to their easy synthesis by click
chemistry. 1,2,3-triazoles are potent antibacterial [12,
1
3], antifungal [14], antiallergic [15], antineoplastic
[16], antimalarial [17], anti-inflammatory [18], anti-
RESULTS AND DISCUSSIONS
tubercular [19, 20], and anti-HIV agents [21, 22]. 1,2,3-
The target 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]-
phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-
1
The text was submitted by the authors in English.
2
011

2
012
KISHORE KUMAR et al.
Scheme 1.
O
H
OH
O
O
Br
O
I2/MeOH
Me
Me
reflux, 30 min
K CO
2 3
DMF
85%
O
OH
8
7%
Me
Me
Me
Me
O
3
1
2
O
O
O
O
R
N
O
CuI, acetonitrile,
room temperature
O
N
N
R−N
3
5
a−5n
Me
Me
Me
Me
Me
Me
Me
Me
O
a−6n
R = n-оctyl (a), n-hexyl (b), n-Bu (c), Ph (d), 2-MePh (e), 3-ClPh (f), n-dodecyl (g), 4-NO
O
6
4
2
Ph (h), 3-NO Ph (i), cyclohexyl
2
(
j), 4-BrPh (k), 4-ClPh (l), 3-BrPh (m), i-Bu (n).
–
1
xanthene-1,8(2H)-dione derivatives 6a‒6n were syn-
thesized by a 3-step protocol, as shown in Scheme 1.
The mixture of 5,5-dimethyl-1,3-cyclohexanedione (1)
and ortho-hydroxybenzaldehyde (2) in the presence of
iodine in methanol was prepared and refluxed for
3390 cm for the hydroxyl group on the phenyl ring,
–
1
1644 cm for the carbonyl group characterized com-
pound 3. Compound 3 was O-alkylated in the presence
of propargyl bromide and anhydrous K CO in dry
2
3
DMF at room temperature to obtain 3,3,6,6-tetra-
methyl-9-[2-(prop-2-yn-1-yloxy)phenyl]-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione (4). Aliphatic
and aromatic azides 5a–5n were synthesized by
protocols [25]. To prepare alkyl azides, corresponding
3
0 min to form 9-(2-hydroxyphenyl)-3,3,6,6-tetra-
methyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (3) in a good yield. The product was well
1
characterized by spectral (IR, H NMR, and MASS)
data. The appearance of a singlet in the region
alkyl halides were heated at 80‒90°C with NaN in
DMF. Aromatic azides were prepared from differently
substituted anilines via diazotization followed by
3
9
4
.66 ppm for the C proton and two singlets in the
region 1.02–1.12 ppm each for two methyl hydrogens
1
in the H NMR spectra and IR signals in the region
treatment with NaN . The final compounds 6a–6n
3
Table 1. Optimization of conditions of the click reaction
a
b
Entry
Catalyst
Solvent
O (1 : 1)
t-BuOH–H O (1 : 1)
THF–H O (1 : 1)
Acetone–H O (1 : 1)
Time, min
Yield , %
1
2
3
4
5
CuSO
CuSO
CuSO
CuSO
CuSO
CuI
4
4
4
4
4
·5H
·5H
·5H
·5H
·5H
2
2
2
2
2
O + NaAsc
O + NaAsc
O + NaAsc
O + NaAsc
O + NaAsc
DMF–H
2
60
60
60
60
60
60
30
75
80
86
77
‒
2
2
2
2
H O
c
6
THF
CH CN
76
98
c
7
CuI
3
a
The reactions were carried out with alkyne 4 (1.0 mmol), azide 5d (1.0 mmol), 5 mol % of Cu catalyst, and 10 mol % of sodium
ascorbate (NaAsc) in 5 mL of solvent at room temperature. Isolated yield. No additive was used.
b
c
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS AND ANTIMICROBIAL SCREENING
Table 2. Antibacterial activity of compounds 6a–6n
2013
Zone of inhibition, mm
gram-negative bacteria
M. tub M. lut MRSA B. sub B. cer P. aer K. pne E. coli P. vul
Concentration,
µg/mL
Comp. no
gram-positive bacteria
S. typ
6
a
75
17
18
16
17
14
16
18
20
11
14
27
30
10
12
23
25
28
32
17
19
21
23
20
23
25
27
22
24
29
32
13
15
13
14
11
13
16
17
10
11
23
25
09
11
22
24
25
26
15
16
19
21
17
19
23
24
21
22
27
30
13
16
12
14
09
10
17
19
08
09
27
28
07
08
20
23
29
30
15
16
18
20
18
19
24
25
19
22
31
33
15
16
14
15
13
13
18
20
10
12
26
28
08
09
23
26
27
29
17
17
19
21
19
20
25
26
21
22
30
33
17
17
16
17
14
15
19
20
13
15
27
29
12
13
24
27
29
30
17
19
22
25
21
22
26
28
23
25
31
34
14
16
13
14
12
12
16
17
10
11
24
25
08
10
22
23
26
27
15
16
19
20
17
19
23
24
21
23
28
31
16
17
15
15
13
14
18
19
11
12
23
25
09
11
20
22
24
26
17
18
19
21
19
20
21
23
20
21
27
30
19
20
18
20
17
18
21
22
15
17
27
29
30
15
25
28
29
31
20
22
23
24
21
23
26
28
24
26
31
33
20
21
19
20
17
19
20
23
16
17
27
28
14
15
24
24
28
29
20
22
24
25
23
25
25
27
24
26
29
31
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
1
00
6
b
75
1
00
6
c
75
1
00
6
d
75
1
00
6
e
75
1
00
6
f
75
1
00
6
g
75
1
00
6
h
75
1
00
6
i
75
1
00
6
j
75
1
00
6
k
75
1
00
6
l
75
1
00
6
m
75
1
00
6
n
75
1
00
Zentamicin
75
00
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

2
014
KISHORE KUMAR et al.
Table 3. Antifungal activity of compounds 6a–6n
Zone of inhibition, mm
T. interdigitale E. floccosum
Comp. no.
Concentration, µg/mL
75
M. canis M. gypseum
T. rubrum
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
6
a
11
12
09
11
08
10
14
15
07
09
22
25
07
08
19
22
23
25
13
15
16
18
15
17
20
23
17
21
25
28
15
15
14
16
12
14
16
16
10
12
19
20
08
10
18
20
18
19
15
16
17
19
16
17
19
19
18
19
19
24
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
No activity
12
13
10
12
09
11
13
14
08
10
18
19
07
07
17
18
19
20
13
13
15
16
14
15
18
19
15
17
20
23
1
00
6
b
75
1
1
00
6
c
75
00
6
d
75
1
1
00
6
e
75
00
6
f
75
1
00
6
g
75
1
00
6
h
75
1
00
6
i
75
1
00
6
j
75
1
00
6
k
75
1
00
6
l
75
1
00
6
m
75
1
00
6
n
75
1
00
Nystatin
75
1
00
were prepared by click reaction of compound 4 with
various aliphatic and aromaticazides 5a–5n. Initially,
we tried different conditions to optimize the reaction
shown in Table 1. Among all conditions, the aceto-
nitrile‒CuI system produced an excellent yield (98%)
at room temperature in 30 min. The structures of
compounds 6a–6n were characterized by IR, NMR,
and MASS. The presence of a 1,2,3-triazole fragment
in the products is evidenced by the observation of a
singlet at 7.73‒8.61 ppm in their H NMR spectra.
1
Compounds 6a–6n were tested for their antibac-
terial activity against Mycobacterium tuberculosis (M.
tub), Micrococcus luteus (M. lut), methicillin-resistant
Staphylococcus aureus (MRSA), Bacillus subtilis (B.
sub), Bacillus cereus (B. cer), Pseudomonas aerugi-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS AND ANTIMICROBIAL SCREENING
2015
Table 4. Minimum inhibitory concentrations of compounds 6a–6n against bacterial and fungal strains
Comp. no.
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
Gram positive bacteria
M. tub
103.5 114.9 >120 92.3 >125 <40 133.6 62.1 <30 >100 >80 87.4 >50 74.6
>110 >120 136.8 89.6 >145 37.6 >150 >55 32.1 >100 73.7 >80 >45 62.2
>110 118.1 126.0 >90 >135 >35 >150 >50 28.1 >110 77.1 86.0 43.3 >60
>100 >110 116.0 83.3 >125 >40 >130 >50 38.9 >90 61.4 >70 45.6 >55
97.1 >105 109.1 82.0 >120 >40 >130 >50 74.0 >90 68.9 >70 47.1 >60
Gram negative bacteria
M. lut
MRSA
B. sub
B. cer
P. aer
K. pne
E. coli
P. vul
S. typ
>100 114.2 >120 >80 >130 >45 >130 63.6 40.2 92.6 >70 77.9 54.1 >60
>95 >100 107.0 88.0 >115 >50 >125 >60
77.0 >80 >85 65.1 >90 34.1 >100 >50
86.3 94.5 >100 >80 >100 >40 >110 >55
NA NA NA NA NA NA NA NA
Dermatophytes
96.8 >100 >100 83.3 >110 >45 >115 53.6 >40
88.3 >100 >110 >75 >117 38.1 >120 >50 32.7 >80 62.3 >70 >45 >50
<50
<30
>40
NA
>90 72.9 >80 >50 66.0
>70 54.2 >60 >40 50
>80 66.0 >70 45.2 >60
NA NA NA NA NA
M. canis
>90 69.0 >75 >50 >60
M. gypseums
T. rubrum
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
>40
NA
NA
NA
NA
NA
NA
NA NA
NA NA
T. interdigitale
E. floccosum
>85 93.2 >100 >60 >110 >40 >115 >45
>75 58.2 >65 >40 >50
a
(
NA) is no activity.
nosa (P. aer), Klebsiella pneumonia (K. pne), Escheri-
chia coli (E. coli), Proteus vulgaris (P. vul), Salmo-
nella typhi (S. typ). The compounds all showed a
significantly stronger inhibition of the test gram-
positive and gram-negative bacterial strains compared
to the standard drug gentamicin sulfate (Table 2). The
most active among the test compounds were found to
be 6f and 6i. Compounds 6h, 6k, 6l–6n, also exhibited
a good antibacterial profile against the test bacterial
strains. The only exception was S. typ, which proved to
be resistant to all the test compounds.
and 20 mm were found for M. canis, M. gypseum, and
E. floccosum, respectively, at 100 µg/mL against the
standard drug Nystatin (23 mm at 100 µg/mL).
Table 4 lists the minimum inhibitory concentrations
of compounds 6a–6n. As see from the MIC values,
compounds 6f and 6i are the most potent antibacterial
and antifungal agents.
EXPERIMENTAL
The melting points were measured in open
capillaries and are uncorrected. The IR spectra were
recorded on a Perkin–Elmer 337 spectrophotometer for
Compounds 6a–6n were also tested for their
antifungal activity against Microsporum canis (M.
canis), Microsporum gypseum (M. gypseum),
Trichophyton rubrum (T. rubrum), Trichophyton
interdigitale (T. interdigitale), and Epidermophyton
floccosum (E. floccosum). According to the resulting
data (Table 3), among all the screened analogs,
compounds 6f and 6i showed the highest antifungal
activity. The maximum zones of inhibition of 25, 19,
1
solid samples in KBr pellets. The H NMR spectra
were run on a Bruker AV 400 MHz instrument for
CDCl solutions. The chemical shifts were measured in
3
ppm against internal TMS. Thin layer chromatography
was carried out on Merck silica gel 60 F254 plates, and
the spots were visualized with UV light at 254 nm or,
alternatively, by staining with aqueous basic potassium
permanganate. Flash column chromatography was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

2
016
KISHORE KUMAR et al.
performed on a Merck silica gel 60A (100–200 mesh).
Commercially available reagents were used as supplied
and some of them were distilled before use. All
reactions were performed in an oven-dried glassware.
thene-1,8(2H)-dione derivatives 6a–6n (general pro-
cedure). Propargyl derivative 4 (100 mg, 0.247 mmol)
is dissolved in 5 mL of acetonitrile and was added CuI
(5 mol %) followed by azide (0.296 mmol). The reac-
tion mixture was stirred for 30 min at room tem-
perature, monitored by TLC. After complete con-
version of starting materials solvent was removed
under reduced pressure, then reaction mixture was
diluted with water (25 mL) and extracted with ethyl
acetate (3×25 mL). The combined organic layers were
washed with brine (2×25 mL). The organic layer was
dried over anhydrous sodium sulphate, filtered and
concentrated in vacuo. The crude product was purified
by column chromatography using 100–200 mesh silica
gel and ethyl acetate in pet ether to afford corres-
ponding 1,4-disubstituted 1,2,3-triazole analogs 6a–6n.
Synthesis of 9-(2-hydroxyphenyl)-3,3,6,6-tetra-
methyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (3). A solution of salicylaldehyde (0.436 g,
3
(
1
.57 mmol) and 5,5-dimethylcyclohexane-1,3-dione
1 g, 7.14 mmol), and iodine (0.113 g, 0.892 mmol) in
0 mL of methanol was heated at 70–80°C. The
progress of the reaction was periodically monitored by
TLC. After completion of the reaction, the solvent was
removed on a rotary evaporator. The crude product
was purified by recrystallization from hot ethanol to
give compound 3. mp 205-206ºC. Yield 87%, off
–
1
white solid, IR spectrum, ν, cm : 3390 (OH), 1644
1
(
C=O). H NMR spectrum (400 MHz, CDCl ), δ, ppm:
3
3
,3,6,6-Tetramethyl-9-[2-[(1-octyl-1H-1,2,3-tri-
1
4
1
0.47 br.s (1H), 7.16–7.25 m (1H), 7.01–7.12 m (3H),
.66 s (1H), 2.60 d (J = 17.6 Hz, 1H), 2.47 d (J =
7.6 Hz, 1H), 2.38 s (2H), 2.37 s (2H), 1.99 d (J = 16.4
azol-4-yl)methoxy]phenyl}-3,4,5,6,7,9-hexahydro-1H-
xanthene-1,8(2H)-dione (6a). Yield 90%, white solid,
–1
mp 92–94°C. IR spectrum, ν, cm : 1684 (C=O), 1651
Hz, 1H), 1.92 d (J = 16.4 Hz , 1H), 1.12 s (6H), 1.02 s
1
(
C=O). H NMR spectrum (400 MHz, CDCl ), δ, ppm:
3
1
3
(
6H). C NMR spectrum (100 MHz, CDCl ), δ , ppm:
3 C
7
.82 s (1H), 7.17–6.89 m (4H), 5.50–4.97 m (3H), 4.30
2
1
3
00.6, 196.7, 170.1, 168.7, 150.8, 128.1, 127.1, 124.6,
24.7, 118.5, 115.6, 111.5, 50.6, 49.9, 43.2, 41.2, 32.2,
0.9, 29.7, 29.2, 27.6, 27.1, 26.6. EI-MS: m/z = 367
t (J = 5.6 Hz, 2H), 2.52–2.31 m (4H), 2.29–2.09 m
(
(
4H), 1.88 s (2H), 1.37–1.27 m (10H), 1.13–0.99 m
9H), 0.92–0.85 m (6H). C NMR spectrum (100 MHz,
13
[
M + 1].
CDCl ), δ , ppm: 196.8 (2C), 169.2, 150.8 (2C), 144.1,
3
C
3
,3,6,6-Tetramethyl-9-(2-(prop-2-ynyloxy)phenyl)-
129.9, 127.7 (2C), 125.0 (2C), 120.3, 116.6 (2C), 63.3,
52.5, 52.0, 43.1, 40.8, 33.8 (2C), 33.7 (2C), 33.4, 31.9,
30.9, 30.8, 30.7, 30.3, 29.4, 29.0, 28.2, 24.4, 15.9.
EI-MS: m/z = 560.5 [M + 1].
3
(
,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione
4). Anhydrous K CO (640 mg, 4.62 mmol) was
2 3
added to a solution of compound 3 (1.13 g, 3.08 mmol)
in 5 mL of anhydrous DMF. Propargyl bromide, 80%
in toluene (331 mg, 3.70 mmol), was added to the
mixture. The resulting mixture was stirred for 16 h at
room temperature. After complete consumption of the
starting materials, as indicated by TLC, ice-cold water
was added to the reaction mixture. The solid that formed
was filtered off and washed with water to give a pure
product 4. Yield 85%, brown solid, mp 164–166°C. IR
spectrum, ν, cm : 1655 (C=O), 1642 (C=O). H NMR
spectrum (400 MHz, CDCl ), δ, ppm: 7.09–7.05 m
2H), 6.96–6.91 m (2H), 5.28 s (1H), 4.58 br.s (2H),
.53–2.39 m (5H), 2.56–2.16 m (4H), 1.08 s (3H), 1.05
s (3H), 1.01 s (3H), 0.99 s (3H). C NMR spectrum
100 MHz, CDCl ), δ , ppm: 197.0, 196.6, 168.1,
50.0 (2C), 128.7, 126.9 (2C), 124.9, 124.5, 124.1
2C), 115.6 (2C), 75.9, 51.0, 41.6, 38.9, 32.2 (2C),
2.0 (2C), 28.8, 28.3, 28.2, 27.8. EI-MS: m/z = 405.2
M + 1].
9
-{2-[(1-Hexyl-1H-1,2,3-triazol-4-yl)methoxy]-
phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
H-xanthene-1,8(2H)-dione (6b). Yield 85%, white
1
–
1
solid, mp 126–128°C. IR spectrum, ν, cm : 1687
1
(
C=O), 1659 (C=O). H NMR spectrum (400 MHz,
CDCl ), δ, ppm: 7.84 s (1H), 7.15–6.85 m (4H), 5.47-
3
5
.00 m (3H), 4.27 t (J = 7.1 Hz, 2H), 2.50–2.29 m
(4H), 2.27–2.08 m (4H), 1.85 s (2H), 1.35–1.24 m
6H), 1.08 s (3H), 1.03 s (3H), 0.98 s (3H), 0.91–0.81
–
1
1
(
3
13
m (6H). C NMR spectrum (100 MHz, CDCl ), δ ,
3
C
(
2
ppm: 196.5 (2C), 168.7, 150.1 (2C), 145.3, 128.8,
126.8 (2C), 124.1 (2C), 119.5, 115.6, 115.5, 62.1,
1
3
5
2
0.9, 50.3, 41.4, 39.0, 32.0 (2C), 31.9 (2C), 31.1, 30.1,
9.1, 28.5, 27.6, 27.2, 26.0, 22.3, 13.9. EI-MS: (ES+)
(
1
(
3
3 C
m/z = 532.5 [M + 1].
9
-{2-[(1-Butyl-1H-1,2,3-triazol-4-yl)methoxy]-
[
phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
9
-{2-[(1H-1,2,3-Triazol-4-yl)methoxy]phenyl}-
1H-xanthene-1,8(2H)-dione (6c). Yield 81%, white
solid, mp 121–123°C. IR spectrum, ν, cm : 1678
–
1
3
,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xan-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS AND ANTIMICROBIAL SCREENING
2017
1
13
(
C=O), 1651 (C=O). H NMR spectrum (400 MHz,
0.85 s (3H). C NMR spectrum (100 MHz, CDCl3),
δC, ppm: 197.1 (2C), 168.1, 150.1 (2C), 145.1, 135.5,
132.4 (2C), 130.8, 128.7, 127.1 (2C), 125.3, 124.3
(2C), 121.6, 120.5, 118.3 (2C), 62.3, 51.0 (2C), 41.6,
39.0, 32.1 (2C), 32.0 (2C), 29.2, 28.5, 27.3. EI-MS:
m/z = 558 [M + 1], 560.5 [M + 3].
CDCl ), δ, ppm: 7.88 s (1H), 7.18–7.01 m (3H), 6.96 t
J = 7.6 Hz, 1H), 5.32 s (1H), 5.17 s (2H), 4.40 t (J =
.3 Hz, 2H), 4.29 br.s (2H), 2.51–2.28 m (2H), 2.26–
.19 m (4H), 1.88 br.s (2H), 1.34 br.s (2H), 1.06 s
3H), 1.03 s (3H), 0.99 s (3H), 0.92–0.83 m (6H).
3
(
7
2
1
3
(
C
NMR spectrum (100 MHz, CDCl ), δ , ppm: 196.8
3
C
9
-{2-[(1-Dodecyl-1H-1,2,3-triazol-4-yl)methoxy]-
phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
H-xanthene-1,8(2H)-dione (6g). Yield 90%, white
(
2C), 169.2, 151.1 (2C), 144.9, 128.8, 127.1 (2C),
1
4
1
24.2 (2C), 119.5, 115.7 (2C), 62.3, 51.2, 50.8, 50.2,
1.5, 39.5, 32.2 (2C), 32.1 (2C), 30.1, 29.3, 28.4, 27.3,
9.2, 13.4. EI-MS: m/z = 504.3 [M + 1].
1
–1
solid, mp 97–99°C. IR spectrum, ν, cm : 1685 (C=O),
650 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
1
1
3
3
,3,6,6-Tetramethyl-9-{2-[(1-phenyl-1H-1,2,3-
triazol-4-yl)methoxy]phenyl}-3,4,5,6,7,9-hexahydro-
H-xanthene-1,8(2H)-dione (6d). Yield 98%, light
ppm: 7.88 s (1H), 7.09 t (J = 7.3 Hz, 1H), 7.05 d (J =
7.5 Hz, 1H), 6.99 t (J = 7.6 Hz, 1H), 6.90 d (1H), 5.33
s (1H), 5.19 s (2H), 4.30 t (J = 7.3 Hz, 2H), 4.27 br.s
(2H), 2.53–2.26 m (2H), 2.26–2.19 m (4H), 1.99–1.89
br.s (2H), 1.32 br.s (6H), 1.26 br.s (14H), 1.07 s (3H),
1
–
1
brown solid, mp 130-132°C. IR spectrum, ν, cm :
655 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
ppm: 8.03 s (1H), 7.90–7.66 m (2H), 7.58 t (J =
1
1
3
1
3
1.03 s (3H), 0.98 s (3H), 0.91–0.81 m (6H). C NMR
9
6
.14 Hz, 2H), 7.52–7.46 m (1H), 7.11–7.05 m (2H),
.96 t (J = 7.5 Hz, 1H), 6.93–6.85 m (1H), 5.58–4.95
spectrum (75 MHz, CDCl ), δ , ppm: 196.7 (2C),
3
C
168.9, 150.2 (2C), 145.5, 129.1, 125.9 (2C), 124.3
(2C), 120.1, 115.4 (2C), 62.8, 51.3 (2C), 50.4, 41.8,
39.1, 32.3 (2C), 32.1 (2C), 31.8, 30.2, 29.6 (2C), 29.5,
29.4, 29.3, 29.3, 28.9, 28.3, 27.5, 26.4, 22.6, 14.1.
EI-MS: m/z = 616.3 [M + 1].
m (3H), 2.58–2.37 m (4H), 2.32–2.12 m (4H), 1.11 s
1
3
(
3H), 1.07 s (3H), 1.02 s (3H), 0.91 s (3H). C NMR
spectrum (100 MHz, CDCl ), δ , ppm 196.8 (2C),
3
C
1
1
6
2
69.0, 150.6 (2C), 143.6, 137.5, 130.4 (2C), 129.7,
29.5, 127.7, 125.0 (2C), 122.1, 121.1 (2C), 116.3,
2.2, 52.3 (2C), 42.8, 40.4, 33.5, 33.4, 30.5 (2C), 29.8,
9.2, 28.7. EI-MS: m/z = 524.1 [M + 1].
3
,3,6,6-Tetramethyl-9-{2-[(1-[4-nitrophenyl]-1H-
,2,3-triazol-4-yl)methoxy]phenyl}-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione (6h). Yield
1
–1
3
,3,6,6-Tetramethyl-9-{2-[(1-[o-tolyl]-1H-1,2,3-
triazol-4-yl)methoxy]phenyl}-3,4,5,6,7,9-hexahydro-
H-xanthene-1,8(2H)-dione (6e). Yield 93%, light
80%, yellow solid, mp 198–200°C. IR spectrum, ν, cm :
1
1660 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
3
1
ppm: 8.41 d (2H), 8.10 d (J = 7.5 Hz, 2H), 7.97 s (1H),
7.11–7.04 m (2H), 7.01–6.95 m (2H), 5.52 s (1H), 5.35
s (2H), 2.69–2.30 m (4H), 2.28–2.12 m (4H), 1.13 s
–
1
brown solid, mp 141–143°C. IR spectrum, ν, cm :
1
MHz, CDCl ), δ, ppm: 7.73 s (1H), 7.51–7.37 m (3H),
1
680 (C=O), 1665 (C=O). H NMR spectrum (400
1
3
(3H), 1.07 s (3H), 0.96 s (3H), 0.84 s (3H). C NMR
3
7
5
.33–7.28 m (1H), 7.03 d (1H), 6.99–6.76 m (3H),
.55–4.99 m (3H), 2.62–2.34 m (4H), 2.29–2.12 m
spectrum (100 MHz, CDCl ), δ , ppm: 196.5 (2C),
3
C
167.7, 150.0 (2C), 147.1, 146.1, 137.2, 131.2, 125.4
(2C), 124.3 (2C), 122.3, 121.8, 121.7, 120.3 (2C),
115.9, 115.9, 61.9, 51.3, 50.5, 41.6, 38.8, 32.0 (2C),
31.2 (2C), 29.1, 28.5, 27.3. EI-MS: m/z = 569.1 [M + 1].
1
3
(
7H), 1.16–0.98 m (9H), 0.94 s (3H). C NMR spec-
trum (100 MHz, CDCl ), δ , ppm: 197.2, 196.8, 169.1,
3
C
1
1
1
3
50.7 (2C), 143.2, 137.0, 134.3, 132.3 (2C), 130.8,
29.8, 127.8, 127.7 (2C), 126.7, 125.6, 125.1 (2C),
16.4, 63.1, 52.2, 43.1, 40.9 (2C), 33.9, 33.7 (2C),
0.9, 30.3, 29.6, 29.1, 19.7. EI-MS: m/z = 538.1 [M + 1].
3
,3,6,6-Tetramethyl-9-{2-[(1-[3-nitrophenyl]-1H-
,2,3-triazol-4-yl)methoxy]phenyl}-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione (6i). Yield
1
–1
9
-{2-[(1-[3-Chlorophenyl]-1H-1,2,3-triazol-4-yl)-
88%, yellow solid, mp 147–149°C. IR spectrum, ν, cm :
1
methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-
1677 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
3
hexahydro-1H-xanthene-1,8(2H)-dione (6f). Yield
ppm: 8.61 s (1H), 8.33 d (J = 7.6 Hz, 1H), 7.78 t (J =
7.5 Hz, 1H), 7.35–7.30 m (1H), 7.13 d (J = 7.5 Hz,
2H), 7.07–6.90 m (3H), 5.71–5.33 m (3H), 2.61–2.43
m (4H), 2.42–2.29 m (4H), 1.14 s (3H), 1.09 s (3H),
–1
8
1
7%, white solid, mp 107–109°C. IR spectrum, ν, cm :
685 (C=O), 1660 (C=O). H NMR spectrum (400
1
MHz, CDCl ), δ, ppm: 8.01 s (1H), 7.70–7.62 m (1H),
3
13
7
(
2
.56–7.34 m (2H), 7.12–7.06 m (2H), 6.99–6.91 m
3H), 5.35 s (1H), 5.19 s (2H), 2.52–2.36 m (4H), 2.35–
.16 m (4H), 1.10 s (3H), 1.05 s (3H), 0.97 s (3H),
0.98 s (3H), 0.86 s (3H). C NMR spectrum (100 MHz,
CDCl ), δ , ppm: 197.1 (2C), 169.1, 151.3 (2C), 145.7,
3
C
143.8, 137.6, 131.0, 128.9, 126.3 (2C), 125.9, 124.8
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

2
018
KISHORE KUMAR et al.
(
4
2C), 121.3, 120.7, 115.8 (2C), 115.2, 62.1, 51.2, 50.8,
1.7, 39.1, 32.1 (2C), 31.3 (2C), 29.1, 28.6, 27.4.
EI-MS: m/z = 569.0 [M + 1].
-{2-[(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)methoxy]-
phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
H-xanthene-1,8(2H)-dione (6j). Yield 85%, white
9-{2-[(1-[3-Bromophenyl]-1H-1,2,3-triazol-4-yl)-
methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexa-
hydro-1H-xanthene-1,8(2H)-dione (6m). Yield 65%,
–1
light yellow solid, mp 161–163°C. IR spectrum, ν, cm :
9
1
1
594 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
3
ppm: 7.99 s (1H), 7.77–7.65 m (2H), 7.69–7.52 m
(2H), 7.09–7.01 m (2H), 7.00–6.84 m (2H), 5.37 s
(1H), 5.30 s (2H), 2.46–2.38 m (4H), 2.32–2.15 m
1
–
1
solid, mp 120–122°C. IR spectrum, ν, cm : 1684
(
CDCl ), δ, ppm: 7.91 s (1H), 7.10 t (J = 7.5 Hz, 1H),
7
(
(
m (2H), 1.80–1.71 m (2H), 1.52–1.40 m (2H), 1.36–
1
0
1
C=O), 1660 (C=O). H NMR spectrum (400 MHz,
(
(
4H), 1.11 s (3H), 1.05 s (3H), 0.99 s (3H), 0.87 s
3
1
3
3H). C NMR spectrum (100 MHz, CDCl ), δ , ppm:
3 C
.07 d (J = 7.4 Hz, 1H), 6.98 t (J = 7.6 Hz, 1H), 6.94 d
J = 7.6 Hz, 1H), 5.38 s (1H), 5.22 s (2H), 4.51–4.40 m
1H), 2.55–2.29 m (4H), 2.28–2.20 m (6H), 1.94–1.92
1
1
1
3
97.1 (2C), 168.7, 151.2 (2C), 144.7, 135.8, 132.9,
30.3, 129.8, 128.7, 127.3 (2C), 124.31, 124.2, 122.4,
21.9 (2C), 115.7 (2C), 61.9, 51.2, 50.6, 42.0, 40.1,
2.4 (2C), 32.1 (2C), 29.2, 28.6, 27.3. EI-MS: m/z =
.22 m (2H), 1.09 s (3H), 1.05 s (3H), 0.99 s (3H),
1
3
602.2 [M + 1], 604.2 [M + 3].
.87 s (3H). C NMR spectrum (100 MHz, CDCl3),
δC, ppm: 197.2 (2C), 168.8, 150.3 (2C), 143.9, 129.3,
9-[2-[(1-Isobutyl-1H-1,2,3-triazol-4-yl)methoxy)-
1
5
2
26.1 (2C), 124.4 (2C), 121.1, 115.6 (2C), 62.1, 60.1,
1.4, 50.6, 41.7, 38.9, 35.5 (2C), 32.1 (2C), 31.7 (2C),
9.2, 28.5, 27.3, 25.1 (2C), 25.0. EI-MS: m/z = 530.1
phenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
1
H-xanthene-1,8(2H)-dione (6n). Yield 72%, white
–
1
solid, mp 97–99°C. IR spectrum, ν, cm : 1690 (C=O),
1
[
M + 1].
1
645 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
3
ppm: 7.93 s (1H), 7.11 t (J = 7.6 Hz, 1H), 7.08 d (1H),
.99 t (1H), 6.95 d (1H), 5.39 s (1H), 5.25 s (2H), 4.19
d (J = 5.6 Hz, 2H), 2.58–2.31 m (4H), 2.28–2.21 m
5H), 1.10 s (3H), 1.06 s (3H), 1.01–0.96 m (9H), 0.89
9
-{2-[(1-[4-Bromophenyl]-1H-1,2,3-triazol-4-yl)-
6
methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione (6k). Yield
8%, light yellow solid, mp 173–175°C. IR spectrum,
ν, cm : 1679 (C=O), 1662 (C=O). H NMR spectrum
400 MHz, CDCl ), δ, ppm: 8.11 s (1H), 8.00–7.78 m
1H), 7.68 d (J = 6.32 Hz, 3H), 7.07 d (J = 6.63 Hz,
H), 6.99–6.85 m (2H), 5.61-5.04 (3H), 2.58–2.33 m
4H), 2.31–2.06 m (4H), 1.10 s (3H), 1.05 s (3H), 0.98
s (3H), 0.86 s (3H). C NMR spectrum (100 MHz,
CDCl ), δ , ppm: 196.5 (2C), 168.2, 150.1 (2C), 144.7,
35.9, 132.8 (2C), 128.9, 128.3, 127.0, 124.3 (2C),
22.4, 121.7 (2C), 115.7, 61.8, 51.1, 50.3, 41.5, 39.0,
2.1 (2C), 32.0 (2C), 29.2, 28.5, 27.3. EI-MS: m/z =
02.0 [M + 1], 604.0 [M + 3].
(
7
1
3
–
1
1
s (3H). C NMR spectrum (100 MHz, CDCl ), δ ,
3
C
ppm: 198.1 (2C), 168.9, 150.5 (2C), 145.1, 129.4,
(
(
2
3
1
5
2
26.4 (2C), 124.9 (2C), 121.1, 115.7 (2C), 61.8, 57.6,
0.9, 50.4, 42.1, 40.9, 32.6 (2C), 32.2 (2C), 29.7, 29.2,
8.7, 27.3, 19.8 (2C). EI-MS: m/z = 504.4 [M + 1]
(
13
Antimicrobial activity testing. Bacterial and fungal
strains. The gram-positive strains Mycobacterium
tuberculosis (ATCC 25177), Micrococcus luteus
3
C
1
1
3
6
(
ATCC 10240), methicillin-resistant Staphylococcus
aureus (MRSA, NCTC 13616), Bacillus subtilis
ATCC 6633), and Bacillus cereus (ATCC 14579) and
(
9
-{2-[(1-[4-Chlorophenyl]-1H-1,2,3-triazol-4-yl)-
the gram-negative strains Pseudomonas aeruginosa
(ATCC 27853), Klebsiella pneumoniae (ATCC
43816), Escherichia coli (ATCC 8739), Proteus
vulgaris (ATCC 13315), and Salmonella typhi (ATCC
19430) were purchased from the American Type
Culture Collection. Methicillin-resistant Staphylococcus
aureus was purchased from the Public Health England
Culture Collections. The fungal strains Microsporumcanis
(ATCC-36299), Microsporumgypseum (ATCC-24102),
Trichophyton rubrum (ATCC-28188), Trichophyton
interdigitale (ATCC-MYA-3108), and Epidermo-
phyton floccosum (ATCC-15694) were collected from
the Department of Biotechnology, Chaitanya Postgraduate
College (autonomous), Kishanpura, Hanamkonda,
Warangal-506001, Telangana, India. All bacterial
methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexa-
hydro-1H-xanthene-1,8(2H)-dione (6l). Yield 74%,
white solid, mp 167–169°C. IR spectrum, ν, cm :
666 (C=O). H NMR spectrum (400 MHz, CDCl ), δ,
ppm: 8.04 s (1H), 7.91–7.60 m (2H), 7.53 d (J = 6.32
Hz, 2H), 7.11–7.05 m (2H), 6.98–6.85 m (2H), 5.55 s
1H), 5.34 s (2H), 2.54–2.32 m (4H), 2.30–2.05 m
4H), 1.10 s (3H), 1.05 s (3H), 0.98 s (3H), 0.87 s
3H). C NMR spectrum (100 MHz, CDCl ), δ , ppm:
96.5 (2C), 168.3, 150.1 (2C), 143.8, 135.4, 134.5,
29.9 (2C), 128.9, 127.0, 124.3, 123.1, 121.5 (2C),
15.7, 115.6, 61.8, 51.1, 50.3, 41.5, 39.0, 32.1 (2C),
2.0 (2C), 29.2, 28.5, 27.3. EI-MS: m/z = 558.2 [M +
], 560.2 [M + 3].
–
1
1
1
3
(
(
(
1
1
1
3
1
1
3
3 C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS AND ANTIMICROBIAL SCREENING
2019
strains stored at ‒80°C were streaked on Luria‒Bertani
LB) agar plates (Hi-media Laboratories, Mumbai,
ACKNOWLEDGMENTS
(
India) and incubated at 37°C for 20 to 24 h. A few
isolated colonies were selected from each plate and
suspended in 5 mL of LB broth in a sterile culture
vessel. The vessel was plugged with cotton and in-
cubated with gentle shaking (140 rpm) at 37°C for 20 h.
K.K. Angajala is grateful to the CSIR, New Delhi,
India, for financial support in the form of senior
research fellowship (SRF) and the Central Facilities
for Research and Development, Osmania University,
Hyderabad, India, for providing analytical support.
Preparation of inoculums. According to the Kirby–
Bauer disk diffusion method [26], an inoculation loop
was touched each of four or five well isolated colonies
of the same morphological type, and the inoculum was
inoculated into 5mL of nutrient broth. The broth
cultures were allowed to incubate at 37°C for 24 h
until a slight visible turbidity appeared. The turbidity
of actively growing broth cultures was then adjusted
with broth to the turbidity of a 0.5 McFarland standard
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2
3
4
8
8
(
1×10 to 5×10 cfu/mL) and used as the starting
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robial cultures were adjusted to 0.5 McFarland
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5
6
. Dimmock, J.R., Raghavan, S.K., and Bigam, G.E., Eur.
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suspension of about 1.5×10 cfu/mL. 20 milliliters of
5
234(88)90182-1
agar medium was poured into each Petri plate and
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bored into the seeded agar plates and these were
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concentrations of 75 and 100 mg/mL of each com-
pound reconstituted in the DMSO. All the plates were
incubated aerobically at 37°C for 24 h. Antimicrobial
activity of each compound was evaluated by measuring
the zone of growth inhibition against the test orga-
nisms with zone reader (HiAntibiotic zone scale).
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drug).
. Wang, H.K., Morris-Natschke, S.L., and Lee, K.H.,
Med. Res. Rev., 1997, vol. 17, p. 367. doi 10.1002/
(
SICI)1098-1128(199707)17:4<367::AID-MED3>3.0.
CO;2-U
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