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Supplementary information
Regioselective synthesis and antimicrobial evaluation of some thioether-amide
linked 1,4-disubstituted 1,2,3-triazoles
C. P. Kaushika, Ashima Pahwaa, Rajesh Thakurb and Pawan Kaurb
aDepartment of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, India
bDepartment of Bio & Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, India
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Experimental detail
All the reagents and solvents were purchased from Alfa-Aesar, Sigma-Aldrich, Hi-Media and used
without any purification. Melting points (ºC) of synthesized compounds were taken by open
capillary method and are uncorrected. The FTIR spectra were observed on SHIMAZDU IR
AFFINITY-I FT-IR spectrometer using potassium bromide powder. The 1H NMR spectra and 13C
NMR spectra were recorded on BRUKER AVANCE II 400 MHz spectrometer at 400 MHz and
100 MHz, respectively in DMSO-d6 (chemical shift in δ, ppm). Coupling constant (J) values were
observed in Hertz (Hz). HRMS were obtained on Waters Micromass Q-Tof Micro (ESI)
spectrometer and values were quoted in m/z. To check the purity of compounds and completion of
reactions, thin layer chromatography (TLC) was employed using readymade silica gel plates (SIL
G/UV254, ALUGRAM) and visualized under ultraviolet lamp.
General procedure for the synthesis of 1,4-disubstituted 1,2,3-triazoles (3a–3x)
The starting material aryl(prop-2-yn-1-yl)sulfanes (1a–1e) were prepared by addition of propargyl
bromide (1.0 mmol) to the aromatic thiols (1.0 mmol) in N,N-dimethylformamide in the presence
of potassium carbonate (3.0 mmol) at 10–25 ºC temperature with constant stirring. After the
completion of addition, stirring was continued for 5–6 h at same temperature. When the reaction
was completed, dilute HCL was added and product extracted with ethyl acetate. Organic layer was
evaporated under reduced pressure to get product in good yield.
For the synthesis of 2-bromo-N-substituted acetamides (2a–2e), bromoacetylbromide (1.2
mmol) was added dropwise into the stirred solution of aromatic amines (1.0 mmol) in
dichloromethane in the presence of potassium carbonate (1.5 mmol) at 0–5 ºC for 15 minutes and
solid product was precipitated after the addition of ice cold water, filtered and dried.
Synthesis of triazoles (3a–3x) was carried out by dissolving 2-bromo-N-substituted
acetamides (1.0 mmol) (2a–2e) in dimethylformamide, aqueous sodium azide (3.0 mmol) was
added and stirring was continued at 25–40 ºC for half an hour. To the above mixture aryl (prop-2-
yn-1-yl)sulfanes (1a–1e), aqueous copper sulphate pentahydrate (0.1 mmol) and sodium ascorbate
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(0.4 mmol) were added and stirring was continued for 6–14 h at same temperature and the reaction
was monitored with TLC until the total conversion of starting material into desired 1,4-disubstituted
1,2,3-triazoles. After completion of reaction, ice cold water was added to reaction mixture. Product
was precipitated, filtered and washed with ammonia solution. Crude product was purified by
washing with ethyl acetate and dried under vaccum to get pure product in good yield.
Spectroscopic data of synthesized compounds (3a–3x)
N-phenyl-2-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3a)
White solid; yield: 93%; m.p.: 141–144 ºC; FTIR (KBr): νmax = 3278 (N-H str.), 3120 (C-H str.,
triazole ring), 3058 (C-H str., aromatic ring), 2986 (C-H str., aliphatic), 1679 (C=O str., amide),
1605, 1553 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.33 (s, 2H, SCH2),
5.29 (s, 2H, NCH2), 7.09 (t, 1H, Ar-H, J=8.0 Hz), 7.19 (t, 1H, Ar-H, J=8.0 Hz), 7.30–7.35 (m, 4H,
Ar-H), 7.40 (d, 2H, Ar-H, J=8.0 Hz), 7.58 (d, 2H, Ar-H, J=8.0 Hz), 8.02 (s, 1H, C-H triazole),
10.45 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.5, 52.7, 119.7, 124.2,
125.4 (C5 triazole), 126.3, 128.4, 129.4, 129.5, 136.5, 138.9, 143.8 (C4 triazole), 164.6 (C=O amide)
ppm; HRMS (m/z) calculated for C17H16N4OS [M+H]+: 325.1078. Found: 325.1128.
N-(4-methoxyphenyl)-2-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3b)
White solid; yield: 90%; m.p.: 164–168 ºC; FTIR (KBr): νmax = 3274 (N-H str.), 3126 (C-H str.,
triazole ring), 3064 (C-H str., aromatic ring), 2952 (C-H str., aliphatic), 1677 (C=O str., amide),
1608, 1542 (C=C str., aromatic ring), 1243 (C-O asym. str., ether), 1032 (C-O sym. str., ether) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 3.72 (s, 3H, OCH3), 4.32 (s, 2H, SCH2), 5.25 (s, 2H, NCH2),
6.91 (d, 2H, Ar-H, J=8.0 Hz), 7.19 (t, 1H, Ar-H, J=8.0 Hz), 7.30–7.40 (m, 4H, Ar-H), 7.49 (d, 2H,
Ar-H, J=8.0 Hz), 8.01 (s, 1H, C-H triazole), 10.32 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 27.5, 52.6, 55.6, 114.5, 121.2, 125.4 (C5 triazole), 126.3, 128.4, 129.5, 132.0,
136.5, 143.8 (C4 triazole), 156.0, 164.1 (C=O amide) ppm; HRMS (m/z) calculated for C18H18N4O2S
[M+H]+: 355.1184. Found: 355.1224.
N-(4-nitrophenyl)-2-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3c)
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White solid; yield: 92%; m.p.: 146–150 ºC; FTIR (KBr): νmax = 3288 (N-H str.), 3154 (C-H str.,
triazole ring), 3053 (C-H str., aromatic ring), 2985 (C-H str., aliphatic), 1706 (C=O str., amide),
1622, 1576 (C=C str., aromatic ring), 1509 (N-O asym. str., NO2), 1347 (N-O sym. str., NO2) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 4.33 (s, 2H, SCH2), 5.38 (s, 2H, NCH2), 7.19 (t, 1H, Ar-H,
J=8.0 Hz), 7.30–7.40 (m, 4H, Ar-H), 7.82 (d, 2H, Ar-H, J=8.0 Hz), 8.03 (s, 1H, C-H triazole), 8.25
(d, 2H, Ar-H, J=8.0 Hz), 11.06 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.5,
52.8, 119.5, 125.4 (C5 triazole), 125.6, 126.3, 128.4, 129.5, 136.4, 143.0, 143.9 (C4 triazole), 145.0,
165.8 (C=O amide) ppm; HRMS (m/z) calculated for C17H15N5O3S [M+H]+: 370.0929. Found:
370.0967.
N-(4-fluorophenyl)-2-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3d)
Light green solid; yield: 93%; m.p.: 160–164 ºC; FTIR (KBr): νmax = 3279 (N-H str.), 3115 (C-H
str., triazole ring), 3059 (C-H str., aromatic ring), 2958 (C-H str., aliphatic), 1678 (C=O str., amide),
1559, 1541 (C=C str., aromatic ring), 1239 (C-F str.) cm-1; 1H NMR (400 MHz, DMSO-d6): δ =
4.32 (s, 2H, SCH2), 5.28 (s, 2H, NCH2), 7.18–7.59 (m, 9H, Ar-H), 8.01 (s, 1H, C-H triazole), 10.51
(s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.5, 52.6, 116.0 (d, 2C, Ar-C,
J=20.0 Hz), 121.45 (d, 2C, Ar-C, J=10.0 Hz), 125.4 (C5 triazole), 126.3, 128.4, 129.5, 135.3, 136.5,
143.9 (C4 triazole), 158.7 (d, 1C, Ar-C, J=240.0 Hz), 164.6 (C=O amide) ppm; HRMS (m/z)
calculated for C17H15FN4OS [M+H]+: 343.0984. Found: 343.1022.
N-(naphthalen-1-yl)-2-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3e)
White solid; yield: 88%; m.p.: 156–160 ºC; FTIR (KBr): νmax = 3264 (N-H str.), 3143 (C-H str.,
triazole ring), 3056 (C-H str., aromatic ring), 2941 (C-H str., aliphatic), 1670 (C=O str., amide),
1550, 1485 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.34 (s, 2H, SCH2),
5.50 (s, 2H, NCH2), 7.19 (t, 1H, Ar-H, J=8.0 Hz), 7.30–7.34 (m, 2H, Ar-H), 7.39–7.41 (m, 2H, Ar-
H), 7.51–7.60 (m, 3H, Ar-H), 7.72 (d, 1H, Ar-H, J=8.0 Hz), 7.79 (d, 1H, Ar-H, J=8.0 Hz), 7.96 (d,
1H, Ar-H, J=8.0 Hz), 8.03 (s, 1H, C-H triazole), 8.07 (d, 1H, Ar-H, J=8.0 Hz), 10.42 (s, 1H, N-H
amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.5, 52.5, 122.0, 123.1, 125.4 (C5 triazole),
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126.1, 126.2, 126.3, 126.5, 126.7, 128.0, 128.4, 128.7, 129.5, 133.2, 134.2, 136.5, 143.8 (C4
triazole), 165.6 (C=O amide) ppm; HRMS (m/z) calculated for C21H18N4OS [M+H]+: 375.1235.
Found: 375.1271.
N-phenyl-2-(4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3f)
White solid; yield: 80% ; m.p.: 174–178 ºC; FTIR (KBr): νmax = 3273 (N-H str.), 3126 (C-H str.,
triazole ring), 3069 (C-H str., aromatic ring), 2916 (C-H str., aliphatic), 1670 (C=O str., amide),
1603, 1556, 1497 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 2.26 (s, 3H,
CH3), 4.27 (s, 2H, SCH2), 5.28 (s, 2H, NCH2), 7.09 (t, 1H, Ar-H, J=8.0 Hz), 7.13 (d, 2H, Ar-H,
J=8.0 Hz ), 7.29 (d, 2H, Ar J=8.0 Hz), 7.34 (t, 2H, Ar-H, J=8.0 Hz), 7.58 (d, 2H, Ar-H, J=8.0 Hz ),
7.98 (s, 1H, C-H triazole), 10.45 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ =
21.0, 28.2, 52.7, 119.7, 124.2, 125.3 (C5 triazole), 129.3, 129.4, 130.1, 132.6, 136.0, 138.9, 143.9
(C4 triazole), 164.6 (C=O amide) ppm; HRMS (m/z) calculated for C18H18N4OS [M+H]+: 339.1235.
Found: 339.1275.
N-(4-methoxyphenyl)-2-(4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3g)
White solid; yield: 94%; m.p.: 182–186 ºC; FTIR (KBr): νmax = 3273 (N-H str.), 3134 (C-H str.,
triazole ring), 3076 (C-H str., aromatic ring), 2951 (C-H str., aliphatic), 1676 (C=O str., amide),
1607, 1549, 1462 (C=C str., aromatic ring), 1242 (C-O asym. str., ether), 1034 (C-O sym. str.,
ether) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.26 (s, 2H,
SCH2), 5.24 (s, 2H, NCH2), 6.91 (d, 2H, Ar-H, J=8.0 Hz), 7.13 (d, 2H, Ar-H, J=8.0 Hz), 7.29 (d,
2H, Ar-H, J=8.0 Hz), 7.48 (d, 2H, Ar-H, J=8.0 Hz), 7.97 (s, 1H, C-H triazole), 10.30 (s, 1H, N-H
amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 21.0, 28.2, 52.6, 55.6, 114.5, 121.2, 125.3 (C5
triazole), 129.3, 130.1, 132.0, 132.6, 136.0, 143.9 (C4 triazole), 156.0, 164.1 (C=O amide) ppm;
HRMS (m/z) calculated for C19H20N4O2S [M+H]+: 369.1341. Found: 369.1380.
N-(4-nitrophenyl)-2-(4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3h)
Light brown solid; yield: 85%; m.p.: 168–172 ºC; FTIR (KBr): νmax = 3273 (N-H str.), 3109 (C-H
str., triazole ring), 3071 (C-H str., aromatic ring), 2984 (C-H str., aliphatic), 1703 (C=O str., amide),
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1616, 1495 (C=C str., aromatic ring), 1516 (N-O asym. str., NO2), 1340 (N-O sym. str., NO2) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3), 4.27 (s, 2H, SCH2), 5.38 (s, 2H, NCH2),
7.13 (d, 2H, Ar-H, J=8.0 Hz), 7.29 (d, 2H, Ar-H, J=8.0 Hz), 7.82 (d, 2H, Ar-H, J=8.0 Hz), 7.99 (s,
1H, C-H triazole), 8.25 (d, 2H, Ar-H, J=8.0 Hz), 11.07 (s, 1H, N-H amide) ppm; 13C NMR (100
MHz, DMSO-d6): δ = 21.0, 28.2, 52.8, 119.5, 125.4 (C5 triazole), 125.6, 129.3, 130.1, 132.6, 136.0,
143.0, 143.9 (C4 triazole), 145.0, 165.8 (C=O amide) ppm; HRMS (m/z) calculated for C18H17N5O3S
[M+H]+: 384.1086. Found: 384.1124.
N-(4-fluorophenyl)-2-(4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3i)
White solid; yield: 92%; m.p.: 186–190 ºC; FTIR (KBr): νmax = 3279 (N-H str.), 3130 (C-H str.,
triazole ring), 3076 (C-H str., aromatic ring), 2920 (C-H str., aliphatic), 1678 (C=O str., amide),
1614, 1558, 1495 (C=C str., aromatic ring), 1230 (C-F str.) cm-1; 1H NMR (400 MHz, DMSO-d6): δ
= 2.26 (s, 3H, CH3), 4.27 (s, 2H, SCH2), 5.28 (s, 2H, NCH2), 7.12–7.20 (m, 4H, Ar-H), 7.29 (d, 2H,
Ar-H, J=8.0 Hz), 7.58–7.62 (m, 2H, Ar-H), 7.98 (s, 1H, C-H triazole), 10.51 (s, 1H, N-H amide)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 21.0, 28.2, 52.6, 116.0 (d, 2C, Ar-C, J=20.0 Hz), 121.45
(d, 2C, Ar-C, J=10.0 Hz), 125.3 (C5 triazole), 129.3, 130.1, 132.6, 135.3, 136.0, 144.0 (C4 triazole),
158.7 (d, 1C, Ar-C, J=240.0 Hz), 164.6 (C=O amide) ppm; HRMS (m/z) calculated for
C18H17FN4OS [M+H]+: 357.1141. Found: 357.1178.
N-(naphthalen-1-yl)-2-(4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3j)
White solid; yield: 90%; m.p.: 178–182 ºC; FTIR (KBr): νmax = 3267 (N-H str.), 3119 (C-H str.,
triazole ring), 3065 (C-H str., aromatic ring), 2918 (C-H str., aliphatic), 1678 (C=O str., amide),
1545, 1460 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3),
4.28 (s, 2H, SCH2), 5.50 (s, 2H, NCH2), 7.13 (d, 2H, Ar-H, J=8.0 Hz), 7.29 (d, 2H, Ar-H, J=8.0
Hz), 7.51–7.60 (m, 3H, Ar-H), 7.71 (d, 1H, Ar-H, J=8.0 Hz), 7.80 (d, 1H, Ar-H, J=8.0 Hz), 7.96 (d,
1H, Ar-H, J=8.0 Hz), 8.03 (s, 1H, C-H triazole), 8.15 (d, 1H, Ar-H, J=8.0 Hz), 10.44 (s, 1H, N-H
amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 21.0, 28.2, 52.5, 122.0, 123.1, 125.3 (C5
triazole), 126.0, 126.2, 126.5, 126.7, 128.0, 128.7, 129.3, 130.1, 132.6, 133.2, 134.2, 136.0, 144.0
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(C4 triazole), 165.6 (C=O amide) ppm; HRMS (m/z) calculated for C22H20N4OS [M+H]+: 389.1391.
Found: 389.1428.
2-(4-(((4-methoxyphenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (3k)
Light brown solid; yield: 89%; m.p.: 148–152 ºC; FTIR (KBr): νmax = 3277 (N-H str.), 3138 (C-H
str., triazole ring), 3063 (C-H str., aromatic ring), 2940 (C-H str., aliphatic), 1672 (C=O str., amide),
1593, 1493 (C=C str., aromatic ring), 1246 (C-O asym. str., ether), 1030 (C-O sym. str., ether) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 3.73 (s, 3H, OCH3), 4.19 (s, 2H, SCH2), 5.28 (s, 2H, NCH2),
6.90 (d, 2H, Ar-H, J=8.0 Hz), 7.09 (t, 1H, Ar-H, J=8.0 Hz), 7.32–7.36 (m, 4H, Ar-H), 7.58 (d, 2H,
Ar-H, J=8.0 Hz), 7.92 (s, 1H, C-H triazole), 10.44 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 29.8, 52.6, 55.6, 115.2, 119.6, 124.2, 125.4 (C5 triazole), 126.1, 129.4, 132.7, 138.9,
143.9 (C4 triazole), 159.0, 164.6 (C=O amide) ppm; HRMS (m/z) calculated for C18H18N4O2S
[M+H]+: 355.1184. Found: 355.1222.
N-(4-methoxyphenyl)-2-(4-(((4-methoxyphenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3l)
White solid; yield: 82%; m.p.: 172–176 ºC; FTIR (KBr): νmax = 3273 (N-H str.), 3117 (C-H str.,
triazole ring), 3065 (C-H str., aromatic ring), 2953 (C-H str., aliphatic), 1674 (C=O str., amide),
1553, 1497 (C=C str., aromatic ring), 1244 (C-O asym. str., ether), 1030 (C-O sym. str., ether) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 3.73 (s, 6H, OCH3), 4.18 (s, 2H, SCH2), 5.24 (s, 2H, NCH2),
6.89–6.92 (m, 4H, Ar-H), 7.34 (d, 2H, Ar-H, J=8.0 Hz), 7.49 (d, 2H, Ar-H, J=8.0 Hz), 7.91 (s, 1H,
C-H triazole), 10.30 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 29.8, 52.6,
55.6, 114.5, 115.2, 121.2, 125.2 (C5 triazole), 126.1, 132.0, 132.7, 143.9 (C4 triazole), 156.0, 158.9,
164.1 (C=O amide) ppm; HRMS (m/z) calculated for C19H20N4O3S [M+H]+: 385.1290. Found:
385.1327.
2-(4-(((4-methoxyphenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl)acetamide (3m)
Brown solid; yield: 79%; m.p.: 152–156 ºC; FTIR (KBr): νmax = 3281 (N-H str.), 3128 (C-H str.,
triazole ring), 3088 (C-H str., aromatic ring), 2947 (C-H str., aliphatic), 1707 (C=O str., amide),
1601, 1558, 1458 (C=C str., aromatic ring), 1501 (N-O asym. str., NO2), 1340 (N-O sym. str.,
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NO2), 1252 (C-O asym. str., ether), 1030 (C-O sym. str., ether) cm-1; 1H NMR (400 MHz, DMSO-
d6): δ = 3.74 (s, 3H, OCH3), 4.19 (s, 2H, SCH2), 5.37 (s, 2H, NCH2), 6.90 (d, 2H, Ar-H, J=8.0 Hz),
7.34 (d, 2H, Ar-H, J=8.0 Hz), 7.83 (d, 2H, Ar-H, J=8.0 Hz), 7.93 (s, 1H, C-H triazole), 8.25 (d, 2H,
Ar-H, J=8.0 Hz), 11.06 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 29.8, 52.7,
55.6, 115.2, 119.5, 125.4 (C5 triazole), 125.6, 126.1, 132.7, 143.0, 143.9 (C4 triazole), 145.0, 159.0,
165.8 (C=O amide) ppm; HRMS (m/z) calculated for C18H17N5O4S [M+H]+: 400.1035. Found:
400.1088.
N-(4-fluorophenyl)-2-(4-(((4-methoxyphenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3n)
White solid; yield: 78%; m.p.: 162–166 ºC; FTIR (KBr): νmax = 3278 (N-H str.), 3119 (C-H str.,
triazole ring), 3076 (C-H str., aromatic ring), 2930 (C-H str., aliphatic), 1677 (C=O str., amide),
1560, 1515, 1496 (C=C str., aromatic ring), 1239 (C-F str.), 1244 (C-O asym. str., ether), 1028 (C-
O sym. str., ether) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 3.73 (s, 3H, OCH3), 4.18 (s, 2H,
SCH2), 5.27 (s, 2H, NCH2), 6.90 (d, 2H, Ar-H, J=8.0 Hz ), 7.16–7.20 (m, 2H, Ar-H), 7.34 (d, 2H,
Ar-H, J=8.0 Hz), 7.58–7.62 (m, 2H, Ar-H), 7.92 (s, 1H, C-H triazole), 10.50 (s, 1H, N-H amide)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 29.8, 52.6, 55.6, 115.2, 116.0 (d, 2C, Ar-C, J=20.0 Hz),
121.45 (d, 2C, Ar-C, J=10.0 Hz), 125.3 (C5 triazole), 126.1, 132.7, 135.3, 143.9 (C4 triazole), 158.7
(d, 1C, Ar-C, J=240.0 Hz), 159.0, 164.6 (C=O amide) ppm; HRMS (m/z) calculated for
C18H17FN4O2S [M+H]+: 373.1090. Found: 373.1127.
2-(4-(((4-bromophenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (3o)
White solid; yield: 69%; m.p.: 202–206 ºC; FTIR (KBr): νmax = 3271 (N-H str.), 3115 (C-H str.,
triazole ring), 3065 (C-H str., aromatic ring), 2956 (C-H str., aliphatic), 1676 (C=O str., amide),
1607, 1551, 1470 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.34 (s, 2H,
SCH2), 5.29 (s, 2H, NCH2), 7.09 (t, 1H, Ar-H, J=8.0 Hz), 7.31–7.36 (m, 4H, Ar-H), 7.49–7.59 (m,
4H, Ar-H), 8.02 (s, 1H, C-H triazole), 10.45 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-
d6): δ = 27.4, 52.7, 119.2, 119.7, 124.2, 125.5 (C5 triazole), 129.4, 130.4, 132.2, 136.1, 138.9, 143.5
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(C4 triazole), 164.6 (C=O amide) ppm; HRMS (m/z) calculated for C17H15BrN4OS [M+H]+:
403.0228 (79Br), 405.0208 (81Br). Found: 403.0219 (79Br), 405.0201 (81Br).
2-(4-(((4-bromophenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide
(3p)
White solid; yield: 70%; m.p.: 228–232 ºC; FTIR (KBr): νmax = 3265 (N-H str.), 3134 (C-H str.,
triazole ring), 3078 (C-H str., aromatic ring), 2957 (C-H str., aliphatic), 1674 (C=O str., amide),
1605, 1553, 1468 (C=C str., aromatic ring), 1246 (C-O asym. str., ether), 1030 (C-O sym. str.,
ether) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 3.72 (s, 3H, OCH3), 4.34 (s, 2H, SCH2), 5.25 (s,
2H, NCH2), 6.91 (d, 2H, Ar-H, J=8.0 Hz), 7.35 (d, 2H, Ar-H, J=8.0 Hz), 7.47–7.51 (m, 4H, Ar-H),
8.01 (s, 1H, C-H triazole), 10.31 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ =
27.4, 52.6, 55.6, 114.5, 119.2, 121.2, 125.4 (C5 triazole), 130.4, 132.0, 132.2, 136.1, 143.5 (C4
triazole), 156.0, 164.1 (C=O amide) ppm; HRMS (m/z) calculated for C18H17BrN4O2S [M+H]+:
433.0334 (79Br), 435.0313 (81Br). Found: 433.0323(79Br), 435.0301(81Br).
2-(4-(((4-bromophenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl)acetamide (3q)
White solid; yield: 93%; m.p.: 202–206 ºC; FTIR (KBr): νmax = 3250 (N-H str.), 3152 (C-H str.,
triazole ring), 3086 (C-H str., aromatic ring), 2957 (C-H str., aliphatic), 1715 (C=O str., amide),
1616, 1560, 1466 (C=C str., aromatic ring), 1501 (N-O asym. str., NO2), 1344 (N-O sym. str., NO2)
cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.35 (s, 2H, SCH2), 5.38 (s, 2H, NCH2), 7.35 (d, 2H, Ar-
H, J=8.0 Hz), 7.49 (d, 2H, Ar-H, J=8.0 Hz), 7.82 (d, 2H, Ar-H, J=8.0 Hz), 8.03 (s, 1H, C-H
triazole), 8.25 (d, 2H, Ar-H, J=8.0 Hz), 11.06 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 27.4, 52.8, 119.2, 119.5, 125.4 (C5 triazole), 125.6, 130.4, 132.2, 136.0, 143.1,
143.9 (C4 triazole), 145.0, 165.8 (C=O amide) ppm; HRMS (m/z) calculated for C17H14BrN5O3S
[M+H]+: 448.0079 (79Br), 450.0059 (81Br). Found: 447.9901 (79Br), 449.9113 (81Br).
2-(4-(((4-bromophenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-fluorophenyl)acetamide (3r)
White solid; yield: 72%; m.p.: 198–202 ºC; FTIR (KBr): νmax = 3277 (N-H str.), 3132 (C-H str.,
triazole ring), 3080 (C-H str., aromatic ring), 2986 (C-H str., aliphatic), 1678 (C=O str., amide),
S9
1616, 1560, 1472 (C=C str., aromatic ring), 1234 (C-F str.) cm-1; 1H NMR (400 MHz, DMSO-d6): δ
= 4.34 (s, 2H, SCH2), 5.29 (s, 2H, NCH2), 7.15–7.20 (m, 2H, Ar-H), 7.35 (d, 2H, Ar-H J=8.0 Hz),
7.49 (d, 2H, Ar-H, J=8.0 Hz), 7.58–7.61 (m, 2H, Ar-H), 8.02 (s, 1H, C-H triazole), 10.51 (s, 1H, N-
H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.4, 52.6, 116.0 (d, 2C, Ar-C, J=20.0 Hz),
119.2, 121.45 (d, 2C, Ar-C, J=10.0 Hz), 125.4 (C5 triazole), 130.4, 132.2, 135.3, 136.1, 143.5 (C4
triazole), 158.7 (d, 1C, Ar-C, J=240.0 Hz), 164.6 (C=O amide) ppm; HRMS (m/z) calculated for
C17H14BrFN4OS [M+H]+: 421.0134 (79Br), 423.0114 (81Br). Found: 420.9962 (79Br), 422.9904(81Br).
2-(4-(((4-bromophenyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(naphthalen-1-yl)acetamide (3s)
Light brown solid; yield: 77%; m.p.: 196–200 ºC; FTIR (KBr): νmax = 3260 (N-H str.), 3119 (C-H
str., triazole ring), 3071 (C-H str., aromatic ring), 2956 (C-H str., aliphatic), 1674 (C=O str., amide),
1543, 1474 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.35 (s, 2H, SCH2),
5.55 (s, 2H, NCH2), 7.35 (d, 2H, Ar-H, J=8.0 Hz), 7.49–7.60 (m, 5H, Ar-H), 7.71 (d, 1H, Ar-H,
J=8.0 Hz), 7.80 (d, 1H, Ar-H, J=8.0 Hz), 7.96 (d, 1H, Ar-H, J=8.0 Hz), 8.07 (s, 1H, C-H triazole),
8.15 (d, 1H, Ar-H, J=8.0 Hz), 10.41 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ =
27.4, 52.5, 119.2, 122.0, 123.1, 125.5 (C5 triazole), 126.0, 126.2, 126.5, 126.7, 128.0, 128.7, 130.4,
132.2, 133.2, 134.2, 136.1, 143.9 (C4 triazole), 165.6 (C=O amide) ppm; HRMS (m/z) calculated for
C21H17BrN4OS [M+H]+: 453.0385 (79Br), 455.0364 (81Br). Found: 453.0212 (79Br), 455.0130 (81Br).
2-(4-((naphthalen-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (3t)
White solid; yield: 71%; m.p.: 160–164 ºC; FTIR (KBr): νmax = 3250 (N-H str.), 3136 (C-H str.,
triazole ring), 3051 (C-H str., aromatic ring), 2940 (C-H str., aliphatic), 1663 (C=O str., amide),
1622, 1537, 1454 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.46 (s, 2H,
SCH2), 5.29 (s, 2H, NCH2), 7.07–7.10 (m, 1H, Ar-H), 7.31–7.35 (m, 2H, Ar-H), 7.45–7.58 (m, 5H,
Ar-H), 7.84–7.92 (m, 4H, Ar-H), 8.06 (s, 1H, C-H triazole), 10.45 (s, 1H, N-H amide) ppm; 13C
NMR (100 MHz, DMSO-d6): δ = 27.4, 52.7, 119.7, 124.2, 125.5 (C5 triazole), 125.9, 126.1, 126.9,
127.1, 127.5, 128.1, 128.8, 129.4, 131.6, 133.9, 134.1, 138.9, 143.7 (C4 triazole), 164.6 (C=O
amide) ppm; HRMS (m/z) calculated for C21H18N4OS [M+H]+: 375.1235. Found: 375.1268.
S10
N-(4-methoxyphenyl)-2-(4-((naphthalen-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3u)
White solid; yield: 80%; m.p.: 184–188 ºC; FTIR (KBr): νmax = 3275 (N-H str.), 3134 (C-H str.,
triazole ring), 3053 (C-H str., aromatic ring), 2955 (C-H str., aliphatic), 1678 (C=O str., amide),
1605, 1555, 1456 (C=C str., aromatic ring), 1244 (C-O asym. str., ether), 1032 (C-O sym. str.,
ether) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 3.72 (s, 3H, OCH3), 4.45 (s, 2H, SCH2), 5.24 (s,
2H, NCH2), 6.90 (d, 2H, Ar-H, J=8.0 Hz), 7.45–7.51 (m, 5H, Ar-H), 7.84–7.92 (m, 4H, Ar-H), 8.05
(s, 1H, C-H triazole), 10.30 (s, 1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.4,
52.6, 55.6, 114.5, 121.2, 125.4 (C5 triazole), 125.9, 126.1, 126.9, 127.1, 127.5, 128.1, 128.8, 131.6,
132.0, 133.9, 134.1, 143.7 (C4 triazole), 156.0, 164.1 (C=O amide) ppm; HRMS (m/z) calculated for
C22H20N4O2S [M+H]+: 405.1341. Found: 405.1371.
2-(4-((naphthalen-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl)acetamide (3v)
White solid; yield: 65%; m.p.: 162–166 ºC; FTIR (KBr): νmax = 3221 (N-H str.), 3143 (C-H str.,
triazole ring), 3051 (C-H str., aromatic ring), 2958 (C-H str., aliphatic), 1706 (C=O str., amide),
1617, 1561 (C=C str., aromatic ring), 1507 (N-O asym. str., NO2), 1340 (N-O sym. str., NO2) cm-1;
1H NMR (400 MHz, DMSO-d6): δ = 4.46 (s, 2H, SCH2), 5.38 (s, 2H, NCH2), 7.46–7.51 (m, 3H,
Ar-H), 7.82–7.92 (m, 6H, Ar-H), 8.07 (s, 1H, C-H triazole), 8.25 (d, 2H, Ar-H, J=8.0 Hz), 11.09 (s,
1H, N-H amide) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 27.5, 52.8, 119.5, 125.4 (C5 triazole),
125.6, 125.9, 126.1, 126.9, 127.1, 127.4, 128.1, 128.8, 131.6, 133.9, 134.0, 143.0, 143.7 (C4
triazole), 145.0, 165.8, (C=O amide) ppm; HRMS (m/z) calculated for C21H17N5O3S [M+H]+:
420.1086. Found: 420.1168.
N-(4-fluorophenyl)-2-(4-((naphthalen-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3w)
White solid; yield: 76%; m.p.: 196–200 ºC; FTIR (KBr): νmax = 3279 (N-H str.), 3132 (C-H str.,
triazole ring), 3053 (C-H str., aromatic ring), 2986 (C-H str., aliphatic), 1676 (C=O str., amide),
1618, 1558, 1464 (C=C str., aromatic ring), 1234 (C-F str.) cm-1; 1H NMR (400 MHz, DMSO-d6): δ
= 4.45 (s, 2H, SCH2), 5.28 (s, 2H, NCH2), 7.15–7.20 (m, 2H, Ar-H), 7.49–7.60 (m, 5H, Ar-H),
7.84–7.92 (m, 4H, Ar-H), 8.06 (s, 1H, C-H triazole), 10.50 (s, 1H, N-H amide) ppm; 13C NMR (100
S11
MHz, DMSO-d6): δ = 27.4, 52.6, 116.0 (d, 2C, Ar-C, J=20.0 Hz), 121.45 (d, 2C, Ar-C, J=10.0 Hz),
125.4 (C5 triazole), 125.9, 126.1, 126.9, 127.1, 127.5, 128.1, 128.8, 131.6, 133.9, 134.1, 135.3,
143.7 (C4 triazole), 158.7 (d, 1C, Ar-C, J=240.0 Hz), 164.6 (C=O amide) ppm; HRMS (m/z)
calculated for C21H17FN4OS [M+H]+: 393.1141. Found: 393.1172.
N-(naphthalen-1-yl)-2-(4-((naphthalen-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (3x)
White solid; yield: 82%; m.p.: 166–170 ºC; FTIR (KBr): νmax = 3262 (N-H str.), 3115 (C-H str.,
triazole ring), 3051 (C-H str., aromatic ring), 2947 (C-H str., aliphatic), 1677 (C=O str., amide),
1542, 1505 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 4.47 (s, 2H, SCH2),
5.50 (s, 2H, NCH2), 7.46–7.58 (m, 6H, Ar-H), 7.71 (d, 1H, Ar-H, J=8.0 Hz), 7.83–7.88 (m, 4H, Ar-
H), 7.93–8.15 (m, 4H, 3 Ar-H & 1 C-H triazole), 10.41 (s, 1H, N-H amide) ppm; 13C NMR (100
MHz, DMSO-d6): δ = 27.5, 52.6, 122.0, 123.0, 125.5 (C5 triazole), 125.9, 126.0, 126.1, 126.5,
126.6, 126.9, 127.1, 127.5, 128.1, 128.7, 128.8, 131.6, 133.2, 133.9, 134.1, 143.7 (C4 triazole),
165.6 (C=O amide) ppm; HRMS (m/z) calculated for C25H20N4OS [M+H]+: 425.1391. Found:
425.1434.
General procedure for in vitro antimicrobial studies
All the synthesized compounds (3a–3x) were accessed for their in vitro antimicrobial activity
against bacteria i.e. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae,
Staphylococcus aureus, and fungi i.e. Candida albicans, Aspergillus niger. Results were recorded
in terms of MIC (minimum inhibitory concentration). The comparative evaluation of minimal
inhibitory concentration (MIC) of all the compounds against bacteria and C. albicans was
performed by micro dilution method[30]. Tetracycline dihydrochloride and Ketoconazole were used
as standard antibacterial and antifungal drugs, respectively. For bacteria, fresh cultures were
inoculated on nutrient agar plates and incubated at 37 °C for 24 h; for C. albicans, fresh cultures
were inoculated on potato dextrose agar (PDA) plates and incubated at 30°C for 72 h, to obtain
single colonies, which were further inoculated into the experimental broth in B.O.D incubator. To
evaluate the minimum inhibitory concentration (MIC), two-fold serially diluted synthesized
S12
compounds, well dispersed in 1 mL of stock solution (200µL DMSO and 800µL of 0.1% tween
solution in distilled water), starting from 2000 µg/mL to 62.5µg/mL, were tested. After incubation,
absorbance was measured by spectrophotometer (ELISA plate reader, Power WaveXS2).
Synthesized compounds were screened against fungus Aspergillus niger by observing the
percentage inhibition of mycelial growth.[31] Stock solutions were prepared by adding 10x103 µg/mL
and 5x103 µg/mL and 2.5x103 µg/mL of compounds to distilled water at room temperature and
neutral pH. For activity against fungus A. niger, about 15 mL of the Potato Dextrose Agar medium
was poured into petri plates and allowed to solidify. After solidification, 500 μL of stock solution
was spread on them using a sterilized swab. 5 mm discs of 7-day-old culture of the test fungi were
placed at the centre of the above petri plates and incubated at 25±2ºC for 7 days.
After incubation the colony diameter was measured. For each treatment, three replicates
were maintained.
Nanoformulations of synthesized compounds 3m and 3q were also tested for their in vitro
antimicrobial activity against one bacterial strain i.e. Klebsiella pneumoniae and one fungal strain
i.e. Candida albicans by using the method described above.
Nanoformulations of synthesized compounds 3m and 3q were also tested for their in vitro
antimicrobial activity against one bacterial strain i.e. Klebsiella pneumoniae and one fungal strain
i.e. Candida albicans by using the method described above.
S13
1 H NMR, 13 C NMR and HRMS of Compounds
Figure S1. 1H NMR of compound 3a.S14
Figure S2. 1H NMR of compound 3b.
S15
Figure S3. 1H NMR of compound 3c.
S16
Figure S4. 1H NMR of compound 3d.
S17
Figure S5. 1H NMR of compound 3e.
S18
Figure S6. 1H NMR of compound 3f.S19
Figure S7. 1H NMR of compound 3g.
S20
Figure S8. 1H NMR of compound 3h.
S21
Figure S9. 1H NMR of compound 3i.
S22
Figure S10. 1H NMR of compound 3j.S23
Figure S11. 1H NMR of compound 3k.
S24
Figure S12. 1H NMR of compound 3l.
S25
Figure S13. 1H NMR of compound 3m.
S26
Figure S14. 1H NMR of compound 3n.
S27
Figure S15. 1H NMR of compound 3o.
S28
Figure S16. 1H NMR of compound 3p.
S29
Figure S17. 1H NMR of compound 3q.S30
Figure S18. 1H NMR of compound 3r.
S31
Figure S19. 1H NMR of compound 3s.
S32
Figure S20. 1H NMR of compound 3t.
S33
Figure S21. 1H NMR of compound 3u.S34
Figure S22. 1H NMR of compound 3v.S35
Figure S23. 1H NMR of compound 3w.
S36
Figure S24. 1H NMR of compound 3x.
S37
Figure S25. 13C NMR of compound 3a.
S38
Figure S26. 13C NMR of compound 3b.
S39
Figure S27. 13C NMR of compound 3c.
S40
Figure S28. 13C NMR of compound 3d.
S41
Figure S29. 13C NMR of compound 3e.
S42
Figure S30. 13C NMR of compound 3f.
S43
Figure S31. 13C NMR of compound 3g.
S44
Figure S32. 13C NMR of compound 3h.
S45
Figure S33. 13C NMR of compound 3i.
S46
Figure S34. 13C NMR of compound 3j.
S47
Figure S35. 13C NMR of compound 3k.
S48
Figure S36. 13C NMR of compound 3l.
S49
Figure S37. 13C NMR of compound 3m.
S50
Figure S38. 13C NMR of compound 3n.
S51
Figure S39. 13C NMR of compound 3o.
S52
Figure S40. 13C NMR of compound 3p.
S53
Figure S41. 13C NMR of compound 3q.
S54
Figure S42. 13C NMR of compound 3r.
S55
Figure S43. 13C NMR of compound 3s.S56
Figure S44. 13C NMR of compound 3t.S57
Figure S45. 13C NMR of compound 3u.S58
Figure S46. 13C NMR of compound 3v.
S59
Figure S47. 13C NMR of compound 3w.
S60
Figure S48. 13C NMR of compound 3x.
S61
Figure S49. HRMS of compound 3a.
S62
Figure S50. HRMS of compound 3b.
S63
Figure S51. HRMS of compound 3c.
S64
Figure S52. HRMS of compound 3d.
S65
Figure S53. HRMS of compound 3e.
S66
Figure S54. HRMS of compound 3f.
S67
Figure S55. HRMS of compound 3g.
S68
Figure S56. HRMS of compound 3h.
S69
Figure S57. HRMS of compound 3i.
S70
Figure S58. HRMS of compound 3j.
S71
Figure S59. HRMS of compound 3k.
S72
Figure S60. HRMS of compound 3l.
S73
Figure S61. HRMS of compound 3m.
S74
Figure S62. HRMS of compound 3n.
S75
Figure S63. HRMS of compound 3o.S76
Figure S64. HRMS of compound 3p.
S77
Figure S65. HRMS of compound 3q.
S78
Figure S66. HRMS of compound 3r.S79
Figure S67. HRMS of compound 3s.
S80
Figure S68. HRMS of compound 3t.
S81
Figure S69. HRMS of compound 3u.
S82
Figure S70. HRMS of compound 3v.
S83
Figure S71. HRMS of compound 3w.
S84
Figure S72. HRMS of compound 3x.
S85