Novel 1,4-substituted-1,2,3-triazoles as antitubercular agents

Article abstract of DOI:10.1002/cmdc.201500051

Tuberculosis (TB) remains a pressing unmet medical need, particularly with the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. Here, a series of 1,4-substituted-1,2,3-triazoles have been synthesized and evaluated as potential antitubercular agents. These compounds were assembled via click chemistry in high crude purity and in moderate to high yield. Of the compounds tested, 12 compounds showed promising antitubercular activity with six possessing minimum inhibitory concentration (MIC) values <10 μg mL^-1, and total selectivity for Mycobacterium tuberculosis (Mtb) growth inhibition. A second set of 21 compounds bearing variations on ring C were synthesized and evaluated. This second library gave an additional six compounds displaying MIC values ≤10 μg mL^-1 and total selectivity for Mtb growth inhibition. These compounds serve as an excellent starting point for further development of antitubercular therapies.

Full text of DOI:10.1002/cmdc.201500051

Supporting Information
Novel 1,4-Substituted-1,2,3-Triazoles as Antitubercular
Agents
[
a]
[a]
[b]
[b]
Jarrad M. Altimari, Samantha C. Hockey, Helena I. Boshoff, Andaleeb Sajid, and
[a]
Luke C. Henderson*
cmdc_201500051_sm_miscellaneous_information.pdf

General Experimental
1
13
All H and C NMR spectra were recorded on a Jeol JNM-EX 270 MHz, Jeol JNM-EX 400 MHz or
Bruker AVANCE III 500 MHz standard bore (solution) as indicated. Samples were dissolved in
deuterated chloroform (CDCl
H 7.26 ppm). Proton spectra are reported as follows: chemical shift δ (ppm), (integral, multiplicity (s
singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m =
3 3
) with the residual solvent peak used as an internal reference (CDCl – δ
=
multiplet), coupling constant J (Hz), assignment).
Thin Layer Chromatography (TLC) was performed using aluminium-backed Merck TLC Silica gel 60
F254 plates, and samples were visualised using 254 nm ultraviolet (UV) light, and potassium
permanganate/potassium carbonate oxidising dip (1:1:100 KMnO :K CO :H O w/w).
4 2 3 2
Column Chromatography was performed using silica gel 60 (70-230 mesh). All solvents used were
AR grade. Specialist reagents were obtained from Sigma-Aldrich Chemical Company and used
without further purification. Petroleum spirits refers to the fraction boiling between 40-60 °C.
HRMS was found via a 6210 MSD TOF mass spectrometer under the conditions: gas temperature
(
350 ⁰C), vaporizer (28 ⁰C), capillary voltage (3.0 kV), cone voltage (40 V), nitrogen flow rate (7.0
L/min), nebuliser (15 psi). Samples were dissolved in MeOH.
Melting points were found on a Stuart Scientific Melting Point Apparatus SMP3, v.5 and are
uncorrected.
Solubility of the compounds was tested by dissolving an amount of the compound in DMSO and then
taking an aliquot and diluting in H O to achieve the required concentration at 0.5% DMSO in H O.
2 2
1
| P a g e

4
-(4-((4-Bromophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-2-(trifluoromethyl)benzonitrile 6i
1
mp 68.0-69.3°C; H NMR (CDCl
3
, 270 MHz): δ 8.19 (1H, s, Ar-H) 8.08-7.98 (2H, m, Ar-H) 7.86
(
(
1
1H, s, Ar-H) 7.53 (2H, d, J = 8.1 Hz, Ar-H) 7.38 (2H, d, J = 8.1 Hz, Ar-H) 6.09 (1H, s, CH) 2.94
13
2
1H, br s, OH); C NMR (d
31.7, 129.4, 124.3, 122.6 (q, J
6
-DMSO, 100 MHz): δ 153.6, 143.4, 140.3, 138.0, 133.2 (q, J C-F = 33 Hz)
1
19
C-F
6
= 273 Hz) 121.8, 121.0, 118.7, 115.6, 108.2, 67.7; F NMR (d -
-
1
DMSO, 470 MHz): δ -62.2; IR (cm ): 3359, 3143, 1615, 1509, 1402, 1183, 1010, 738; HRMS (ES)
calced for (C H BrF N ONa) 444.9823, found 444.9846
+
1
7
10
3
4
2
| P a g e

3
| P a g e

(
4-Bromophenyl)(1-(4-nitro-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methanol 6j
1
mp 66.5-67.5°C; H NMR (CDCl
3
, 270 MHz): δ 8.00 (1H, s, Ar-H) 7.83-7.74 (2H, m, Ar-H) 7.63
13
(
(
1
1H, d, J = 10 Hz, Ar-H) 7.49 (2H, J = 8.1 Hz, Ar-H) 6.06 (1H, s, CH), OH not observed C NMR
d -DMSO, 100 MHz): δ 153.2, 143.5, 136.2, 133.8, 131.6, 129.3, 128.4 (q, J C-F = 31 Hz) 125.8,
6
2
1
3
19
22.9 (q, J = 272 Hz) 121.5, 120.9, 119.9 (q, J = 6 Hz) 67.7; F NMR (d -DMSO, 470 MHz): δ
C-F C-F 6
-
1
+
-
63.0; IR (cm ): 3353, 3153, 1490, 1290, 1143, 1036, 825; HRMS (ES) calced for (C H BrF N O )
16 11 3 4 3
4
42.9961, found 442.9924
4
| P a g e

5
| P a g e

(
1-(4-Nitro-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)(perfluorophenyl)methanol 6e
1
mp 153.6-155.3°C; H NMR (d -DMSO, 270 MHz): δ 9.07 (1H, s, Ar-H) 8.58 (1H, s, Ar-H) 8.53
6
(
5
1
1H, d, J = 8.1 Hz, Ar-H) 8.41 (1H, d, J = 10.8 Hz, Ar-H) 6.89 (1H, d, J= 5.4 Hz, CH) 6.31 (1H, d, J =
1
3
6
.4 Hz, Ar-H); C NMR (d -DMSO, 100 MHz): δ 150.8, 146.2 (m) 143.8 (m) 140.2, 138.8 (m)
2
1
3
38.0, 136.4 (m) 133.26 (q, J C-F = 32 Hz) 124.3, 123.6 (q, J C-F = 273 Hz) 122.3, 118.8 (q, J C-F = 5
1
9
-
6
Hz) 117.1 (m) 115.5, 108.4; F NMR (d -DMSO, 470 MHz): δ -62.2, -142.7, -152.7, -160.8; IR (cm
1
+
)
: 3384, 1616, 1506, 1312, 1124, 996; HRMS (ES) calced for (C17
7 8 4
H F N O) 435.04866, found
4
35.04435.
6
| P a g e

7
| P a g e

(
1-(4-Nitro-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)(perfluorophenyl)methanol 6f
1
mp 148.0-149.8°C; H NMR (d
6
-DMSO, 270 MHz): δ 9.07 (1H, s, Ar-H) 8.40 (1H, d, J = 2.7 Hz, Ar-
H) 8.32 (1H, d, J = 2.7 Hz, Ar-H) 8.29 (1H, d, J = 2.7 Hz, Ar-H) 7.97 (1H, d, J = 8.1 Hz, Ar-H) 6.83
1
3
(
(
=
1
4
6
1H, d, J = 5.4 Hz, CH) 6.30 (1H, d, J = 2.7 Hz, OH); C NMR (d -DMSO, 100 MHz): δ 150.4, 146.2
2
1
m) 143.8 (m) 138.9 (m) 136.4 (m) 136.1, 133.9, 131.0, 128.5 (q, J C-F = 31 Hz) 125.9, 122.9 (q, J C-F
272 Hz) 121.1, 120.0 (m) 117.2 (m); F NMR (d -DMSO, 470 MHz): δ -63.1, -142.7, -153.1, -
6
61.0; IR (cm ): 3337, 1522, 1311, 1179, 1037, 996: HRMS calced for C H F N O [MH]
19
-
1
+
1
6
7
8
4
3
55.0385, found 455.0410
8
| P a g e

9
| P a g e

4
-(4-((3,5-Dibromophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-2-(trifluoromethyl)benzonitrile
6
g
1
mp 164.6-165.4°C; H NMR (d
6
-DMSO, 400 MHz): δ 9.06 (1H, s, ArH) 8.56 (1H, s, ArH) 8.50 (1H,
d, J = 8 Hz, ArH) 8.41 (1H, d, J = 8 Hz, ArH) 7.76 (1H, s, ArH) 7.68 (1H, s, ArH) 6.53 (1H, d, J = 4
1
3
Hz, CH), 6.00 (1H, d, J = 4 Hz, OH) C NMR (d -DMSO, 100 MHz): δ 152.7, 148.6, 140.3, 139.0,
6
2
1
1
6
9
33.2 (q, J C-F = 32 Hz) 132.8, 129.1, 124.4, 122.9, 122.6 (q, J C-F = 272 Hz), 122.1, 118.8 (m) 115.6,
7; F NMR (d -DMSO, 470 MHz): δ 59.1; IR (cm ): 3381, 3074, 1615, 1467, 1355, 1184, 1143,
98, 666, 50; HRMS calced for C17H10Br F N O [MH] 500.9168, found 500.9214
2 3 4
19
-1
6
+
+
1
0 | P a g e

1
1 | P a g e

(
3,5-Dibromophenyl)(1-(4-nitro-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methanol 6h
1
mp 167.2-168°C; H NMR (d
6
-DMSO, 400 MHz): δ 9.06 (1H, s, Ar-H) 8.56 (1H, d, J = 2.7 Hz, Ar-
H) 8.51-8.49 (1H, m, Ar-H) 8.41 (1H, d, J = 5.4z, Ar-H) 7.76 (1H, m, Ar-H) 7.68 (2H, m, Ar-H) 6.53
1
3
(
6
1H, d, J = 2.7 Hz, CH) 6.00 (1H, d, J = 2.7 Hz, OH); C NMR (d -DMSO, 100 MHz): δ 152.7,
2
1
1
1
1
5
48.6, 138.0, 133.2 (q, J
18.8, 115.6, 66.98; F NMR (d
= 33 Hz) 132.8, 129.1, 124.4, 122.9, 122.6 (q, J
6
-DMSO, 470 MHz): δ -60.8; IR (cm ): 3449, 2853, 1615, 1585,
313, 1183, 1143, 1082, 841, 740, HRMS calced for C H Br F N O [MH] 520.9066, found
= 272 Hz) 122.1,
C-F
C-F
1
9
-1
+
+
1
6
10
2
3
4
3
20.9054
1
2 | P a g e

1
3 | P a g e

4
-(4-((4-Fluorophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-2-(trifluoromethyl)benzonitrile 6k
1
3
H NMR (CDCl , 500 MHz): δ 8.20 (1H, s, ArH) 8.08 (1H, d, J = 10 Hz, ArH) 8.01 (1H, d, J = 5 Hz,
ArH) 7.98 (1H, s, ArH) 7.43 (2H, t, J = 10 Hz, ArH) 7.01 (2H, t, J = 10 Hz, ArH) 6.09 (1H, s, CH) No
1
3
1
3
OH observed; C NMR (CDCl , 125 MHz): δ 162.5 (d, J C-F = 250 Hz) 153.2, 139.6, 137.2, 136.6,
2
3
1
1
(
(
34.8 (q, J
= 33.75 Hz) 128.3 (d, J
= 8.75 Hz) 123.0, 121.6 (q, J
= 272.5 Hz) 119.6, 118.3
C-F
C-F
C-F
2
19
m) 115.6 (d, J = 22.5 Hz) 114.4, 109.6, 68.2 ; F NMR (d -DMSO, 470 MHz): δ -62.2, -113.6; IR
C-F 6
-
1
+
cm ): 3403, 3107, 1654, 1504, 1320, 1150, 990, 831; HRMS (ES) calced for (C17
63.0864, found 363.0875
11 4 4
H F N O)
3
1
4 | P a g e

1
5 | P a g e

(
4-Fluorophenyl)(1-(4-nitro-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methanol 6l
1
3
H NMR (CDCl , 500 MHz): δ 8.04 (1H, s, ArH) 7.87-7.84 (2H, m, ArH) 7.67 (1H, d, J = 10 Hz,
ArH) 7.50-7.47 (2H, m, ArH) 7.08 (2H, t, J = 10 Hz, ArH) 6.12 (1H, s, CH) No OH peak observed;
1
3
1
2
C NMR (CDCl
3
, 125 MHz): δ 162.6 (q, J
= 245 Hz) 137.3, 135.4, 133.0, 132.6, 130.0 (q, J
C-F
C-
3
1
2
F=32.5 Hz) 128.2 (d, J C-F=8.75 Hz) 126.7, 124.3, 122.0 (q, J
2
1
= 272.5) 119.6 (m) 115.6 (d, J
=
C-F
C-F
19
-1
1.3 Hz) 53.4; F NMR (CDCl , 470 MHz): δ -63.1,-113.7; IR (cm ): 3352, 2924, 1604, 1539, 1312,
226, 1144, 1037, 829, 731; HRMS (ES) calced for (C16
3
+
H
11
F
4
N
4
O
3
) 383.0762, found 383.0775
1
6 | P a g e

1
7 | P a g e

1
-(3,5-dibromophenyl)prop-2-yn-1-ol
-
1
1
IR (thin film) ʋ, cm 3844, 3724, 2361, 1694, 1548, 1426, 1029, 708, 406; H NMR (d
3
-MeOH, 270
1
3
MHz): 7.65 (3H, s, Ar-H) 5.39 (1H, s, CH) 4.86 (1H, s, OH) 3.08 (1H, s, CH); C NMR (d-CDCl ,
3
1
9 7 2
25 MHz): δ 143.6, 134.0, 128.5, 123.1, 82.3, 76.0, 62.9; m.p. 68.5 °C; HRMS calced for C H Br O
+
[MH] 288.8858, found 288.8832.
1
8 | P a g e

1
-(pyren-2-yl)prop-2-yn-1-ol
-
1
1
6
IR (thin film) ʋ, cm 3870, 3750, 3566, 2364, 1699, 1418, 1027, 740, 707; H NMR (d -DMSO, 500
MHz): 8.62 (1H, d, J= 10 Hz, Ar-H) 8.36 (1H, d, J= 10 Hz, Ar-H) 8.31 (3H, apparent t, J= 5 Hz, Ar-
H) 8.25 (1H, d, J= 10 Hz, Ar-H) 8.17 (2H, apparent s, Ar-H) 8.09 (1H, t, J= 5 Hz, Ar-H) 6.34 (1H, dd,
13
J= 5, 3 Hz, CH) 6.25 (1H, d, J= 5.5 Hz, OH) 3.50 (1H, s, CH); C NMR (d
6
-DMSO, 125 MHz): δ
1
8
35.6, 131.3, 131.1, 130.7, 127.9, 127.7, 127.7, 127.3, 126.7, 125.8, 125.7, 125.1, 124.7, 124.5, 124.2,
6.1, 76.9, 61.5; m.p. 156.7 °C; HRMS predicted C19H13O [MH] 257.0961, found 257.0994.
+
+
1
9 | P a g e

JMA6-044
JMA6-044 1H DMSO
PROTON DMSO {C:\Data_500\Jarrad} nmr 7
7
6
0000
5000
CH
HO
60000
5
5
4
4
3
3
2
2
1
1
5
0
5000
0000
5000
0000
5000
0000
5000
0000
5000
0000
000
-
5000
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
f1 (ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
JMA6-044
JMA6-044 13C DMSO
C13CPD DMSO {C:\Data_500\Jarrad} nmr 7
2
2
E+06
E+06
CH
1E+06
HO
1
1
1
1
9
8
7
6
5
4
3
2
1
0
E+06
E+06
E+06
E+06
E+05
E+05
E+05
E+05
E+05
E+05
E+05
E+05
E+05
-
1E+05
2
10
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
2
0 | P a g e

4
-(4-[hydroxy(phenyl)methyl]-1H-1,2,3-triazol-1-yl}-2-(trifluoromethyl)benzonitrile 6a
-
1
1
IR (thin film) ʋ, cm xxx; H NMR (d
6
-DMSO, 500 MHz): 8.79 (1H, s, Ar-H) 8.35 (1H, d, J= 2.5, Ar-
H) 8.26 (1H, ) 7.92 (1H, d, J= 8.5 Hz, Ar-H) 7.49 (2H, d, J= 7.5 Hz, Ar-H) 7.36 (2H, apparent t, J= 7
1
3
Hz, Ar-H) 7.29-7.25 (1H, m, Ar-H) 5.98 (1H, d, J= 4.5 Hz, OH) 5.94 (1H, d, 4.5, CH); C NMR (d
6
-
DMSO, 125 MHz): δ 136.3, 136.11, 133.7, 133.7, 128.6, 128.2, 128.1 (q, J= 255, 102.5 Hz) 127.6,
+
1
27.0, 125.7, 125.6; HRMS predicted for (C H F N O) [MH] 345.0958, found 345.0942.
17 12 3 4
2
1 | P a g e

{
1-[4-nitro-3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-yl}(pyren-1-yl)methanol 6b
-
1
1
IR (thin film) ʋ, cm 3368, 2822, 2233, 1613, 1444, 1312, 1180, 1083, 995, 844, 638, 480; H NMR
-DMSO, 500 MHz): 8.93 (1H, s, Ar-H) 8.53 (1H, d, J = 1.5 Hz, Ar-H) 8.48 (1H, dd, J = 2, 8.5 Hz,
Ar-H) 8.36 (1H, d, J = 8.5, Ar-H) 7.50 (2H, d, J = 7.5 Hz, Ar-H) 7.36 (2H, t, J = 7.5 Hz, Ar-H) 7.28
(d
6
1
3
(
6
1H, t, J = 7.5 Hz, Ar-H) 6.04 (1H, d, J = 4.5 Hz, OH) 5.96 (1H, d, J = 4 Hz, CH); C NMR (d -
3
DMSO, 125 MHz): δ 153.9, 143.9, 140.4, 137.8, 136.7, 133.2 (q, J = 32.5 Hz) 128.6, 127.7, 127.0,
1
3
C-F
4
+
+
24.3, 118.7 (q, J = 3.75 Hz) 68.5; HRMS predicted for C H F N O [MH] 365.0856, found
16 12 3 4 3
65.0845.
2
2 | P a g e

2
3 | P a g e

4
-{4-[hydroxy(pyren-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-2-(trifluoromethyl)benzonitrile 6c
-
1
1
Brown Solid; IR (thin film) ʋ, cm 3902, 3801, 2364, 1792, 1653, 1396, 1026, 740, 717, 444; H
NMR (d -DMSO, 270 MHz): δ 9.06 (1H, s, Ar-H) 8.52 (2H, m, Ar-H) 8.46 (1H, d, J = 8.6, Ar-H)
.37 (2H, d, J = 3Hz, Ar-H) 8.30 (3H, m, Ar-H) 8.21 (1H, s, Ar-H) 8.18 (2H, s, Ar-H) 8.07 (1H, t, J =
6
8
7
1
3
3
.8 Hz, Ar-H) 6.98 (1H, d, J = 4.6 Hz, OH) 6.63 (1H, d, J = 4.6, CH); C NMR (d-CDCl , 67.5
MHz): δ 136.3, 131.5, 131.3, 130.5, 128.4, 128.0, 127.9, 127.4, 126.4, 125.8, 125.7, 125.6, 125.2,
1
9
1
-
25.0, 124.9, 124.7, 124.6, 123.9, 122.9, 122.6, 122.5, 118.1, 62.9; F NMR (d
6
-DMSO, 470 MHz): δ
+
60.85; m.p. 135.4 °C; HRMS predicted for (C27H F N O) [MH] 471.1427, found 471.1458.
18 3 4
2
4 | P a g e

2
5 | P a g e

{
1-[4-Nitro-3-(trifluoromethyl)phenyl]-1H-1,2,3- triazol-4-yl}(pyren-1-yl)methanol 6d
-
1
Tan Solid; IR (thin film) ʋ, cm 3902, 3801, 3566, 2342, 1868, 1733, 1540, 1396, 1060, 1027, 743,
1
7
8
03, 419; H NMR (d
6
-DMSO, 500 MHz): δ 8.93 (1H, s, Ar-H) 8.53 (1H, d, J = 9 Hz, Ar-H) 8.41-
.17 (11H, m, Ar-H) 8.12-8.06 (1H, m, Ar-H) 7.91 (1H, d, J = 8.5 Hz, Ar-H) 6.98 (1H, d, J = 4.5 Hz,
OH) 6.58 (1H, d, J = 4.5 Hz, CH); C NMR (d
1
3
6
-DMSO, 125 MHz): δ 153.6, 137.5, 136.1, 135.4,
1
1
33.6, 131.3, 130.7, 130.6, 128.4, 127.9, 127.8, 127.64, 127.60, 126.8, 126.7, 125.8, 125.75, 125.6,
19
25.4, 125.2, 125.1, 124.5, 124.4, 124.2, 123.9, 121.7, 119.7, 65.9; F NMR (d -DMSO, 470 MHz): δ
6
+
-
61.49; m.p. 182.8 °C; m.p. 182.8 °C; HRMS predicted for (C26
H
18
F
3
N
4
O
3
) [MH] 491.1326, found
1
3
4
3
91.1358. Note: due to the complexity in the C NMR arising from the CF group and the pyrene
resolution of the C-F multiplets was not possible.
2
6 | P a g e

2
7 | P a g e

3‐(1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)aniline 13d
-
1
1
IR (thin film) ʋ, cm 3344, 2969, 2931, 2360, 1378, 1108, 816, 624; mp 121.4 °C; H NMR (DMSO-
d , 270 MHz) δ 9.15 (1H, s, Ar-H) 7.94-7.98 (2H, m, Ar-H) 7.59-7.65 (2H, m, Ar-H) 7.47-7.53 (1H,
6
1
3
m, Ar-H) 7.21 (1H, t, J = 2.7 Hz, Ar-H) 7.03-7.15 (2H, m, Ar-H) 6.55-6.59 (1H, m, NH); C NMR
(
1
DMSO-d , 67.5 MHz) 149.5, 148.5, 137.2, 131.1, 130.4, 129.9, 129.0, 120.4, 119.6, 114.4, 113.7,
6
+
11.0; HRMS calced for C H N [MH] 237.11347, found 237.11310.
1
4
12
4
2
8 | P a g e

2
9 | P a g e