Efficient synthesis and antimicrobial evaluation of 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehydes and their oxime derivatives

Article abstract of DOI:10.1007/s00044-017-1845-6

A series of 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehydes was prepared by the propargylation of 2-hydroxynaphthaldehyde followed by Copper(I)-catalyzed azide-alkyne cycloaddition with various organic azides. 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehyde analogues were transformed to corresponding oxime derivatives upon grinding with hydroxylamine hydrochloride under solvent free conditions. All the synthesized compounds were characterized by various analytical and spectral techniques and screened in vitro for antimicrobial activity. The activity data revealed that most of the compounds exhibited good to significant activities. Compounds 4c and 5c exhibited very good and broad spectrum activity towards all the tested bacterial strains. Further, to understand the binding interactions, 4c and 5c were docked into the active sites of E. coli topoisomerase II DNA gyrase.

Full text of DOI:10.1007/s00044-017-1845-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1845-6
ORIGINAL RESEARCH
Efficient synthesis and antimicrobial evaluation of
2
-((1-substituted-1H-1,2,3-triazol-4-yl)-1-
naphthaldehydes and their oxime derivatives
1 ●
1 ●
1 ●
1 ●
2 ●
Pinki Yadav Kashmiri Lal Poonam Rani Satbir Mor Ashwani Kumar
Anil Kumar
3
Received: 27 June 2016 / Accepted: 2 March 2017
©
Springer Science+Business Media New York 2017
Abstract A series of 2-((1-substituted-1H-1,2,3-triazol-4-
yl)-1-naphthaldehydes was prepared by the propargylation
of 2-hydroxynaphthaldehyde followed by Copper(I)-cata-
lyzed azide-alkyne cycloaddition with various organic
azides. 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthal-
dehyde analogues were transformed to corresponding
oxime derivatives upon grinding with hydroxylamine
hydrochloride under solvent free conditions. All the syn-
thesized compounds were characterized by various analy-
tical and spectral techniques and screened in vitro for
antimicrobial activity. The activity data revealed that most
of the compounds exhibited good to significant activities.
Compounds 4c and 5c exhibited very good and broad
spectrum activity towards all the tested bacterial strains.
Further, to understand the binding interactions, 4c and 5c
were docked into the active sites of E. coli topoisomerase II
DNA gyrase.
Introduction
Five-membered heterocyclic compounds occupy a sig-
nificant place among several classes of organic compounds
owing to their diverse biological activities (Joule and Mills
2000; Saracoglu 2007). Among a wide variety of pharma-
ceutically important heterocyclic compounds, 1,2,3-triazole
moiety has been extensively studied as an promising drug
candidate with antimicrobial (Abdel-Wahab et al. 2012;
Banday et al. 2012), anticancer (Ying et al. 2015; Xu et al.
2016), antiprotozoal (Bakunov et al. 2010), antitubercular
(Keri et al. 2015), anti-HIV potential (Rai et al. 2014) etc.
Ever since the development of a Copper(I)-catalyzed variant
of Huisgen thermal azide-alkyne cycloaddition yielding 1,4-
disubstituted 1,2,3-triazoles (Huisgen 1984; Tornoe et al.
2002; Rostovtsev et al. 2002), this moiety has attracted
increased attention not only from organic chemists but also
of medicinal chemists for the development of novel libraries
of biologically active molecules. This so called “click”
reaction has numerous advantages over Huisgen thermal
cycloaddition such as high selectivity, better yield, and
accelerated rate of the reaction.
●
●
Keywords 1,2,3-Triazoles Click Chemistry Green
●
●
chemistry Homogenous catalysis Molecular modeling
Oximes are the important class of organic compounds,
which are highly crystalline, stable and are used for the
purification, protection, and characterization of carbonyl
compounds (Greene et al. 1999). These are broadly used as
intermediates for the preparation of amides (Kleeman et al.
*
Kashmiri Lal
klal_iitd@yahoo.com
1
999), nitriles (Chakravarti et al. 2014), nitrones (Kirilmis
1
2
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar, Haryana 125001, India
et al. 2009) nitrile oxides (Xu et al. 2010; Donaruma and
Helst 1960), hydroximinoyl chlorides, amines (Dewan et al.
2
nitro compounds (Liu et al. 1980). Further, compounds
containing oxime moiety are known to possess wide range
of bioactivities (Chiang 1971) such as anticancer (Negi
et al. 1996), antiallergic (Kataoka et al. 2002), antimicrobial
Department of Pharmaceutical Sciences, Guru Jambheshwar
University of Science and Technology, Hisar, Haryana 125001,
India
006), chiral α-sulfinyloximes (Smith and Gloyer 1975) and
3
Department of Bio and Nanotechnology, Guru Jambheshwar
University of Science and Technology, Hisar, Haryana 125001,
India

Med Chem Res
(
Hajipour and Mahboubghah 1998), antidotal (Jokanovic
silica gel plates (SIL G/UV254, ALUGRAM) and visua-
lized under Ultraviolet lamp. Starting materials were used
without further purification.
and Stojiljkovic 2006), antifungal (Dave and Forshar 1996),
herbicidal activity (Song et al. 2005), antiepileptic (Hainzl
et al. 2002), anti-inflammatory (Chen et al. 2006), etc.
Oximes are easily accessed via reaction of carbonyl com-
pounds with hydroxylamine hydrochloride in refluxing
alcohol using pyridine (Kizil and Murphy 1997; Hwu et al.
Procedure for the synthesis of 2-(prop-2-yn-1-yloxy)-1-
naphthaldehyde (2)
1
999). However, this method is associated with many
To a mixture of 2-hydroxy-1-naphthaldhyde (1.0 mmol) and
anhydrous potassium carbonate (1.5 mmol) in dimethy-
formamide (DMF) (10 mL), propargyl bromide (80% in
toluene, 1.5 mmol) was added slowly at 0 °C and stirred for
8 h. After the completion of the reaction as monitored by
TLC, ice cold water was added to it. The solid residue thus
obtained was filtered and crystallized from chloroform-
hexane to yield the desired alkyne (2).
drawbacks like long reaction time, tedious work up, toxicity
of pyridine, low product yields, and environmental pollu-
tion by the use of organic solvents, etc. The synthesis of
oximes has also been reported under solvent free conditions
by simply grinding aldehydes with hydroxylamine hydro-
chloride at room temperature without using any solvent
(
Saikia et al. 2011; Damljanovic et al. 2006). This method
can circumvent above-mentioned problems and has attrac-
ted attention of the researchers interested in green chemistry
2-(Prop-2-yn-1-yloxy)-1-naphthaldehyde (2)
(
Tanaka and Toda 2000).
Therefore, keeping in view of the pharmacological
importance of 1,2,3-triazoles and oximes and in continua-
tion of our interest in the synthesis of biologically active
Light-yellow solid, 79% yield, mp: 94–96 °C. IR (KBr,
νmax/cm ): 3255 (C–H, alkyne), 2978, 2871, 2806 (C–H
str, CHO), 2118 (alkyne), 1654 (C=O str), 1623, 1458,
–
1
1
,2,3-triazoles (Lal et al. 2014, 2015; Kaushik et al. 2014),
1437, 1365, 1268, 1211 (C–O str), 1149 (C–O str), 1072,
1
it was thought worthwhile to synthesize some 1,2,3-triazole-
oximes hybrids via molecular hybridization approach which
allows the combination of two or more pharmacophores
with possible enhanced biological potential (Tietze et al.
1054, 1025, 806. H NMR (CDCl , 400 MHz): δ 2.60 (t,
3
1H, J = 2.4 Hz, CH), 4.95 (d, 2H, J = 2.4 Hz, OCH ), 7.39
2
(d, J = 9.2 Hz, 1H, CH ), 7.46–7.49 (m, 1H, CH ),
Ar
Ar
7.63–7.65 (m, 1H, CH ), 7.80 (d, J = 8.0 Hz, 1H, CH ),
Ar
Ar
2
003). Herein, we report the efficient synthesis and anti-
microbial evaluation of 2-((1-substituted-1H-1,2,3-triazol-
-yl)-1-naphthaldehydes (4a–4h) and their oxime deriva-
8.08 (d, J = 9.2 Hz, 1H, CH ), 9.30 (d, J = 8.0 Hz, 1H,
Ar
3
1
CH ), 10.92 (s, 1H, CHO). C NMR (CDCl , 100 MHz):
Ar
3
4
δ 191.94 (CHO), 161.88 (C ), 137.26 (C ), 131.45 (C ),
Ar Ar Ar
tives (5a–5h).
129.89 (C ), 129.15 (C ), 128.25 (C ), 125.22 (C ),
Ar Ar Ar Ar
1
5
25.13 (C ), 118.09 (C ), 114.04 (C ), 77.69, 76.80,
Ar Ar Ar
7.43 (OCH2).
Materials and methods
Chemistry
General procedure for synthesis of 1,4-disubtituted 1,2,3-
triazoles (4a–4e)
Melting points (°C) of all the synthesized compounds were
determined by using electrothermal melting apparatus and
are uncorrected. The infrared (IR) spectra were recorded in
KBr on SHIMAZDU IR AFFINITY-I FTIR spectro-
A mixture of substituted benzyl bromide (3, 1.0 mmol),
sodium azide (3.0 mmol), alkyne (2, 1.0 mmol), copper
sulfate pentahydrate (10 mol %), and sodium ascorbate (20
mol%) in DMF :water (1:1) was stirred with the aid of a
magnetic stirrer for 6–10 h at room temperature. Then the
reaction mixture was poured in to ice cold water while
stirring. The solid product thus formed was filtered, washed
with aqueous ammonium chloride: ammonia (9:1) solution
followed by water and recrystallized from ethyl acetate-
hexane to give the 1,4-disubstituted 1,2,3-triazoles (4a–4e).
1
photometer. The H nuclear magnetic resonance (NMR)
1
3
and C NMR spectra were recorded on BrukerAvance III
00 nano bay in CDCl3 using tetramethysilane as an
4
internal standard at 400 and 100 MHz, respectively. Che-
mical shift are reported in δ (ppm) and coupling constants
are given in Hz. Mass spectra (MS) of all the synthesized
compounds were recorded on waters 2618 EQD, ESI
instrument. Elemental analysis of the synthesized com-
pounds were performed on Thermo Scientific FLASH-2000
CHN analyzer. The results for C, H, and N were found to be
within ± 0.4% of the theoretical values. Monitoring of
reaction progress and the purity of reported compounds was
checked by thin-layer chromatography (TLC) on readymade
2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde (4a)
White solid, 87% yield, mp: 96–98 °C. IR (KBr,
–
1
νmax/cm ): 3143 (C–H str, triazole), 3106, 2942, 2882,
2803 (C–H str, CHO), 1655 (C=O str), 1517, 1242 (C–O

Med Chem Res
1
+
str), 1189, 1154 (C–O str), 1084, 1048, 864, 819, 714. H
NMR (CDCl , 400 MHz): δ 5.48 (s, 2H, NCH ), 5.57 (s,
MS (m/z) 384.11 (M + Na) . Anal. Calcd for
C H FN O : C, 69.80; H, 4.46; N, 11.63. Found: C,
3
2
21 16
3 2
2
H, OCH ), 7.28–7.30 (m, 2H, CH ), 7.38–7.49 (m, 5H,
69.93; H, 4.32; N, 11.73.
2
Ar
CH ), 7.59 (s, 1H, triazolyl–H), 7.62–766 (m, 1H, CH ),
Ar
Ar
7
.80 (d, J = 8.4 Hz, 1H, CH ), 8.08 (d, J = 9.2 Hz, 1H,
2-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde (4d)
Ar
CH ), 9.26 (d, J = 8.4 Hz, 1H, CH ), 10.86 (s, 1H, CHO).
Ar
Ar
1
3
C NMR (CDCl , 100 MHz): δ 191.81 (CHO), 162.12
3
(
(
(
C ), 137.57 (C–4), 129.92 (C ), 129.24 (C ), 128.97
Light-yellow solid, 85% yield, mp: 110–112 °C. IR (KBr,
νmax/cm ): 3145 (C–H str, triazole), 3109, 2947, 2882,
2801 (C–H str, CHO), 1657 (C=O str), 1590, 1511, 1436,
Ar
Ar
Ar
–
1
C ), 128.27 (C ), 128.11 (C ), 125.09 (C ), 124.96
Ar
Ar
Ar
Ar
C–5), 113.99 (C ), 63.57 (OCH ), 54.43 (NCH ). MS (m/
Ar
2
2
+
z) 366.12 (M + Na) . Anal. Calcd for C H N O : C,
7
1345, 1270, 1246 (C–O str), 1152, 1120 (C–O str), 1057,
2
1 17 3 2
1
3.45; H, 4.99; N, 12.24. Found: C, 73.53; H, 4.82; N,
821, 756. H NMR (CDCl , 400 MHz): δ 5.48 (s, 2H,
3
1
2.39.
NCH ), 5.51 (s, 2H, OCH ), 7.15 (d, J = 8.4 Hz, 2H,
2
2
CH ), 7.44–7.52 (m, 3H, CHAr+triazolyl-H), 7.61–7.66
Ar
2
-((1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
(m, 3H, CH ), 7.80 (d, J = 8.0 Hz, 1H, CH ), 8.07 (d, J =
Ar
Ar
naphthaldehyde (4b)
9.2 Hz, 1H, CH ), 9.25 (d, J = 8.8 Hz, 1H, CH ), 10.87
Ar Ar
1
3
(
s, 1H, CHO). C NMR (CDCl , 100 MHz): δ 191.78
3
Light-yellow solid, 85% yield, mp: 116–118 °C. IR (KBr,
νmax/cm ): 3145 (C–H str, triazole), 3109, 2930, 2874,
(CHO), 162.49 (C ), 137.58 (C–4), 133.27 (C ), 132.42
Ar Ar
(C ), 131.46 (C ), 129.96 (C ), 129.68 (C ), 128.94
Ar Ar Ar Ar
–
1
2
1
8
809 (C–H str, CHO), 1656 (C=O str), 1515, 1464, 1438,
(C ), 128.29 (C ), 125.14 (C ), 124.96 (C–5), 123.17
Ar Ar Ar
349, 1271, 1252 (C–O str), 1156, 1122 (C–O str), 1086,
(C ), 114.00 (C ), 63.59 (OCH ), 53.68 (NCH ). MS (m/
Ar Ar 2 2
1
79
+
81
+
07, 752, 714. H NMR (CDCl , 400 MHz): δ 5.51 (s, 2H,
z) 444.04 [(M+Na) ( Br)] ,446.98 [(M+Na) ( Br)] .
3
NCH ), 5.67 (s, 2H, OCH ), 7.40 (d, J = 8.8 Hz, 2H,
Anal. Calcd for C H BrN O : C, 59.73; H, 3.82; N, 9.95.
2
2
21 17
3 2
CH ), 7.45–7.48 (m, 2H, CH ), 7.62–7.66 (m, 1H, CH ),
Found: C, 59.67; H, 3.99; N, 9.81.
Ar
Ar
Ar
7
8
9
.68 (s, 1H, triazolyl–H), 7.80 (d, J = 8.0 Hz, 1H, CHAr),
.08 (d, J = 9.2 Hz, 1H, CH ), 8.19–8.23 (m, 2H, CH ),
2-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde (4e)
Ar
Ar
1
3
.22 (d, J = 8.4 Hz, 1H, CH ), 10.86 (s, 1H, CHO).
C
Ar
NMR (CDCl , 100 MHz): δ 191.72 (CHO), 162.34 (C ),
3
Ar
1
1
1
1
5
48.17 (C ), 144.24 (C ), 141.24 (C ), 137.61 (C–4),
White solid, 89% yield, mp: 98–100 °C. IR (KBr, νmax/
cm ): 3151 (C–H str, triazole), 3098, 2944, 2883, 2806
Ar
Ar
Ar
–
1
31.42 (C ), 130.02 (C ), 128.98 (C ), 128.60 (C ),
Ar
Ar
Ar
Ar
28.31 (C ), 125.24 (C ), 124.90 (C ), 124.39 (C ),
(C–H str, CHO), 1665 (C=O str), 1513, 1266, 1248 (C–O
Ar
Ar
Ar
Ar
1
23.11 (C–5), 117.62 (C ), 114.00 (C ), 63.56 (OCH ),
str), 1152, 1123 (C–O str), 1062, 1024, 816, 751. H NMR
Ar
Ar
2
+
3.28 (NCH ). MS (m/z) 411.12 (M + Na) . Anal. Calcd
(CDCl , 400 MHz): δ 2.37 (s, 3H), 5.47 (s, 2H, NCH ),
2
3
2
for C H N O : C, 64.94; H, 4.15; N, 14.43. Found: C,
5.52 (s, 2H, OCH ), 7.19–7.24 (m, 4H, CH ), 7.44–7.49
2 Ar
2
1
16
4
4
6
4.79; H, 4.02; N, 14.55.
(m, 2H, CH ), 7.57 (s, 1H, triazolyl–H), 7.62–7.66 (m, 1H,
Ar
CH ), 7.80 (d, J = 8.0 Hz, 1H, CH ), 8.07 (d, J = 9.2 Hz,
Ar
Ar
2
-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
1H, CH ), 9.26 (d, J = 8.8 Hz, 1H, CH ), 10.86 (s, 1H,
CHO). C NMR (CDCl , 100 MHz): δ 191.85 (CHO),
3
Ar Ar
1
3
naphthaldehyde (4c)
1
62.61 (C ), 138.93 (C ), 137.56 (C–4), 131.48 (C ),
Ar Ar Ar
White solid, 79% yield, mp: 94–96 °C. IR (KBr, νmax/
cm ): 3147 (C–H str, triazole), 3081, 2942, 2880, 2818
131.20 (C ), 129.90 (C ), 128.91 (C ), 128.27 (C ),
Ar Ar Ar Ar
128.18 (C ), 125.07 (C ), 124.98 (C–5), 117.43(C ),
Ar Ar Ar
–
1
(
(
7
C–H str, CHO), 1671 (C=O str), 1610, 1513, 1430, 1244
114.01 (C ), 63.63 (OCH ), 53.22 (NCH ), 21.16 (CH ).
Ar 2 2 3
+
C–O str), 1220, 1151, 1109 (C–O str), 1043, 1021, 812,
MS (m/z) 380.12 (M+Na) . Anal. Calcd for C H N O :
22 19 3 2
1
55. H NMR (CDCl , 400 MHz): δ 5.48 (s, 2H, NCH ),
C, 73.45; H, 4.99; N, 12.24. Found: C, 73.62; H, 4.81; N,
12.39.
3
2
5
.53 (s, 2H, OCH ), 7.05–7.10 (m, 2H, CH ), 7.26–7.30
2
Ar
(
m, 2H, CH ), 7.44–7.48 (m, 2H, CH ), 7.59 (s, 1H,
Ar Ar
triazolyl–H), 7.62–7.66 (m, 1H, CH ), 7.80 (d, J = 8.0 Hz,
General procedure for the synthesis of 1,4-disubtituted
Ar
1
H, CH ), 8.07 (d, J = 9.2 Hz, 1H, CH ), 9.23 (d, J = 8.8
1,2,3-triazoles (4f–4h)
Ar
Ar
1
3
Hz, 1H, CH ), 10.86 (s, 1H, CHO). C NMR (CDCl3,
Ar
1
1
1
1
00 MHz): δ 191.80 (CHO), 162.53 (C ), 137.59 (C–4),
A mixture of substituted phenyl azide 3f–3h (1.0 mmol),
alkyne 2 (1.0 mmol) in DMF/water (1:1), copper sulfate
pentahydrate (10 mol%) and sodium ascorbate (20 mol %)
was stirred for 6 h to 10 h at room temperature. The progress
Ar
31.45 (C ), 130.04 (C ), 129.95 (C ), 128.92 (C ),
Ar
Ar
Ar
Ar
28.29 (C ), 125.12 (C ), 124.94 (C–5), 116.36 (C ),
Ar
Ar
Ar
16.15 (C ), 113.99 (C ), 63.56 (OCH ), 53.28 (NCH ).
Ar
Ar
2
2

Med Chem Res
1
of the reaction was monitored by TLC and after completion
of the reaction; the reaction mixture was diluted with ice
cold water (30 mL). The solid residues were filtered,
washed with aqueous ammonium chloride:ammonia solu-
tion (9:1) followed by water and recrystallized with ethyl
acetate:hexane to get the desired 1,2,3-triazoles derivatives
(C–O str), 1180, 1156 (C–O str), 1042, 816, 644. H NMR
(CDCl , 400 MHz): δ 5.59 (s, 2H, OCH ), 7.45–7.53 (m,
1H, CH ), 7.53 (s, 1H, triazolyl–H), 7.64–7.71 (m, 5H,
CH ), 7.82 (d, J = 8.0 Hz, 1H, CH ), 8.11 (d, J = 8.8 Hz,
2H, CH ), 9.26 (d, J = 8.8 Hz, 1H, CH ), 10.96 (s, 1H,
3
2
Ar
Ar
Ar
Ar
1
Ar
3
CHO). C NMR (CDCl , 100 MHz): δ 191.68 (CHO),
3
(
4f–4h).
162.38 (C ), 137.65 (C–4), 133.03 (C ), 130.02 (C ),
Ar
Ar
Ar
1
29.00 (C ), 128.31 (C ), 125.19 (C ), 124.97 (C–5),
Ar Ar Ar
2
-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
122.04 (C ), 117.52 (C ), 113.79 (C ), 63.44 (OCH ).
Ar Ar Ar 2
7
9
+
naphthaldehyde (4f)
MS (m/z) 430.04 [(M+Na) ( Br)] ,432.04 [(M+Na)
8
1
+
(
Br)] . Anal. Calcd for C H ClN O : C, 58.84; H, 3.46;
20 14 3 2
Yellow solid, 82% yield, mp: 110–112 °C. IR (KBr, νmax/
N, 10.29. Found: C, 58.99; H, 3.59; N, 10.46.
–
1
cm ): 3123 (C–H str, triazole), 3048, 2978, 2878, 2814
C–H str, CHO), 1660 (C=O str), 1596, 1342, 1244 (C–O
(
General procedure for the synthesis of oximes (5a–5h)
1
str), 1170, 1136 (C–O str), 1046, 854, 728. H NMR
(
3
1
CDCl , 400 MHz): δ 5.63 (s, 2H, OCH ), 7.47–7.53 (m,
Triazole derivatives (4a–4h) (1.0 mmol), hydroxylamine
hydrochloride (1.2 mmol) and sodium hydroxide (1.2
mmol) were grinded for 1–2 h using mortar and pestle under
solvent free conditions. Thereafter, the reaction mixture was
left overnight, washed with water to remove inorganic salt
and recrystallized with ethyl acetate-hexane to yield the
corresponding oxime derivatives (5a–5h).
3
2
H, CH ), 7.65–7.69 (m, 1H, CH ), 7.83 (d, J = 8.0 Hz,
Ar Ar
H, CH ), 8.03 (d, J = 9.2 Hz, 2H, CH ), 8.13 (d, J = 9.2
Ar
Ar
Hz, 1H, CH ), 8.25 (s, 1H, triazolyl–H), 8.46 (d, J = 8.8
Hz, 2H, CH ), 9.26 (d, J = 8.0 Hz, 1H, CH ), 10.98 (s,
1
1
1
1
1
Ar
Ar
3
Ar
1
H, CHO). C NMR (CDCl , 100 MHz): δ 191.86 (CHO),
3
62.68 (C ), 137.64 (C–4), 135.88 (C ), 134.98 (C ),
Ar
Ar
Ar
32.56 (C ), 130.65 (C ), 130.45 (C ), 129.09 (C ),
Ar
Ar
Ar
Ar
28.62 (C ), 125.79 (C ), 124.97 (C–5), 122.42 (C ),
2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde oxime (5a)
Ar
Ar
Ar
+
14.28 (C ), 63.87 (OCH ). MS (m/z) 397.10 (M+Na) .
Ar
2
Anal. Calcd for C H N O : C, 64.17; H, 3.77; N, 14.97.
2
0 14 4 4
Found: C, 64.29; H, 3.91; N, 14.85.
White solid, 86% yield, mp: 138–140 °C. IR (KBr, νmax/
–
1
cm ): 3169, 3147 (C–H str, triazole), 3065, 2997, 1624
(C=N), 1508, 1458, 1436, 1315, 1249 (C–O str), 1180,
2
-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
1
naphthaldehyde (4g)
1146, 1126 (C–O str), 1060, 965, 923, 804, 732, 629. H
NMR (CDCl , 400 MHz): δ 5.39 (s, 2H, OCH ), 5.52 (s,
3
2
Light-pink solid, 92% yield, mp: 178–180 °C. IR (KBr,
2H, NCH ), 7.25–7.27 (m, 2H, CH ), 7.34–7.41 (m, 5H,
2 Ar
–
1
νmax/cm ): 3124 (C–H str, triazole), 3043, 2978, 2878,
804 (C–H str, CHO), 1667 (C=O str), 1502, 1414, 1244
CH +CH), 7.49–7.53 (m, 1H, CH ), 7.61 (s, 1H,
Ar Ar
2
triazolyl–H), 7.77 (d, J = 7.6 Hz, 1H, CH ), 7.82 (d, J =
Ar
1
(
C–O str), 1180, 1157 (C–O str), 1054, 817, 643. H NMR
8.8 Hz, 1H, CH ), 8.67 (d, J = 8.8 Hz, 1H, CH ), 8.82
Ar
1
Ar
3
(
CDCl , 400 MHz): δ 5.59 (s, 2H, OCH ), 7.45–7.55 (m,
(bs, NOH, 1H). C NMR (CDCl , 100 MHz): δ 155.53
3
2
3
3
H, CH ), 7.51 (s, 1H, triazolyl–H), 7.63–7.73 (m, 3H,
(C ), 147.70(C=N), 144.29 (C–4), 134.40 (C ), 132.13
Ar
Ar
Ar
CH ), 7.72 (d, J = 8.0 Hz, 1H, CH ), 8.11 (d, J = 9.2 Hz,
(C ), 129.52 (C ), 129.16 (C ), 128.82 (C ), 128.38
Ar Ar Ar Ar
Ar
Ar
2
H, CH ), 9.26 (d, J = 8.4 Hz, 1H, CH ), 10.96 (s, 1H,
(C ), 128.08 (C ), 127.87 (C ), 125.66 (C ), 124.43
Ar Ar Ar Ar
Ar
1
Ar
3
CHO). C NMR (CDCl , 100 MHz): δ 191.70 (CHO),
(C–5), 122.90 (C ), 114.54 (C ), 63.76 (OCH ), 54.28
Ar Ar 2
3
+
1
1
1
1
62.39 (C ), 137.67 (C–4), 135.31 (C ), 134.96 (C ),
(NCH ). MS (m/z) 381.13 (M+Na) . Anal. Calcd for
Ar
Ar
Ar
2
31.51 (C ), 130.05 (C ), 130.02 (C ), 128.99 (C ),
C H N O : C, 70.38; H, 5.06; N, 15.63. Found: C, 70.51;
Ar
Ar
Ar
Ar
21 18 4 2
28.32 (C ), 125.19 (C ), 124.96 (C–5), 121.82 (C ),
H, 5.29; N, 15.47.
Ar
Ar
Ar
+
13.78 (C ), 63.43 (OCH ). MS (m/z) 386.07 (M+Na) .
Ar
2
Anal. Calcd for C H ClN O : C, 66.03; H, 3.88; N,
2-((1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde oxime (5b)
2
0
14
3 2
1
1.55. Found: C, 66.19; H, 3.79; N, 11.38.
2
-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
White solid, 78% yield, mp: 162–164 °C. IR (KBr, νmax/
–
1
naphthaldehyde (4h)
cm ): 3185, 3146 (C–H str, triazole), 3074, 2986, 1624
C=N), 1522, 1345, 1250 (C–O str), 1160, 1136, 1111
(
1
Light-pink solid, 93% yield, mp: 184–186 °C. IR (KBr,
(C–O str), 1060, 959, 814, 636. H NMR (DMSO–d , 400
6
–
1
νmax/cm ): 3124 (C–H str, triazole), 3048, 2986, 2878,
8803 (C–H str, CHO), 1669 (C=O str), 1514, 1268, 1244
MHz): δ 5.42 (s, 2H, OCH ), 5.81 (s, 2H, NCH ),
2
2
2
7.41–7.48 (m, 3H, CH ), 7.54–7.56 (m, 1H, CH ), 7.67
Ar Ar

Med Chem Res
(
8
d, J = 9.2 Hz, 1H, CH ), 7.90 (d, J = 8.0 Hz, 1H, CH ),
57.68; H, 3.92; N, 12.81. Found: C, 57.51; H, 3.76; N,
12.92.
Ar
Ar
.00 (d, J = 9.2 Hz, 1H, CH ), 8.18 (d, J = 8.8 Hz, 2H,
Ar
CH ), 8.37 (s, 1H, triazolyl–H), 8.62 (s, 1H, CH), 8.85 (d,
Ar
1
3
J = 8.4 Hz, 1H, CH ), 11.33 (bs, NOH, 1H). C NMR
2-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde oxime (5e)
Ar
(
DMSO–d , 100 MHz): δ 155.09 (C ), 147.17 (C=N),
6 Ar
1
1
1
1
45.31 (C ), 143.39 (C–4), 142.98 (C ), 131.40 (C ),
Ar Ar Ar
30.73 (C ), 129.04 (C ), 128.82 (C ), 128.35 (C ),
White solid, 84% yield, mp: 108–110 °C. IR (KBr, νmax/
Ar
Ar
Ar
Ar
–
1
27.51 (C ), 125.63 (C ), 125.23 (C ), 124.15 (C–5),
cm ): 3170, 3108 (C–H str, triazole), 3056, 2920, 1622
(C=N), 1591, 1514, 1458, 1436, 1337, 1249 (C–O str),
Ar
Ar
Ar
23.83 (C ), 114.63 (C ), 62.76 (OCH ), 51.89 (NCH ).
Ar
Ar
2
2
+
1
MS (m/z) 426.15 (M+Na) . Anal. Calcd for C H N O :
1183, 1125 (C–O str), 1049, 1021, 968, 812, 746, 627. H
2
1 17 5 4
C, 62.53; H, 4.25; N, 17.36. Found: C, 62.71; H, 4.39; N,
NMR (CDCl , 400 MHz): δ 2.34 (s, 3H, CH ), 5.43 (s, 2H,
3
3
1
7.25.
OCH ), 5.51 (s, 2H, NCH ), 7.13–7.28 (m, 5H, CH +CH),
2 2 Ar
7
.39–7.48 (m, 2H, CH ), 7.55–7.56 (m, 1H, CH ), 7.69
Ar Ar
(
(
s, 1H, triazolyl–H), 7.78 (d, J = 7.6 Hz, 1H, CH ), 7.84
Ar
2
-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
d, J = 9.2 Hz, 1H, CH ), 8.75 (d, J = 8.4 Hz, 1H, CH ),
Ar
1
Ar
naphthaldehyde oxime (5c)
3
8
1
1
1
1
5
.81 (bs, NOH, 1H). C NMR (CDCl , 100 MHz): δ
3
55.46 (C=N), 145.78 (C=N), 143.88 (C–4), 132.03 (CAr),
White solid, 82% yield, mp: 148–150 °C. IR (KBr, νmax/
cm ): 3167, 3143 (C–H str, triazole), 3072, 1608 (C=N),
31.36 (C ), 129.84 (C ), 129.80 (C ), 129.19 (C ),
–
1
Ar
Ar
Ar
Ar
28.37 (C ), 128.14 (C ), 127.81 (C ), 125.63 (C ),
Ar
Ar
Ar
Ar
1
513, 1311, 1250 (C–O str), 1166, 1134 (C–O str), 1057,
24.39 (C–5), 114.57 (C ), 113.75 (C ), 63.76 (OCH ),
1
Ar
Ar
2
1
022, 967, 808, 711, 748, 538. H NMR (CDCl , 400
3
+
4.14 (NCH ), 21.14 (CH ). MS (m/z) 395.14 (M+Na) .
2
3
MHz): δ 5.41 (s, 2H, OCH ), 5.52 (s, 2H, NCH ),
7
7
2
2
Anal. Calcd for C H N O : C, 70.95; H, 5.41; N, 15.04.
Found: C, 70.71; H, 5.28; N, 15.26.
2
2 20 4 2
.04–7.08 (m, 2H, CH ), 7.25–7.28 (m, 3H, CH ),
Ar Ar
.39–7.44 (m, 2H, CH ), 7.54–7.57 (m, 2H, CH ,
Ar
Ar
triazolyl–H), 7.80 (d, J = 7.6 Hz, 1H, CH ), 7.87 (d, J =
Ar
2
-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
8
.8 Hz, 1H, CH ), 8.81 (d, J = 8.8 Hz, 1H, CH ), 8.83
Ar Ar
1
naphthaldehyde oxime (5f)
3
(
(
(
(
(
(
bs, NOH, 1H). C NMR (CDCl , 100 MHz): δ 162.44
C ), 148.67 (C=N), 144.68 (C–4), 142.54 (C ), 132.36
C ), 130.06 (C ), 129.97 (C ), 129.54 (C ), 128.41
C ), 127.99 (C ), 125.47 (C ), 124.90 (C ), 124.58
C–5), 123.11 (C ), 116.25 (C ), 116.03 (C ), 63.58
OCH ), 53.48 (NCH ). MS (m/z) 399.11 (M+Na) . Anal.
3
Ar
Ar
Light-yellow solid, 76% yield, mp: 106–108°C. IR (KBr,
νmax/cm ): 3149, 3142 (C–H str, triazole), 3075, 2979,
Ar
Ar
Ar
Ar
–1
Ar
Ar
Ar
Ar
1618 (C=N), 1516, 1404, 1333, 1248 (C–O str), 1112
Ar
Ar
Ar
1
(C–O str), 1072, 1018, 972, 822, 725, 643. H NMR
+
2
2
(DMSO-d , 400 MHz): δ 5.49 (s, 2H, OCH ), 7.44–7.46
6
2
Calcd for C H FN O : C, 67.01; H, 4.55; N, 14.89.
2
1
17
4 2
(m, 1H, CH ), 7.54–7.57 (m, 1H, CH ), 7.69–7.78 (m,
Ar Ar
Found: C, 67.24; H, 4.71; N, 14.71.
3H, CH ), 7.82 (d, J = 8.4 Hz, 1H, CH ), 7.98 (d, J = 8.8
Ar Ar
Hz, 2H, CH ), 8.13 (d, J = 9.2 Hz, 1H, CH ), 8.69 (s, 1H,
Ar
Ar
2
-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
triazolyl–H), 8.86 (d, J = 8.4 Hz, 1H, CH ), 9.23 (s, 1H,
Ar
1
3
naphthaldehyde oxime (5d)
CH), 11.35 (bs, 1H, NOH). C NMR (DMSO-d , 100
6
MHz): δ 155.19(C ), 145.51 (C=N), 143.76 (C–4), 135.70
Ar
Offwhite solid, 81% yield, mp: 164–166 °C. IR (KBr, νmax/
(C ), 134.65 (C ), 132.45 (C ), 131.88 (C ), 129.89
(C ), 129.22 (C ), 128.87 (C ), 127.65 (C ), 125.98
Ar Ar Ar Ar
(C ), 124.43 (C–5), 123.67 (C ), 121.78 (C ), 115.34
Ar Ar Ar
Ar
Ar
Ar
Ar
–
1
cm ): 3176, 3168 (C–H str, triazole), 3074, 2986, 1624
C=N), 1590, 1508, 1250 (C–O str), 1164, 1138 (C–O str),
(
1
1
054, 1010, 928, 809, 632. H NMR (CDCl , 400 MHz): δ
(C ), 114.56 (C ), 63.51 (OCH ). MS (m/z) 412.13 (M
Ar Ar 2
3
+
5
.41 (s, 2H, OCH ), 5.51 (s, 2H, NCH ), 7.14 (d, J = 8.4
+Na) . Anal. Calcd for C H N O : C, 61.69; H, 3.88; N,
2
2
20 15 5 4
Hz, 2H, CH ), 7.39–7.51 (m, 6H, CH +CH), 7.56 (s, 1H,
17.99. Found: C, 61.84; H, 3.65; N, 17.71.
Ar
Ar
triazolyl–H), 7.81 (d, J = 7.6 Hz, 1H, CH ), 7.88 (d, J =
Ar
8
1
1
1
1
1
5
.8 Hz, 1H, CH ), 8.82 (d, J = 8.4 Hz,1H, CH ), 8.86 (bs,
2-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde oxime (5g)
Ar
Ar
1
3
H, NOH). C NMR (CDCl , 100 MHz): δ 155.05 (C ),
3
Ar
47.67 (C=N), 145.48 (C ), 144.37 (C–4), 142.56 (C ),
Ar
Ar
31.23 (C ), 130.12 (C ), 129.01 (C ), 128.26 (C ),
Offwhite solid, 86% yield, mp: 156–158 °C. IR (KBr, νmax/
Ar
Ar
Ar
Ar
–
1
28.25 (C ), 127.15 (C ), 125.33 (C ), 125.12 (C ),
cm ): 3150, 3142 (C–H str, triazole), 3074, 2986, 1618
Ar
Ar
Ar
Ar
24.22 (C–5), 123.43 (C ), 114.45 (C ), 62.66 (OCH ),
(C=N), 1516, 1408, 1333, 1250 (C–O str), 1145 (C–O str),
Ar
Ar
2
7
9
+
1
1.39 (NCH ). MS (m/z) 459.09 [(M+Na) ( Br)] , 461.98
1091, 1016, 819, 732, 643. H NMR (DMSO–d , 400
2
6
8
1
+
[
(M+Na) ( Br)] . Anal. Calcd for C H ClN O : C,
MHz): δ 5.48 (s, 2H, OCH ), 7.41–7.44 (m, 1H, CH ),
2
1
17
4
2
2
Ar

Med Chem Res
7
.52–7.56 (m, 1H, CH ), 7.67–7.72 (m, 3H, CH ), 7.91
suspension of respective microorganism in sterile saline.
The inoculated test tubes were incubated at 37 ± 1°C for 24
h for bacterial strains and at 37 ± 1°C for 48 h in case of C.
albicans and at 25 ± 1 °C for 120 h in case of A. niger.
Ciprofloxacin and Fluconazole were used as standard drugs
for bacteria and fungi, respectively, and were also evaluated
under similar conditions for comparison with the synthe-
sized compounds.
Ar
Ar
(
d, J = 8.4 Hz, 1H, CH ), 7.97 (d, J = 8.8 Hz, 2H, CH ),
Ar Ar
8
8
1
.03 (d, J = 9.2 Hz, 1H, CH ), 8.68 (s, 1H, triazolyl–H),
Ar
.85 (d, J = 8.4 Hz, 1H, CH ), 9.03 (s, 1H, CH), 11.34 (bs,
Ar
1
3
H, NOH). C NMR (DMSO–d , 100 MHz): δ 155.09
6
(
(
(
(
(
C ), 145.31 (C=N), 143.86 (C–4), 135.30 (C ), 133.05
C ), 131.47 (C ), 130.78 (C ), 129.84 (C ), 129.02
C ), 128.37 (C ), 127.54 (C ), 125.64 (C ), 124.14
C–5), 123.03 (C ), 121.85 (C ), 115.06 (C ), 114.43
Ar Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
+
C ), 62.50 (OCH ). MS (m/z) 401.08 (M+Na) . Anal.
Computational studies
Ar
2
Calcd for C H ClN O : C, 63.41; H, 3.99; N, 14.79.
2
0
15
4 2
Found: C, 63.63; H, 3.75; N, 14.63.
The docking studies were performed as per the procedure
reported in the literature (Kumar et al. 2013). The crystal
structure of E. Coli topoisomerase II DNA gyrase B was
taken from the Brookhaven Protein Data Bank http://www.
rcsb.org/pdb (PDB entry: 1kzn). The two-dimensional
structures of various ligands drawn were changed into
three-dimensional before minimizing their energy (Marvin
2
-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-
naphthaldehyde oxime (5h)
Offwhite solid, 88% yield, mp: 160–162 °C. IR (KBr, νmax/
–
1
cm ): 3150, 3124 (C–H str, triazole), 3074, 2986, 1618
_
(
C=N), 1508, 1426, 1325, 1243 (C–O str), 1191, 1155
Sketch 5.0.3 copyright ©1998 2008 Chem Axon Ltd A).
1
(
C–O str), 1072, 1047, 826, 734, 643. H NMR (DMSO–d ,
Co-crystallized ligand was removed from pdb files and
protein molecule was prepared by removing solvent mole-
cules and non-complex ions using UCSF Chimera (Petter-
sen et al. 2004). Incomplete side chains were completed
using Dunbrack Rotamer library (Dunbrack 2002). Gastei-
ger charges were determined using Antechamber (Wang
et al. 2006) and the prepared file was saved as pdb format
and used for further studies. All the files were converted
into pdbqt format. Docking studies were performed on Auto
Dock Vina 1.1.2 using the center and size of grid box as
6
4
7
00 MHz): δ 5.48 (s, 1H, OCH ), 7.41–7.44 (m, 1H, CH ),
2 Ar
.52–7.56 (m, 1H, CH ), 7.64–7.72 (m, 4H, CH ), 7.81
Ar
Ar
(
d, J = 8.4 Hz, 2H, CH ), 8.03 (d, J = 9.2 Hz, 1H, CH ),
Ar Ar
8
9
.68 (s, 1H, triazolyl–H), 8.85 (d, J = 8.4 Hz, 1H, CH ),
Ar
.03 (s, 1H, CH), 11.33 (bs, 1H, NOH). C NMR (DMSO–
1
3
d , 100 MHz): δ 155.09 (C ), 145.30 (C=N), 143.88
6
Ar
(
C–4), 137.82 (C ), 135.71 (C ), 132.76 (C ), 131.47
Ar Ar Ar
(
C ), 129.76 (C ), 129.03 (C ), 128.59 (C ), 128.37
Ar Ar Ar Ar
(
C ), 127.54 (C ), 125.64 (C ), 124.88 (C ), 124.13
Ar Ar Ar Ar
(
C–5), 123.93 (C ), 122.98 (C ), 122.08 (C ), 121.42
center_x = 19.0577118729,
center_y = 29.6584661732,
Ar
Ar
Ar
(
+
C ), 115.06 (C ), 62.51 (OCH ). MS (m/z) 445.04[(M
Na) ( Br)] , 447.04 [(M+Na) ( Br)] . Anal. Calcd for
center_z = 36.0719212982 and size_x = 25.0, size_y =
25.0, size_z = 25.0. Exhaustiveness of the global search
algorithm was set to be 8. The docked poses were visualized
using Discovery studio 4 (Discovery Studio 2012) and
Pymol (PyMol 2008). The protocols used for docking were
validated by redocking co-crystalized ligand CBN into the
active site of DNA gyrase B (1KZN). These parameters
resulted in conformation of CBN similar to X-ray structure
conformation. The root-mean square deviation between the
conformations of the CBN from AutoDockVina and that
from X-ray crystal structure was <2 Å (0.5275 Å). Hence,
the used protocols were applied for docking studies of our
compounds into the active site of DNA Gyrase B. Binding
affinity of the docked compounds was calculated in kcal/
mol using scoring function of AutoDockVina.
Ar
Ar
2
81
7
9
+
+
C H BrN O : C, 56.75; H, 3.57; N, 13.24. Found: C,
5
2
0
15
4 2
6.46; H, 3.73; N, 13.38.
Pharmacology
All the synthesized 2-((1-substituted-1H-1,2,3-triazol-4-yl)-
1
(
microbial activity against two Gram-positive bacteria (Sta-
phylococcus epidermidis MTCC 6880 and Bacillus subtilis
MTCC 441) and two Gram-negative bacteria (Escherichia
coli MTCC 16521 and Pseudomonas aeruginosa MTCC
4
8
-naphthaldehydes along with their oxime derivatives
4a–4h, 5a–5h) were evaluated in vitro for their anti-
24) and two fungal strains viz. Aspergillus niger (MTCC
189) and Candida albicans (MTCC 227) following stan-
dard serial dilution method. Double strength nutrient broth
and Sabouraud dextrose broth were used as culture media
for bacteria and fungi, respectively. Dimethyl sulphoxide
Results and discussion
Chemistry
(
DMSO) was used as solvent control. The stock solutions of
the test compounds were serially diluted in test tubes con-
taining 1 mL of sterile medium to get the concentration of
The outlines for the synthesis of 2-((1-substituted-1H-1,2,3-
triazol-4-yl)-1-naphthaldehydes and their oxime derivatives
_
5
0 3.12 µg/mL and then inoculated with 100 µL of

Med Chem Res
Scheme 1 Synthesis of triazoles
(4a–4h)
2
3
6
5
2
2
6
4
2
3
6
4
2
4
2
3
6
4
2
4
2
3
6
4
2
2
2
6 4
2
6
6
4
4
(
2
5a–5h) as per literature procedure (Damljanovic et al.
006). The process employed enabled us to prepare the
2
oxime derivatives in good to high yield under solvent free
conditions, which has drawn large attention in green
chemistry methodologies.
The structures of all the newly synthesized products were
established on the basis of their elemental analysis and
spectral (FTIR, H NMR, C NMR, LCMS) data. For
6
5
2
2
6
4
2
6
4
2
6
6
4
2
1
13
3
6
4
2
2
6 4
6
4
4
example, the IR spectrum of compound 4b exhibited a
−
1
Scheme 2 Solvent free synthesis of triazole-oximes (5a–5h)
characteristic peak at 3145 cm due to =C–H stretching of
triazole ring. The signals due to C=O stretching and for
C–H stretching of aldehyde group were observed at 1656
−1
−1
−1
is presented in Scheme 1 and Scheme 2. Initially the O-
alkylation of commercially available 2-hydroxy-1-
naphthaldehyde (1) was performed with propargyl bro-
mide in presence of anhydrous K CO using DMF by
cm , 2874 cm , and 2809 cm , respectively. The pre-
−
1
−1
sence of two peaks at 1515 cm and 1349 cm indicated
1
the presence of nitro functional group. The H NMR
spectrum of compound 4b exhibited characteristic singlets
at δ 7.68 and δ 10.86 due to triazolyl and aldehydic protons,
respectively. The two singlets each integrating for protons
of two methylene groups were observed at δ 5.51 and δ 5.67
and all the aromatic protons resonated in the region δ
7.38–9.23. In the C NMR spectrum of compound 4b, the
peaks at δ 137.61 and δ 123.11 were assigned to the C-4
and C-5 carbon atoms of the triazole ring, respectively. A
peak at δ 191.72 confirmed the presence of aldehydic car-
bon atom and the signals due to methylene carbons
appeared at δ 63.56 and δ 53.28. The mass spectrum of
compound 4b displayed a peak at m/z 389.12 (M+H) ,
which is consistent with the molecular formula.
In the IR spectrum of compound 5b, the disappearance of
peak corresponding to aldehyde and the appearance of
abroad peak due to =N-OH stretching in the region 3185
2
3
reported procedure (Singh et al. 2016). The 2-O-
propargylated naphthaldehyde (2) was reacted in one-pot
multicomponent click reaction with variedly substituted
benzyl bromides (3a–3e), sodium azide in presence of
catalytic amount of copper sulfate pentahydrate and sodium
ascorbate in aqueous DMF to furnish 2-((1-substituted-1H-
1
3
1
,2,3-triazol-4-yl)-1-naphthaldehydes (4a–4e) in very high
yield. On the other hand, the compounds (4f–4h) were
prepared in good yield by reacting substituted phenyl azides
(
3f–3h) with alkyne (2) by copper (I)-catalyzed azide-
+
alkyne cyclo addition reaction. The substituted phenyl
azides were in turn prepared from corresponding substituted
aniline derivatives utilizing reported procedure (Xu et al.
2
013).
Finally, all the triazole derivatives (4a–4h) with free
−1
aldehyde group were transformed into their corresponding
oximes. The simple grinding of triazoles (4a–4h) with
hydroxylamine hydrochloride in the presence of sodium
hydroxide at room temperature yielded the expected 2-((1-
substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehyde oximes
cm showed formation of oxime. The presence of triazole
ring was confirmed by a peak at 3146 cm due to =C–H
stretching of triazole ring. The H NMR spectrum of
compound 5b in DMSO-d6 exhibited a broad singlet
−
1
1
exchange able with D O at δ 11.33, corresponding to the
2

Med Chem Res
Table 1 In vitro antibacterial
screening of compounds 4a–4h,
Entry
Compounds
R
S. epidermidis
B. subtilis
E. coli
P. aeruginosa
5
a–5h (MIC in µM/mL)
1
2
3
4
5
6
7
8
9
4a
C
6
H
5
CH
NC
4-FC
4-BrC
4-CH
4-O NC
4-ClC
4-Br-C
CH
NC
4-FC
4-BrC
4-CH
4-O NC
4-ClC
2
0.0728
0.0322
0.0346
0.0592
0.1399
0.1336
0.0344
0.0306
0.0349
0.0620
0.0286
0.0332
0.0671
0.0642
0.0661
0.0295
0.0047
0.0364
0.0644
0.0346
0.0592
0.0699
0.0668
0.0687
0.0612
0.0572
0.0620
0.0286
0.0664
0.0671
0.0321
0.0330
0.0295
0.0047
0.0364
0.0322
0.0346
0.0296
0.0699
0.0334
0.0687
0.0612
0.0349
0.0310
0.0286
0.0664
0.0671
0.0642
0.0661
0.0591
0.0047
0.0364
0.0322
0.0346
0.0296
0.0699
0.0334
0.0344
0.0306
0.0349
0.0310
0.0286
0.0664
0.0336
0.0642
0.0330
0.0148
0.0047
4b
4-O
2
6
H
4
CH
2
4c
6
H
4
CH
2
4d
6
H
4
CH
2
4e
3 6 4
C H CH
2
4f
2
6 4
H
4g
6 4
H
4h
6 4
H
5a
C
H
6 5
2
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
5b
4-O
2
6
H
4
CH
2
5c
6
H
4
CH
2
5d
6
H
4
CH
2
5e
3 6 4
C H CH
2
5f
2
6 4
H
5g
6 4
H
5h
6 4
4-BrC H
Ciprofloxacin
–
proton of hydroxyl group of oxime. Two characteristic
In case of S. epidermidis, the insertion of election with-
drawing group on benzyl enhances the activity to some
extent while electron releasing group decreases the same.
Compound 4h containing bromine atom on benzene
exhibited highest activity with MIC value 0.0306 µM/mL
among compounds (4a–4h). Among the oxime derivatives,
compound (5c) containing fluorine exhibited most potent
activity with MIC value 0.0206 µM/mL. Compounds 5c and
5h exhibited promising activity against B. subtilis with MIC
value 0.0286 and 0.0295 µM/mL, respectively. Bromo
derivative of triazole (4d) and fluoro derivative of oxime
(5c) showed good activity against E. coli with the MIC
value 0.0296 and 0.0286 µM/mL, respectively. Among all
the tested compounds (4a–4h, 5a–5h), compound 5h was
found most potent with MIC value 0.0148 µM/mL against
P. aeruginosa. On the basis of structure activity relationship
analysis, it was observed that in most of the cases com-
pounds containing electron-withdrawing substituent exhib-
ited better activity than those with electron-releasing
substituent. It was also observed that compounds 4c and 5c
containing fluorine substituent displayed good and broad
spectrum activity toward all the bacterial strains under
study.
singlets observed at δ 8.62 and δ 8.37 were assigned to –CH
1
3
of oxime and triazole functionalities, respectively. The
NMR spectrum of compound 5b displayed a peak at δ
47.17, which was assigned to –C=N of oxime moiety. The
C
1
peaks at δ 143.39 and δ 124.15 were assigned to the C-4
and C-5 carbon atoms of the triazole ring, respectively. The
mass spectrum of compound 5b showed a peak at m/z
+
4
04.14 (M+H) , which is in good agreement with the
molecular formula of the compound. Likewise, the
remaining compounds showed the expected pattern as
reported in case of 4b and 5b.
Pharmacology
Antibacterial activity
The synthesized 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-
naphthaldehydes along with their oxime derivatives (4a–4h,
5
a–5h) were screened in vitro for antibacterial activity
against two Gram-positive bacteria (Staphylococcus epi-
dermidis MTCC 6880 and Bacillus subtilis MTCC 441) and
two Gram-negative bacteria (Escherichia coli MTCC 16521
and Pseudomonas aeruginosa MTCC 424) following
standard serial dilution method (Cappucino and Sherman
Antifungal activity
1
999). Ciprofloxacin was used as standard drug and the
minimum inhibitory concentrations (MIC) in µM/mL are
listed in Table 1.
As evident from the antibacterial evaluation data most of
the synthesized compounds exhibited good to significant
activity with MIC value ranging from 0.0148 to 0.1399 µM/mL.
All the synthesized triazoles and oximes (4a–4h, 5a–5h)
were also tested in vitro for antifungal activity against two
fungal strains viz. Aspergillus niger (MTCC 8189) and
Candida albicans (MTCC 227) following standard serial
dilution method (Cappucino and Sherman 1999).

Med Chem Res
Table 2 In vitro antifungal screening of compounds 4a–4h, 5a–5h
(
MIC in µM/mL)
Entry
Compounds
R
A. niger
C. albicans
1
2
3
4
5
6
7
8
9
4a
C
6
H
5
CH
NC
4-FC
4-BrC
4-CH
4-O NC
4-ClC
4-Br-C
CH
NC
4-FC
4-BrC
4-CH
4-O NC
4-ClC
2
0.0364
0.0322
0.0346
0.0592
0.0350
0.0167
0.0344
0.0153
0.0349
0.0620
0.0332
0.0143
0.0336
0.0161
0.0165
0.0148
0.0102
0.0728
0.1287
0.0692
0.0592
0.0699
0.0668
0.0687
0.1225
0.0698
0.0310
0.0332
0.0572
0.0336
0.0321
0.0661
0.0295
0.0051
4b
4-O
2
6
H
4
CH
2
4c
6
H
4
CH
2
4d
6
H
4
CH
2
4e
3 6 4
C H CH
2
4f
2
6 4
H
4g
6 4
H
4h
6 4
H
5a
C
H
6 5
2
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
5b
4-O
2
6
H
4
CH
2
5c
6
H
4
CH
2
Fig. 1 Interactions (dotted lines) of compound 5c docked in active site
of DNA gyrase B showing hydrogen bonding (green), pi-donor
hydrogen bond (light green), hydrophobic (light pink) and electrostatic
5d
6
H
4
CH
2
5e
3 6 4
C H CH
2
5f
2
6 4
H
(yellow) interactions
5g
6 4
H
5h
6 4
4-BrC H
Fluconazole
–
Fluconazole was used as reference and MICs (MIC in µM/mL)
are presented in Table 2. The activity data revealed that
most of the compounds exhibited good to high antifungal
activity. Furthermore, most of the tested compounds dis-
played better potency against A. niger than C. albicans.
Compounds 4f, 4h, 5d, 5f, 5g, and 5h exhibited good
potency with MIC value ranging 0.0148–0.0167 µM/mL
compared to fluconazole (MIC=0.0102 µM/mL) against A.
niger. The oxime derivative with bromine group (5h) was
found to be most active and exhibited better activity among
all the synthesized compounds with MIC values in the range
0
.0148 µM/mL to 0.0295 µM/mL.
Computational studies
Fig. 2 Interactions (dotted lines) of compound 4c docked in active site
of DNA gyrase B showing hydrogen bonding (green), pi-donor
hydrogen bond (light green), hydrophobic (light pink) and electrostatic
Molecular docking study
(yellow) interactions
The E. coli DNA gyrase B enzyme has been a validated
target for the antibacterial drugs (Pokrovskaya et al. 2009;
Plech et al. 2015). Therefore, in an attempt to find out the
binding conformation of most active compound in DNA
gyrase B and to study its interactions with the active site
residues, docking simulations of compound 5c was per-
formed in the active site of DNA gyrase B. Further, to
unearth the reason behind more activity of this compound
than its aldehyde counterpart 4c, docking studies of the later
were also carried out in the same active site. Fluorine
containing compounds are known to exhibit better biolo-
gical activities than their non-fluorinated counterparts
because of good lipophilicity, bioavailability, and metabolic
stability (Purser et al. 2008). The binding interactions of
docked compounds with the E. coli DNA gyrase enzyme
are shown in Fig. 1 and Fig. 2. Compound 5c was found to
be most promising molecule among all the tested com-
pounds. Phenyl and triazole rings of the compound 5c
interacted with Asn46 by pi-donor type hydrogen bonds
while naphthyl ring showed pi-anion type electrostatic
interactions with Asp49. Further, these three rings also
exhibited pi-alkyl type hydrophobic interactions with Ile78,

Med Chem Res
Ile90, Val120, and Val167 residues. This compound also
showed pi-sigma interactions with Asn46. The binding
affinity of compound 5c was −8.4 kcal/mol.
oxime group in the molecule resulted in better anchoring of
the compound in the active site of the enzyme, which
caused more activity of compound 5c as compared to
compound 4c as proved in our wet experimentation. This
may be due to the greater molecular volume of compound
5c, which is the result of oxime incorporation. Therefore, it
can be assumed that the compounds under study inhibits the
DNA gyrase B successfully, which may be the reason
behind their antibacterial action. Surface diagram of the
enzyme along with docked conformations of both com-
pounds is depicted in Fig. 3.
On the other hand compound 4c presented hydrogen
bond interactions with Asn46. All other interactions of this
compound were similar and with same residues as that were
of compound 5c except hydrogen bonding with Val120, a
pi-sigma interaction with Asn46 and one pi-alkyl type
interaction Ile78 in case of the latter. The binding affinity of
compound 4c (−8.1 kcal/mol) was less than that of com-
pound 5c. Therefore, it can be said that introduction of
In silico absorption, distribution, metabolism, and
elimination (ADME) properties of the synthesized
compounds
To explore the drug-likeness of all the synthesized com-
pounds (4a−4h, 5a−5h), in silico study for ADME pre-
diction was performed and depicted in Table 3. In the
present study, we have calculated molecular weight (MW),
logarithm of partition coefficient (milog P), number of
hydrogen bond acceptors (n-ON), number of hydrogen
bonds donors (n-OHNH), topological polar surface area
(TPSA), number of rotatable bonds (n-ROTB) molecular
volume, and Lipinski’s rule of five using the Molinspiration
online property calculation toolkit (Molinspiration Che-
moinformatics Brastislava 2014).
All the synthesized compounds display good conforma-
tional flexibility because these are having sufficient number
of rotatable bonds (5–7). It was also observed that all the
compounds exhibits good absorption (% ABS = 68.16
Fig. 3 Surface diagram topoisomerase II DNA gyrase B along with
docked inhibitor compounds 4c and 5c
–
89.33). Absorption (% ABS) was calculated by
%
ABS = 109−(0.345 × TPSA) (Zhao et al. 2002).
Table 3 Molinspiration score
of compounds 4a–4h, 5a–5h
Entry Compounds % Absorption MW
ClogP TPSA n-ON n-OHNH n-ROTB Volume
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
4a
4b
4c
4d
4e
4f
89.33
89.33
73.52
89.33
89.33
73.52
89.33
89.33
83.97
83.97
68.16
83.97
83.97
68.16
83.97
83.97
343.39 4.24
357.41 4.69
388.38 4.20
422.28 5.05
361.38 4.40
374.36 3.88
363.80 4.60
408.25 4.73
358.40 4.87
372.43 5.32
403.40 4.83
437.30 5.68
376.39 5.03
389.37 4.51
378.82 5.23
423.27 5.36
57.02
57.02
102.85
57.02
57.02
102.85
57.02
57.02
72.54
72.54
118.37
72.54
72.54
118.37
72.54
72.54
5
5
8
5
5
8
5
5
6
6
9
6
6
9
6
6
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
6
6
7
6
6
6
5
5
6
6
7
6
6
6
5
5
309.48
326.04
332.81
327.36
314.41
316.01
306.21
310.56
321.77
338.33
345.11
339.66
326.70
328.31
318.51
322.86
4g
4h
5a
5b
5c
5d
5e
5f
0
1
2
3
4
5
6
5g
5h

Med Chem Res
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A molecule likely to be developed as an orally active drug
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lyzed azide-alkyne cycloaddition and were transformed to
their corresponding oximes under solvent free conditions.
All the synthesized compounds were tested in vitro for their
antimicrobial activity and most of the derivatives exhibited
good to high activity. Two fluorinated compounds 4c and
5
c exhibiting broad spectrum antibacterial activity were
docked into the active sites of E. Coli topoisomerase II
DNA gyrase. The various interactions of these compounds
with target enzymes indicate the good antibacterial prop-
erties of the compounds. Further, the ADME prediction of
all the synthesized compounds displayed good absorption
and predicted to have good bioavailability. The results of
present study can be utilized for the further development of
potential antimicrobial leads.
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Acknowledgements We are grateful to Central instrumentation
laboratory, Guru Jambheshwar University of Science & Technology,
Hisar for running NMR and IR spectra of the synthesized compounds.
One of the authors (PY) thanks Haryana State Council for Science &
Technology (HSCST) for providing financial support in form of Junior
Research Fellowship.
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Conflict of interest The authors declare that they have no competing
interests.
Jokanovic M, Stojiljkovic MP (2006) Current understanding of the
application of pyridinium oximes as cholinesterase reactivators in
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