Synthesis, characterization and antimicrobial activity of 4-((1-benzyl/phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde analogues

Article abstract of DOI:10.1007/s00044-016-1515-0

A diverse series of 4-((1-benzyl/phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde analogues has been synthesized in good yield by the click reaction between 4-O-propargylated benzaldehyde and various organic bromides/azides. All the synthesized compounds

Full text of DOI:10.1007/s00044-016-1515-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1515-0
ORIGINAL RESEARCH
Synthesis, characterization and antimicrobial activity of 4-((1-
benzyl/phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde
analogues
Kashmiri Lal1 Pinki Yadav1 Ashwani Kumar2
•
•
Received: 15 March 2015 / Accepted: 23 January 2016
Ó Springer Science+Business Media New York 2016
Abstract A diverse series of 4-((1-benzyl/phenyl-1H-
1,2,3-triazol-4-yl)methoxy)benzaldehyde analogues has
been synthesized in good yield by the click reaction
between 4-O-propargylated benzaldehyde and various
organic bromides/azides. All the synthesized compounds
were tested in vitro for their antimicrobial activity against
Gram-positive bacteria (Staphylococcus epidermidis and
Bacillus subtilis), Gram-negative bacteria (Escherichia coli
and Pseudomonas aeruginosa) and fungi (Candida albi-
cans and Aspergillus niger). Most of the compounds
exhibited good-to-excellent antimicrobial activity. Com-
pound 7b was found to be more potent than ciprofloxacin
against B. subtilis, whereas it showed activity comparable
to ciprofloxacin against E. coli. Compounds 4h and 4i
showed activity comparable to fluconazole against A.
niger. Further, the binding mode of compound 7b into the
active site of E. coli topoisomerase II DNA gyrase B has
also been investigated.
Introduction
Nitrogen-containing heterocycles play an important role
in medicinal chemistry because of their presence in a
vast number of natural and synthetic therapeutically
important compounds. In particular, 1,2,3-triazoles are
among the most studied five-membered heterocyclic
compounds (El-Sagheer and Brown, 2010; Schulzeab and
Schubert, 2014; Pola et al., 2014). The copper-catalyzed
variant (Tornoe et al., 2002; Rostovtsev et al., 2002) of
Huisgen azide–alkyne cycloaddition (Huisgen, 1984) for
the synthesis of 1,4-disubstituted 1,2,3-triazoles has
attracted scientific community all over the world. The
diverse libraries of molecules can be achieved by
installing azide and alkyne functionalities to different
molecules using various routes (Millward et al., 2013,
Thirumurugan et al., 2013). The 1,4-disubstituted 1,2,3-
triazoles are surrogate for the peptide bond (Bock et al.,
2007) and show chemical as well as biological stability
(Agalave et al., 2011). The triazole ring can act as a
hydrogen bond acceptor and donor, simultaneously
(Whiting et al., 2006), thereby offering various types of
binding to the target enzyme. Additionally, 1,2,3-tria-
zoles are also associated with a broad range of phar-
macological activities including anticancer (Kumbhare
et al., 2014; Ma et al., 2014; Zhou et al., 2014), anti-
tubercular (Gonzaga et al., 2013; Mir et al., 2014),
antimalarial (Kumar et al., 2014) and antimicrobial
activity (Genin et al., 2000, Kaushik et al., 2014). On
the basis of above facts and in continuation of our
studies on 1,2,3-triazoles (Lal et al., 2012, 2014;
Kaushik et al., 2014), we report herein the synthesis and
antimicrobial evaluation of a diverse series of 4-((1-
benzyl/phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde
analogues.
Keywords 1,4-Disubstituted 1,2,3-triazoles Á
Click chemistry Á Antimicrobial activity Á Docking studies
& Kashmiri Lal
klal_iitd@yahoo.com
1
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar 125001, India
2
Department of Pharmaceutical Sciences, Guru Jambheshwar
University of Science and Technology, Hisar, Haryana
125001, India
123

Med Chem Res
monitored by TLC, ice-cold water (30 mL) was added to
the reaction mixture. The resulting solid residue was fil-
tered, washed with aqueous ammonium chloride/ammonia
(9:1) solution and water and recrystallized with chloro-
form/hexane (8:2) to get 1,4-disubstituted 1,2,3-triazoles
(7a–7e).
Materials and methods
Chemistry
The melting points (°C) were observed in open capillaries
and are uncorrected. The IR spectra were recorded on
SHIMAZDU IR AFFINITY-I FTIR spectrophotometer.
The 1H NMR and 13C NMR spectra were recorded on
Bruker Avance III 400 nano bay spectrometer at 400 and
100 MHz, respectively. Tetramethylsilane (TMS) was used
as an internal standard (chemical shift d, in ppm, coupling
constant J in Hertz (Hz)). The high-resolution mass spectra
(HRMS) were obtained on Micromass QTOF micro-mass
spectrometer. The thin-layer chromatography (TLC) was
run on readymade silica gel plates (SIL G/UV254, ALU-
GRAM) and visualized under ultraviolet lamp. Azide
precursors (5a–5e) were prepared via reported procedure
(Xu et al., 2013). The spectral data of compounds 7a–7e
were in accordance with the reported data (Kumar et al.,
2013).
Synthesis of alkyne (2)
4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethoxy)-benzaldehyde
(4a) White solid, 86 % yield, mp: 85–87 °C. IR (KBr,
m
H str, CHO), 1682 (C=O str), 1604, 1578, 1506, 1456,
To a solution of 4-hydroxy benzaldehyde (1.0 mmol) in
20 mL acetone, anhydrous potassium carbonate
(1.5 mmol) was added, and the resulting suspension was
refluxed for 30 min. Propargyl bromide (80 % in toluene,
1.5 mmol) was added to it slowly, and the reaction mixture
was refluxed for 8 h. After completion of the reaction as
monitored by TLC, the solvent was evaporated and the
resulting solid residue was washed with ice-cold water and
recrystallized from chloroform/hexane (8:2).
max/cm-1): 3132 (C–H str, triazole), 3066, 2843, 2760 (C–
1431, 1254 (C–O str), 1169, 1113 (C–O str), 997, 869, 835,
1
752, 721, 696, 611, 515. H NMR (CDCl3, 400 MHz): d
5.27 (s, 2H, NCH2), 5.56 (s, 2H, O-CH2), 7.09 (d,
J = 8.8 Hz, 2H, 20-H, 60-H), 7.28–7.31 (m, 2H, 200-H, 600-
H), 7.38–7.39 (m, 3H, 300-H, 4-H00, 500-H), 7.58 (s, 1H,
triazolyl-H), 7.84 (d, J = 8.8 Hz, 2H, 30-H, 50-H), 9.89 (s,
1H, CHO). 13C NMR (CDCl3, 100 MHz): d 190.81 (CHO),
163.13 (Ar–C), 143.61 (C-4), 134.34 (Ar–C), 132.01 (Ar–
C), 130.32 (Ar–C), 129.22 (Ar–C), 128.93 (Ar–C), 122.88
(C-5), 115.09 (Ar–C), 62.18 (OCH2), 54.34 (NCH2).
HRMS: m/z (M?) Cacld. for C17H15N3O2: 293.1164,
found: 294.1229 (M ? H)?.
General procedure for the synthesis of 1,4-disubstituted
1,2,3-triazoles (4a–4o) To a mixture of substituted ben-
zyl bromide 3a–3o (1.0 mmol), sodium azide (3.0 mmol),
alkyne 2 (1.0 mmol) in DMF/water (8:2), copper sulfate
pentahydrate (10 mol%) and sodium ascorbate (20 mol%)
were added. The reaction mixture was stirred for 4–16 h at
room temperature, and the progress of the reaction was
monitored by TLC. After completion of the reaction, ice-
cold water (30 mL) was added to the reaction mixture. The
residue thus obtained was filtered, washed with aqueous
ammonium chloride/ammonia (9:1) solution and water and
recrystallized with chloroform/hexane (8:2) to get 1,4-
disubstituted 1,2,3-triazoles (4a–4o).
4-[1-(2-Methyl-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4b) Off-white solid, 89 % yield, mp:
88–90 °C. IR (KBr, mmax/cm-1): 3151 (C–H str, triazole),
2878, 2752 (C–H str, CHO), 1682 (C=O str), 1604, 1576,
1512, 1429, 1255 (C–O str), 1166, 1119 (C–O str), 1001,
1
835. H NMR (CDCl3, 400 MHz): d 2.37 (s, 1H, CH3),
5.26 (s, 2H, NCH2), 5.51 (s, 2H, OCH2), 7.09 (d,
J = 8.8 Hz, 2H, 2-H, 60-H), 7.2 (s, 4H, 200-H, 300-H, 400-H,
500-H, 4H), 7.56 (s, 1H, triazolyl-H), 7.84 (d, J = 8.8 Hz,
2H, 30-H, 50-H), 9.89 (s, 1H, CHO). 13C NMR (CDCl3,
100 MHz): d 190.82 (CHO), 163.15 (Ar–C), 143.52 (C-4),
138.91 (Ar–C), 132.01 (Ar–C), 131.27 (Ar–C), 130.32
(Ar–C), 129.87 (Ar–C), 128.24 (Ar–C), 122.75 (C-5),
115.08 (Ar–C), 62.19 (OCH2), 54.15 (NCH2), 21.19 (CH3).
General procedure for the synthesis of 1,4-disubtituted
1,2,3-triazoles (7a–7e) A mixture of substituted phenyl
azide 6a–6e (1.0 mmol), alkyne 2 (1.0 mmol) in DMF/
water (8:2), copper sulfate pentahydrate (10 mol%) and
sodium ascorbate (20 mol%) was stirred for 4–10 h at
room temperature. After the reaction was complete as
123

Med Chem Res
HRMS: m/z (M?) Cacld. for C18H17N3O2: 307.1321,
62.07 (OCH2), 53.24 (NCH2). HRMS: m/z (M?) Cacld. for
?
?
found: 308.1411 (M ? H)
.
C17H14N4O4: 338.1015, found: 339.1093 (M ? H)
.
4-[1-(3-Methyl-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4c) White solid, 83 % yield, mp:
60–62 °C. IR (KBr, mmax/cm-1): 3144 (C–H str, triazole),
3088, 2920, 2839, 2754, (C–H str, CHO), 1682 (C=O str),
1603, 1575, 1508, 1431, 1309, 1257 (C–O str), 1219, 1110
4-[1-(3-Nitro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-ben-
zaldehyde (4f) White solid, 84 % yield, mp: 130–132 °C.
IR (KBr, mmax/cm-1): 3146 (C–H str, triazole), 3086, 2922,
2837, 2753 (C–H str, CHO), 1695 (C=O str), 1604, 1579,
1517 (N=O str), 1344 (N=O str), 1255 (C–O str), 1219,
1
1
(C–O str), 1026, 835, 775. H NMR (CDCl3, 400 MHz): d
1161, 1108 (C–O str), 1039, 864, 731. H NMR (CDCl3,
2.35 (s, 3H, CH3), 5.27 (s, 2H, NCH2), 5.51 (s, 2H, OCH2),
7.08–7.11 (m, 4H, 20-H, 60-H, 400-H, 600-H), 7.19 (m, 1H,
200-H), 7.26–7.30 (m, 1H, 600-H), 7.58 (s, 1H, triazolyl-H),
7.82–7.85 (d, 2H, 30-H, 50-H), 9.88 (s, 1H, CHO). 13C
NMR (CDCl3, 100 MHz): d 190.82 (CHO), 163.15 (Ar–C),
143.55 (C-4), 139.08 (Ar–C), 134.22 (Ar–C), 132.00 (Ar–
C), 130.32 (Ar–C), 129.66 (Ar–C), 129.08 (Ar–C), 128.89
(Ar–C), 125.24 (Ar–C), 122.89 (C-5), 115.09 (Ar–C),
62.18 (OCH2), 54.34 (NCH2), 21.34 (CH3). HRMS: m/
400 MHz): d 5.33 (s, 2H, NCH2), 5.97 (s, 2H, OCH2), 7.12
(d, 2H, J = 8.8 Hz, 20-H, 60-H), 7.19 (d, J = 7.8 Hz, 1H,
500-H), 7.57 (dt, J = 8.0 Hz, 1.6 Hz, 600-H), 7.65 (dt,
J = 7.8 Hz, 1.6 Hz, 400-H), 7.84–7.88 (m, 3H, 30-H, 50-H,
triazolyl-H), 8.17 (dd, 1H, 200-H, J = 8.0 Hz, 1.2 Hz), 9.91
(s, 1H, CHO). 13C NMR (CDCl3, 100 MHz): d 190.80
(CHO), 163.07 (Ar–C), 143.75 (C-4), 134.46 (Ar–C),
130.80 (Ar–C), 132.03 (Ar–C), 130.42 (Ar–C), 129.94
(Ar–C), 125.49 (Ar–C), 124.03 (C-5), 115.11 (Ar–C),
z (M?) Cacld. for C18H17N3O2: 307.1321, found: 308.1420
62.11 (OCH2), 50.99 (NCH2). HRMS: m/z (M?) Cacld. for
?
?
(M ? H)
.
C17H14N4O4: 338.1015, found: 339.1089 (M ? H)
.
4-[1-(4-Methyl-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4d) White solid, 86 % yield, mp:
68–70 °C. IR (KBr, mmax/cm-1): 3155 (C–H str, triazole),
3072, 2868, 2758 (C–H str, CHO), 1689 (C=O str), 1603,
1574, 1508, 1466, 1431, 1256 (C–O str), 1225, 1165, 1118
4-[1-(4-Nitro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-ben-
zaldehyde (4g) White solid, 88 % yield, mp: 118-120 °C.
IR (KBr, mmax/cm-1): 3133 (C–H str, triazole), 2850, 2754
(C–H str, CHO), 1687 (C=O str), 1604, 1516 (N=O, str),
1348 (N=O, str), 1251 (C–O str), 1077 (C–O str), 1002,
1
(C–O str), 1005, 870, 839, 756, 609. H NMR (CDCl3,
1
806. H NMR (CDCl3, 400 MHz): d 5.31 (s, 2H, NCH2),
400 MHz): d 2.28 (s, 1H, CH3), 5.25 (s, 2H, NCH2), 5.56
(s, 2H, OCH2), 7.08 (d, J = 8.8 Hz, 2H, 20-H, 60-H),
7.16–7.31 (m, 4H, 200-H, 300-H, 500-H, 600H), 7.47 (s, 1H,
triazolyl-H), 7.82 (d, J = 8.8 Hz, 2H, 30-H, 50-H), 9.87 (s,
1H, CHO). 13C NMR (CDCl3, 100 MHz): d 190.81 (CHO),
163.13 (Ar–C), 143.37 (C-4), 136.97 (Ar–C), 132.24 (Ar–
C), 131.98 (Ar–C), 131.48 (Ar–C), 131.12 (Ar–C), 130.31
(Ar–C), 129.50 (Ar–C), 129.30 (Ar–C), 126.73 (Ar–C),
122.76 (C-5), 115.09 (Ar–C), 62.16 (OCH2), 52.50
5.69 (s, 2H, OCH2), 7.09–7.12 (d, J = 8.8 Hz, 2H, 20-H,
60-H), 7.44 (d, J = 8.8 Hz, 2H, 200-H, 600-H), 7.69 (s, 1H,
triazolyl-H), 7.85 (d, J = 9.2 Hz, 2H, 30-H, 50-H), 8.25 (d,
J = 8.4 Hz, 2H, 300-H, 500-H), 9.90 (s, 1H, CHO). 13C
NMR (CDCl3, 100 MHz): d 190.77 (CHO), 162.99 (Ar–C),
144.24 (C-4), 141.35 (Ar–C), 132.03 (Ar–C), 130.46 (Ar–
C), 128.69 (Ar–C), 124.39 (Ar–C), 123.10 (C-5), 115.04
(Ar–C), 62.09 (OCH2), 53.27 (NCH2). HRMS: m/z (M?)
Cacld. for C17H14N4O4: 338.1015, found: 339.1083
?
(NCH2), 18.99 (CH3). HRMS: m/z (M?) Cacld. for
(M ? H)
.
?
C18H17N3O2: 307.1321, found: 308.1417 (M ? H)
.
4-[1-(2-Bromo-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4h) White solid, 90 % yield, mp:
78–80 °C. IR (KBr, mmax/cm-1): 3130 (C–H str, triazole),
3093, 3070, 2935, 2883, 2835, 2756 (C–H str, CHO), 1901,
1687 (C=O str), 1602, 1575, 1510, 1433, 1305, 1246 (C–O
str), 1226, 1168, 1109 (C–O str), 1037, 1003, 869, 821,
750, 648, 516. 1H NMR (CDCl3, 400 MHz): d 5.26 (s, 2H,
NCH2), 5.65 (s, 2H, OCH2), 7.08 (d, J = 8.0 Hz, 2H, 20-H,
60-H), 7.16–7.32 (m, 3H, 400-H, 500-H, 600-H), 7.6 (d,
J = 7.6 Hz, 1H, 300-H), 7.72 (s, 1H, triazolyl-H), 7.81 (d,
J = 8.0 Hz, 2H, 30-H, 50-H), 9.86 (s, 1H, CHO). 13C NMR
(CDCl3, 100 MHz): d 190.81 (CHO), 163.12 (Ar–C),
143.42 (C-4), 133.89 (Ar–C), 133.28 (Ar–C), 131.99 (Ar–
C), 130.59 (Ar–C), 130.50 (Ar–C), 130.30 (Ar–C), 128.30
(Ar–C), 123.57 (Ar–C), 123.39 (C-5), 115.10 (Ar–C),
4-[1-(2-Nitro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-ben-
zaldehyde (4e) Off-white solid, 92 % yield, mp:
90–92 °C. IR (KBr, mmax/cm-1): 3149 (C–H str, triazole),
3088, 2939, 2850, 2750 (C–H str, CHO), 1668 (C=O str),
1602, 1577, 1531 (N=O, str), 1514, 1429, 1350 (N=O, str),
1259 (C–O str), 1221, 1163, 1105 (C–O str), 1008, 866,
831, 727, 675. 1H NMR (CDCl3, 400 MHz): d 5.29 (s, 2H,
NCH2), 5.69 (s, 2H, OCH2), 7.08 (d, J = 8.8 Hz, 2H, 20-H,
60-H), 7.58–7.64 (m, 2H, 400-H, 600-H), 7.74 (s, 1H, tria-
zolyl-H), 7.82 (d, J = 8.4 Hz, 2H, 30-H, 50-H), 8.21 (d,
J = 8.0 Hz, 1H, 300-H), 8.16 (bs, 1H, 500-H), 9.87 (s, 1H,
CHO). 13C NMR (CDCl3, 100 MHz): d 190.83 (CHO),
163.02 (Ar–C), 148.53 (Ar–C), 144.12 (C-4), 136.51 (Ar–
C), 134.02 (Ar–C), 132.01 (Ar–C), 130.39 (Ar–C), 123.87
(Ar–C), 123.18 (Ar–C), 122.92 (C-5), 115.06 (Ar–C),
123

Med Chem Res
62.11 (OCH2), 53.96 (NCH2). HRMS: m/z (M?) Cacld. for
C17H14BrN3O2: 371.0269, found: 372.0349 (M ? H)?.
(NCH2). HRMS: m/z (M?) Cacld. for C17H14FN3O2:
?
311.1070, found: 312.1144 (M ? H)
.
4-[1-(3-Bromo-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4i) White solid, 94 % yield, mp:
81–83 °C. IR (KBr, mmax/cm-1): 3155 (C–H str, triazole),
3071, 2922, 2843, 2753 (C–H str, CHO), 1681 (C=O str),
1590, 1508, 1463, 1317, 1213 (C–O str), 1157, 1109 (C–O
4-[1-(3-Fluoro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4l) Off-white solid, 96 % yield, mp:
60–62 °C. IR (KBr, mmax/cm-1): 3149 (C–H str, triazole),
3070, 2930, 2848, 2760 (C–H str, CHO), 1680 (C=O str),
1604, 1512, 1481, 1309, 1261 (C–O str), 1224, 1116 (C–O
1
1
str), 1031, 825, 771, 634. H NMR (CDCl3, 400 MHz): d
str), 1041, 947, 893. H NMR (CDCl3, 400 MHz): d 5.28
5.26 (s, 2H, NCH2), 5.51 (s, 2H, OCH2), 7.07 (d,
J = 8.4 Hz, 2H, 20-H, 60-H), 7.24 (m, 4H, 200-H, 400-H, 500-
H, 600-H), 7.65 (s, 1H, triazolyl-H), 7.81 (d, J = 8.8 Hz,
2H, 30-H, 50-H), 9.86 (s, 1H, CHO). 13C NMR (CDCl3,
100 MHz): d 190.82 (CHO), 163.08 (Ar–C), 143.79 (C-4),
136.59 (Ar–C), 132.02 (Ar–C), 132.01 (Ar–C), 131.04
(Ar–C), 130.76 (Ar–C), 126.68 (Ar–C), 123.10 (C-5),
115.08 (Ar–C), 62.10 (OCH2), 53.48 (NCH2). HRMS: m/
(s, 2H, NCH2), 5.55 (s, 2H, OCH2), 6.96 (d, J = 1.6 Hz,
1H, 500-H), 6.98–7.10 (m, 3H, 200-H, 400-H, 600-H),
7.33–7.37 (m, 2H, 20-H, 60-H), 7.63 (s, 1H, triazolyl-H),
7.82 (d, 2H, J = 9.4 Hz, 30-H, 50-H), 9.88 (s, 1H, CHO).
13C NMR (CDCl3, 100 MHz): d 190.81, 164.23 (Ar–C),
163.08 (Ar–C), 161.76 (Ar–C), 143.81 (C-4), 136.69 (Ar–
C), 132.01 (Ar–C), 130.92 (Ar–C), 130.83 (Ar–C), 130.36
(Ar–C), 123.65 (Ar–C), 123.00 (C-5), 115.83 (Ar–C),
114.95 (Ar–C), 62.12 (OCH2), 53.64 (NCH2). HRMS: m/
z (M?) Cacld. for C17H14BrN3O2: 371.0269, found:
?
372.0343 (M ? H)
.
z (M?) Cacld. for C17H14FN3O2: 311.1070, found:
?
312.1148 (M ? H)
.
4-[1-(4-Bromo-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4j) Off-white solid, 88 % yield, mp:
70–72 °C. IR (KBr, mmax/cm-1): 3149 (C–H str, triazole),
3070, 2939, 2885, 2752 (C–H str, CHO), 1674 (C=O str),
1602, 1575, 1500, 1429, 1400, 1307, 1251 (C–O str), 1226,
1165, 1114 (C–O str), 1043, 1006, 831, 777, 644, 611, 516,
4-[1-(4-Fluoro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4m) White solid, 94 % yield, mp:
69–71 °C. IR (KBr, mmax/cm-1): 3149 (C–H str, triazole),
3070, 3039, 2943, 2841, 2760 (C–H str, CHO), 1674 (C=O
str), 1604, 1512, 1417, 1301, 1259 (C–O str), 1222, 1161,
1105 (C–O str), 866, 829, 648, 611, 520. 1H NMR (CDCl3,
400 MHz): d 5.29 (s, 2H, NCH2), 5.54 (s, 2H, OCH2),
7.06–7.12 (m, 4H, 20-H, 60-H, 200-H, 600-H), 7.29–7.32 (m,
2H, 30-H, 50-H), 7.58 (s, 1H, triazolyl-H), 7.85 (dt, 2H,
J = 8.8 Hz, J = 2.4 Hz, 300-H, 500-H), 9.90 (s, 1H, CHO).
13C NMR (CDCl3, 100 MHz): d 190.82 (CHO), 163.09
(Ar–C), 143.78 (C-4), 132.03 (Ar–C), 130.38 (Ar–C),
130.12 (Ar–C), 130.04 (Ar–C), 122.70 (C-5), 116.36 (Ar–
C), 116.15 (Ar–C), 115.07 (Ar–C), 62.16 (OCH2), 53.61
1
487. H NMR (CDCl3, 400 MHz): d 5.27 (s, 2H, NCH2),
5.51 (s, 2H, OCH2), 7.09 (d, J = 8.8 Hz, 2H, 200-H, 600-H),
7.17 (d, J = 8.4 Hz, 2H, 20-H, 60-H), 7.51 (d, J = 8.4 Hz,
2H, 300-H, 500-H), 7.6 (s, 1H, triazolyl-H), 7.83 (d,
J = 8.4 Hz, 2H, 30-H, 50-H), 9.88 (s, 1H, CHO). 13C NMR
(CDCl3, 100 MHz): d 190.80 (CHO), 163.08 (Ar–C),
143.82 (C-4), 133.36 (Ar–C), 132.38 (Ar–C), 132.01 (Ar–
C), 130.37 (Ar–C), 129.77 (Ar–C), 123.10 (Ar–C), 122.86
(C-5), 115.07 (Ar–C), 62.12 (OCH2), 53.63 (NCH2).
HRMS: m/z (M?) Cacld. for C17H14BrN3O2: 371.0269,
(NCH2). HRMS: m/z (M?) Cacld. for C17H14FN3O2:
?
?
found: 372.0340 (M ? H)
.
311.1070, found: 312.1154 (M ? H)
.
4-[1-(2-Fluoro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
benzaldehyde (4k) Pale yellow solid, 92 % yield, mp:
89–91 °C. IR (KBr, mmax/cm-1): 3134 (C–H str, triazole),
3062, 2920, 2845, 2756 (C–H str, CHO), 1685 (C=O str),
1602, 1500, 1456, 1303, 1251 (C–O str), 1165, 1109 (C–O
str), 1002, 869, 837, 756, 642, 513. 1H NMR (CDCl3,
400 MHz): d 5.26 (s, 2H, NCH2), 5.65 (s, 2H, OCH2),
7.09–7.17 (m, 4H, 300-H, 400-H, 500-H, 600-H), 7.29–7.40 (m,
2H, 20-H, 60-H), 7.69 (s, 1H, triazolyl-H), 7.83 (d,
J = 8.8 Hz, 2H, 30-H, 50-H), 9.86 (s, 1H, CHO). 13C NMR
(CDCl3, 100 MHz): d 190.82 (CHO), 163.13 (Ar–C),
159.35 (Ar–C), 143.58 (C-4), 132.00 (Ar–C), 131.17 (Ar–
C), 131.09 (Ar–C), 130.73 (Ar–C), 130.70 (Ar–C), 130.33
(Ar–C), 124.94 (Ar–C), 124.91 (Ar–C), 123.13 (Ar–C),
123.12 (C-5), 121.72 (Ar–C), 121.58 (Ar–C), 116.02 (Ar–
C), 115.81 (Ar–C), 115.08 (Ar–C), 62.12 (OCH2), 47.90
4-(1-Pyridin-4-ylmethyl-1H-[1,2,3]triazol-4-ylmethoxy)-
benzaldehyde (4n) Yellow colored liquid, 79 % yield.
IR (KBr, mmax/cm-1): 3140 (C–H str, triazole), 3062, 2922,
2846, 2746 (C–H str, CHO), 1687 (C=O str), 1600, 1575,
1508, 1417, 1309, 1253 (C–O str), 1220, 1103 (C–O str),
1
1001, 833. H NMR (CDCl3, 400 MHz): d 5.30 (s, 2H,
NCH2), 5.59 (s, 2H, OCH2), 7.69 (s, 1H, triazolyl-H), 7.84
(d, J = 8.8 Hz, 20-H, 60-H), 7.99 (bs, 2H, 30-H, 50-H), 8.60
(d, J = 5.6 Hz, 4H, 200-H, 300-H, 500-H, 600-H), 9.88 (s, 1H,
CHO). 13C NMR (CDCl3, 100 MHz): d 190.85 (CHO),
163.01 (Ar–C), 162.63 (Ar–C), 150.45 (Ar–C), 150.00
(Ar–C), 144.70 (Ar–C), 144.11 (Ar–C), 143.48 (C-4),
132.04 (Ar–C), 130.40 (Ar–C), 123.33 (Ar–C), 122.47 (C-
5), 122.22 (Ar–C), 115.05 (Ar–C), 62.05 (OCH2), 53.23
(NCH2). HRMS: m/z (M?) Cacld. for C16H14N4O2:
?
294.1117, found: 295.1204 (M ? H)
.
123

Med Chem Res
4-[1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-[1,2,3]
triazol-4-ylmethoxy]-benzaldehyde (4o) White solid, 87 %
yield, mp: 160–162 °C. IR (KBr, mmax/cm-1): 3145 (C–H
str, triazole), 3062, 2922, 2852, 2746 (C–H str, CHO),
1710 (C=O str), 1601, 1510, 1462, 1311, 1250 (C–O str),
1163, 1106 (C–O str), 1005, 835. 1H NMR (CDCl3,
400 MHz): d 5.25 (s, 2H, NCH2), 5.80 (s, 2H, OCH2),
7.33–7.37 (m, 2H, 20-H, 60-H), 7.72 (s, 1H, triazolyl-H),
7.84–7.99 (m, 4H, 30-H, 50-H, 200-H, 500-H, 300-H 400-H),
9.80 (s, 1H, CHO). 13C NMR (CDCl3, 100 MHz): d 190.89
(CHO), 168.28 (C=O), 163.09 (Ar–C), 144.27 (C-4),
134.34 (Ar–C), 132.66 (Ar–C), 130.38 (Ar–C), 123.62 (C-
5), 115.07 (Ar–C), 114.96 (Ar–C), 114.77 (Ar–C), 60.30
Results and discussion
Chemistry
The synthetic route for the desired 1,2,3-triazoles is out-
lined in Schemes 1 and 2. The first step involves the O-
propargylation of commercially available 4-hydroxy ben-
zaldehyde (1) by propargyl bromide in the presence of
anhydrous K2CO3 in dry acetone under reflux. The 4-O-
propargylated benzaldehyde (2) was subjected to one-pot
multicomponent click reaction with various organic bro-
mides (3a–3o) in the presence of catalytic amount of
copper sulfate pentahydrate and sodium ascorbate in
aqueous DMF to furnish desired 1,2,3-triazoles (4a–4o) in
good-to-excellent yield.
(OCH2), 53.45 (NCH2). HRMS: m/z (M?) Cacld. for
?
C19H14N4O4: 362.1015, found: 363.1083 (M ? H)
.
The organic azides (6a–6e) were synthesized from var-
ious aniline derivatives (5a–5e) by classical diazotization–
azidation process adapted from the literature (Xu et al.,
2013). Without further purification, organic azides (6a–6e)
were treated with 4-O-propargylated benzaldehyde (2)
using copper sulfate pentahydrate as catalyst and sodium
ascorbate in DMF/water system to produce 1,2,3-triazoles
(7a–7e) in better yield as compared to the yield reported
earlier (Kumar et al., 2013).
Pharmacology
The procedure reported by Kaushik et al. (2014) was used
for the evaluation of antimicrobial activities of the syn-
thesized compounds.
The structure of all the products was established on the
1
basis of their FTIR, H NMR, 13C NMR and HRMS data.
Computational details
The FTIR spectra of all compounds (4a–4o) demonstrated
a characteristic peak due to =C–H stretching of triazole
ring in the region 3155–3130 cm-1. The C–H stretching
bands of aldehyde group were observed at 2850–2835 and
2760–2746 cm-1. The C=O stretching bands appeared in
the region of 1687–1668 cm-1. The bands in the region
1261–1246 and 1119–1103 cm-1 showed the presence of
ether linkage (C–O stretching). The 1H NMR spectra of all
The docking studies were carried out by using Auto Dock
Vina 1.1.2 (Kaushik et al., 2014). Grid center was placed on
the active site. The center and size of grid box were cen-
ter_x = 19.0577118729, center_y = 29.6584661732 and
center_z = 36.0719212982, and size_x = 25.0, size_y =
25.0 and size_z = 25.0 for DNA gyrase (PDB: 1 KZN),
respectively.
Scheme 1 Synthesis of 1,4-
disubstituted 1,2,3-triazoles
(4a–4o) by one-pot reaction.
Reagents and conditions
(i) propargyl bromide, K2CO3,
acetone, reflux; 8 h (ii) NaN3,
sodium ascorbate,
CuSO4Á5H2O, DMF/H2O, RT
123

Med Chem Res
Scheme 2 Synthesis of 1,4-
disubstituted 1,2,3-triazoles
(7a–7e). Reagents and
conditions: (i) HCl, NaNO2,
NaN3; (ii) sodium ascorbate,
CuSO4Á5H2O, DMF/H2O, RT
Table 1 In vitro antibacterial activity of compounds 4a–4o; 7a–7e (MIC in lM/mL)
Entry
Compounds
R/R1
S. epidermidis
B. subtilis
E. coli
P. aeruginosa
1
4a
–C6H5
0.0054
0.0101
0.0203
0.0203
0.0369
0.0185
0.0185
0.0336
0.0168
0.0168
0.0201
0.0201
0.0402
0.0849
0.0172
0.0349
0.0202
0.0771
0.0426
0.0199
0.0047
0.0213
0.0407
0.0203
0.0407
0.0369
0.0093
0.0369
0.0336
0.0168
0.0168
0.0201
0.0201
0.0402
0.0212
0.0172
0.0174
0.0027
0.0193
0.0213
0.0398
0.0047
0.0213
0.0407
0.0407
0.0407
0.0369
0.0369
0.0185
0.0336
0.0336
0.0336
0.0201
0.0402
0.0402
0.0424
0.0172
0.0174
0.0054
0.0385
0.0426
0.0199
0.0047
0.0213
0.0203
0.0203
0.0203
0.0738
0.0185
0.0185
0.0336
0.0168
0.0168
0.0402
0.0402
0.0201
0.0849
0.0344
0.0349
0.0202
0.0193
0.0213
0.0199
0.0047
2
4b
2-CH3-C6H4
3-CH3-C6H4
4-CH3-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
2-F-C6H4
3-F-C6H4
4-F-C6H4
4-Pyridinyl
Phthalimido
4-Br
3
4c
4
4d
5
4e
6
4f
7
4g
8
4h
9
4i
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
4m
4n
4o
7a
7b
4-OCH3
7c
4-NO2
7d
4-CH3
7e
4-Cl
Ciprofloxacin
–
Pharmacology
Antibacterial activity
the compounds (4a–4o) exhibited a characteristics singlet
due to triazolyl proton in the range of d 7.47–7.74 and
aldehydic proton appeared at d 9.86–9.90. In the 13C NMR
spectra of all the compounds, peaks in the region d
143.37–144.27 and d 122.47–123.62 were assigned to the
C-4 and C-5 carbon atoms of the triazole ring. A peak in
the region d 190.77–190.95 showed the presence of alde-
hydic carbon atom. Further, HRMS data of all the com-
pounds confirmed their assigned structure.
The in vitro antibacterial activity of all the synthesized
compounds was tested in vitro on two Gram-positive
bacteria (Staphylococcus epidermidis MTCC 6880 and
Bacillus subtilis MTCC 441) and two Gram-negative
bacteria (Escherichia coli MTCC 16521 and Pseudomonas
123

Med Chem Res
Table 2 In vitro antifungal activity of compounds 4a–4o; 7a–7e (MIC in lM/mL)
Entry
Compounds
R/R0
A. niger
C. albicans
1
4a
–C6H5
0.0426
0.0203
0.0204
0.0407
0.0185
0.0369
0.0185
0.0084
0.0084
0.0336
0.0201
0.0100
0.0100
0.0106
0.0172
0.0174
0.0202
0.0193
0.0213
0.0398
0.0102
0.0107
0.0102
0.0102
0.0102
0.0185
0.0185
0.0093
0.0084
0.0084
0.0084
0.0201
0.0100
0.0200
0.0106
0.0344
0.0087
0.0404
0.0097
0.0213
0.0199
0.0051
2
4b
2-CH3-C6H4
3-CH3-C6H4
4-CH3-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
2-F-C6H4
3-F-C6H4
4-F-C6H4
4-Pyridinyl
Phthalimido
4-Br
3
4c
4
4d
5
4e
6
4f
7
4g
8
4h
9
4i
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
4m
4n
4o
7a
7b
4-OCH3
7c
4-NO2
7d
4-CH3
7e
4-Cl
Fluconazole
–
aeruginosa MTCC 424) by standard serial dilution method
(Cappucino and Sherman, 1999). Ciprofloxacin was used
as standard drug, and the minimum inhibitory concentra-
tions (MIC) were recorded in lM/mL and are listed in
Table 1.
more potent than pyridinyl derivative 4n against all bac-
terial strains except B. subtilis.
Antifungal activity
From the antibacterial screening, it was observed that
most of the compounds exhibited good-to-high activity.
Compound 7b with 4-methoxy group displayed very good
activity against E. coli with MIC value of 0.0054 lM/mL
and was found to be comparable to reference drug cipro-
floxacin (MIC, 0.0047 lM/mL). Moreover, compound 7b
(MIC, 0.0027 lM/mL) also exhibited excellent potency
against B. subtilis and was found to be almost two times
more active than standard used. It was also observed that
compounds with electron withdrawing group (4e–4m) on
benzene ring exhibited better activity than the compounds
containing electron releasing group (4b–4d).
All the synthesized triazoles were also screened for anti-
fungal activity against two fungal strains viz. Aspergillus
niger (MTCC 8189) and Candida albicans (MTCC 227) by
standard serial dilution method (Cappucino and Sherman,
1999). Fluconazole was used as standard drug and mini-
mum inhibitory concentrations (MIC in lM/mL) were
recorded and are depicted in Table 2. The activity data
revealed good-to-high antifungal activity of most of the
compounds. Compounds 4h and 4i showed better potency
with MIC value of 0.0084 lM/mL than fluconazole
(MIC = 0.0102 lM/mL) against A. niger. Similarly, 4l,
4m and 4n showed activity comparable to the standard
against A. niger. In case of C. albicans, the compounds
with bromo group (4h, 4i, 4j and 7a) exhibited better
activity than all other triazoles with MIC values in the
range 0.0084–0.0087 lM/mL.
In case of B. subtilis, compounds 4f and 7b exhibited
high activity among all the compounds under study with
MIC values of 0.0093 and 0.0027 lM/mL, respectively. In
case of S. epidermidis, compounds 4a and 4b were found to
be more active than others with MIC values of 0.0054 and
0.0101 lM/mL, respectively. It was also observed that the
presence of methyl and nitro groups on benzyl increased
the activity as compared to that present on benzene ring.
Further, compound 4a with benzyl group was found to be
Docking studies
From the antibacterial screening, compound 7b was
found to be the most promising molecule. Therefore, in
123

Med Chem Res
Fig. 1 Binding mode of
compound 7b in the active site
of topoisomerase II DNA gyrase
showing various types of
interactions (dotted lines), i.e.,
hydrogen bond (green), pi-alkyl
(pink), pi-sigma (purple) (Color
figure online)
Conclusion
In conclusion, we have synthesized twenty 4-((1-benzyl/
phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde ana-
logues from 4-O-propargylated benzaldehyde and various
organic bromides/azides in good-to-excellent yield by
using the click reaction. The antimicrobial evaluation of
these compounds revealed good-to-high activities of most
of the compounds against all the bacterial and fungal
strains under study. Compound 7b exhibited excellent and
better potency than ciprofloxacin against B. subtilis.
Compounds 4h and 4i showed activity comparable to flu-
conazole against A. niger. In silico docking studies of most
promising compound 7b with E. coli topoisomerase II
DNA gyrase B showed various types of interactions with
the active residues of the enzyme. The results of the present
work can be used for further design and development of
novel molecules against microbial infections.
Fig. 2 Surface diagram of topoisomerase II DNA gyrase docked with
compound 7b
Acknowledgments The authors are thankful to Dr. Anil Kumar,
Department of Bio and Nanotechnology and Central Instrumentation
Laboratory, Guru Jambheshwar University of Science and Technol-
ogy, Hisar, India, for assisting in antimicrobial studies and providing
NMR spectra of the compounds.
order to investigate a possible mechanism of action of
7b, docking simulations into the active site of E. coli
topoisomerase II DNA gyrase
B were performed
(Kaushik et al., 2014). The binding mode of 7b into
active site of topoisomerase II DNA gyrase B and its
surface diagram are shown in Figs. 1 and 2, respectively.
It can be observed that the oxygen atom of carbonyl
group is engaged in hydrogen bonding with Ser121 and
His95 residues. Triazole ring and phenyl ring directly
attached to triazole are involved in pi-alkyl interactions
with Ile78, while same phenyl ring also demonstrate pi-
alkyl interactions with Ala47. Another phenyl ring
exhibits pi-alkyl interactions with Ala96 and pi-sigma
interactions with Ile90. Therefore, it can be said that the
compounds under study may inhibit DNA topoisomerase
successfully via these interactions.
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