Design, synthesis, antimicrobial evaluation and in silico studies of symmetrical bis (urea-1,2,3-triazole) hybrids

Article abstract of DOI:10.1007/s11164-020-04318-1

Abstract: In search of 1,2,3-triazole-based antimicrobials, some symmetrical bis(urea-1,2,3-triazole) hybrids were synthesized via clicked Huisgen cycloaddition. The structural characterization was done by different physical and spectral techniques like N

Full text of DOI:10.1007/s11164-020-04318-1

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04318-1
Design, synthesis, antimicrobial evaluation and in silico
studies of symmetrical bis (urea‑1,2,3‑triazole) hybrids
1
1
2
Nisha Poonia · Kashmiri Lal · Ashwani Kumar
Received: 11 September 2020 / Accepted: 23 October 2020
©
Springer Nature B.V. 2020
Abstract
In search of 1,2,3-triazole-based antimicrobials, some symmetrical bis(urea-1,2,3-
triazole) hybrids were synthesized via clicked Huisgen cycloaddition. The structural
characterization was done by diꢀerent physical and spectral techniques like NMR,
FTIR and HRMS. In vitro antimicrobial evaluation of all the synthesized com-
pounds was performed against three bacterial strains (Staphylococcus epidermidis,
Escherichia coli and Bacillus subtilis) and two fungal strains (Aspergillus niger
and Candida albicans). All the synthesized urea-linked bis(1,2,3-triazole) hybrids
(
4a–4o) were found to exhibit higher potency than their alkyne precursors (3a–3c).
Also, all the synthesized hybrids elicited better antifungal activity than the refer-
ence drug Fluconazole against both the fungal strains. Compound 4e and 4o were
found to be more potent toward C. albicans with lowest MIC values 0.0112 µmol/
mL and 0.0105 µmol/mL, respectively. The docking studies of compounds 4e and
4
o and their respective alkynes 3b and 3c were carried out in the active site of sterol
4-α-demethylase of C. albicans.
1
Graphic abstract
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4
-020-04318-1) contains supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(012
1
3456789)
3

N. Poonia et al.
Keywords Urea · Bis-triazoles · Antimicrobial activity · In silico studies
Introduction
The day-by-day increase in antimicrobial resistance has hampered the eꢀective treat-
ment of diꢀerent human diseases caused by various microbes. There is a need for
integral eꢀorts to develop methodologies to provide new classes of drugs with bet-
ter eꢁcacy and low toxicity because the cases of multidrug resistance among vari-
ous microorganisms toward currently available drugs continue to spread inevitably
[
1–4]. In this regard, clicked Huisgen cycloaddition chemistry has evolved as an
important strategy for rapid and selective synthesis of 1,4-disubstituted 1,2,3-tria-
zoles [5–7]. This cycloaddition has been proved to be a very useful technique in
the functional modiꢂcation of biomolecules mainly because of its high selectiv-
ity, yield and biocompatibility as well as its stability toward metabolic degradation
[
8–11]. This reaction has been studied extensively because of its number of applica-
tions counting drug discovery [12, 13], bioconjugation [14], ion recognition [15],
polymer chemistry [16], radiochemistry, etc. 1,4-Disubstituted 1,2,3-triazoles pos-
sess high dipole moment, and exhibit various interactions like Van der Waals forces,
hydrogen bonding, dipole–dipole, hydrophobic and other non-covalent interactions
with a diversiꢂed range of biomolecular targets [17]. Organic molecules containing
1
,2,3-triazole framework are reported to possess a diverse range of pharmacological
activities including anticancer [18, 19], antimicrobial [20–22], antidiabetic [23–25],
anti-inꢃammatory [26, 27], anti-oxidant [28], antiviral [29], antituberculosis [30,
3
1], etc.
Urea linkage has also been recognized as an important pharmacophore present
in a number of naturally occurring and synthetic bioactive molecules [32]. Some
symmetrical and unsymmetrical mono- and bis-amides linked with thiophene are
reported with antiproliferative activity [33]. There are various reports on urea deriv-
atives exhibiting a plethora of pharmacological activities such as antitubercular [34],
antimicrobial [35], antidiabetic [36] and anti-HIV [37]. It has been observed that
with slight structural modiꢂcations in the molecular framework around the urea
skeleton, signiꢂcant changes in the pharmacological properties of the hybrid mole-
cules are reported. Further, a synergistic improvement of the biological potential has
been achieved by the covalent attachment of combination of urea linkage with one
or more pharmacophores including aziridine, triꢃuoromethyl coumarinyl, 1,2,4-tria-
zole, 1,2,3-triazole, 4-piperazinyl quinoline [38, 39], etc.
1
,2,3-Bistriazole derivatives are of signiꢂcant importance due to the presence
of two triazole scaꢀolds which will further enhance their practical utility in the
ꢂeld of supramolecular chemistry [40, 41], medicinal chemistry [42, 43], polymer
chemistry [44], etc. The synthesis of 1,2,3-bistriazoles with diꢀerent spacers can
be achieved either by reacting diacetylenes with azides or by diazides with acety-
lenes. 1,2,3-Bistriazoles have been synthesized from dialkyne spacers linked with
1
3

Design, synthesis, antimicrobial evaluation and in silico…
ester, amide, amino acids, carbohydrates, benzothiazoles, chalcones, phenanthro-
line, pyridine, etc. with good-to-moderate antimicrobial and anticancer activities
[
45–51]. Also, some articles are available on the synthesis of biologically active
1
,2,3-bistriazoles through diazide spacers linked with ferrocene, anthracene, pyri-
dine [52–54], etc. The structures of some pharmacologically active 1,2,3-bistria-
zoles (I–VI) are shown in (Fig. 1).
Therefore, in view of the aforementioned and our interest in the development
of bioactive 1,2,3-triazole hybrids [18, 21, 25, 38, 61], we planned to synthe-
size some symmetrical bis(urea-1,2,3-triazole) hybrids with diꢀerent aliphatic
and aromatic spacers. Herein, we depict the synthesis of some new symmetrical
bis(urea-1,2,3-triazole) hybrids as antimicrobial agents from diꢀerent aliphatic
and aromatic diazides.
Fig.1 Structures of some pharmacologically important 1,2,3-bistriazoles
1
3

N. Poonia et al.
Materials and methods
General
Commercially available chemicals were used for the preparation of reactants (2a–2e)
and (3a–3c). Then, the products were synthesized and open capillaries were used for
examining their melting points, which were reported as such. After monitoring the
reaction by TLC on silica plated aluminum sheets (SIL G/UV254, ALUGRAM),
successful visualization was done under the UV chamber. Then, SHIMADZU IR
AFFINITY-I FTIR spectrophotometer was used for recording the IR spectra of the
−
1
synthesized compounds in the range of 400–4000 cm . Bruker 400 MHz spectro-
photometer was used for determining the NMR spectra of the compounds with TMS
as the internal standard. The chemical shift values and the coupling constant values
were reported in δ and Hz, respectively.
General method for synthesizing bis‑urea‑triazoles (4a–4o) Dibromides of
n-alkanes and m-xylylene (1a–1e; 1.042 mmol) were used for the synthesis of
diazides (2a–2e) by reacting with sodium azide (6.252 mmol) in dimethylforma-
mide (4 mL). The reaction mixture was allowed to stir for 8 h at 70 °C. Then, urea-
alkynes (3a–3c; 2.084 mmol) dissolved in dimethylformamide (2 mL) were trans-
ferred to the ongoing reaction. After the addition of copper sulfate (0.2084 mmol)
dissolved in water (2 mL) and sodium ascorbate, the mixture was heated at 45 °C
for 4–5 h. The mixture was ꢂltered after the successful completion of the reaction,
providing the white colored solid. Then, the obtained solid was washed with ice-
cold aqueous ammonia, water and a small amount of ethyl acetate to yield pure sym-
metrical bis(urea-1,2,3-triazole) hybrids (4a–4o).
1
,1′‑((1,1′‑(Propane‑1,3‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑ꢀuorophenyl)urea) (4a) Yield 71%; White solid; mp: 286–289 °C; IR
−1
(
(
KBr, ν /cm ): 3312 (NH str), 3128 (C–H str, triazole), 1630 (C=O str), 1515
max
1
C=C str). H NMR (400 MHz, DMSO-d ): δ 8.58 (s, 2H, 2NH), 7.99 (s, 2H, tri-
6
azolyl-2H), 7.40 (dd, J=7.7, 4.8 Hz, 4H, Ar–H), 7.06 (t, J=8.6 Hz, 4H, Ar–H),
6
.57 (broad triplet, 2H, 2NH), 4.35 (dd, J=16.4, 6.0 Hz, 8H), 2.42–2.33 (m, 2H).
1
3
C NMR (101 MHz, DMSO-d ): δ 158.57, 156.22, 155.58, 146.08, 137.18, 123.21,
6
+
1
19.81, 119.74, 115.66, 115.44, 47.06, 35.34, 30.81. HRMS: m/z (M+H) cacld.
for C H F N O : 511.2130 found: 511.2121.
2
3
25
2
10
2
1
,1′‑((1,1′‑(Propane‑1,3‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑chlorophenyl)urea) (4b) Yield 75%; White solid; mp: 262–264 °C; IR
−
1
(
KBr, ν /cm ): 3319 (NH str), 3134 (NH str), 3091 (C–H str, triazole), 1633
max
1
(
C=O str), 1598 (C=C str). H NMR (400 MHz, DMSO-d ): δ 8.72 (s, 2H, 2NH),
6
8
6
7
.00 (s, 2H, triazolyl-2H), 7.44–7.41 (m, 4H, Ar–H), 7.28–7.24 (m, 4H, Ar–H),
.64 (t, J=5.6 Hz, 2H, 2NH), 4.35 (dd, J=15.4, 6.3 Hz, 8H), 2.37 (dt, J=14.0,
1
3
.0 Hz, 2H). C NMR (101 MHz, DMSO-d ): δ 155.37, 145.94, 139.83, 128.93,
6
1
3

Design, synthesis, antimicrobial evaluation and in silico…
+
1
25.06, 123.23, 119.63, 47.06, 35.32, 30.80. HRMS: m/z (M+Na) cacld. For
C H Cl N NaO : 565.1358 found: 565.3611.
2
3
24
2
10
2
1
,1′‑((1,1′‑(Propane‑1,3‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑methoxyphenyl)urea) (4c) Yield 74%; White solid; mp: 272–274 °C; IR (KBr,
−
1
ν
/cm ): 3313 (NH str), 3133 (C–H str, triazole), 1634 (C=O str), 1578 (C=C str).
max
1
H NMR (400 MHz, DMSO-d ): δ 8.34 (s, 2H, 2NH), 7.98 (s, 1H, triazolyl-2H), 7.31–
6
7
.26 (m, 4H, Ar–H), 6.84–6.79 (m, 4H, Ar–H), 6.46 (t, J=5.6 Hz, 2H), 4.39–4.31 (m,
13
8
H), 3.69 (s, 6H, 2OCH ), 2.38 (p, J=7.1 Hz, 2H). C NMR (101 MHz, DMSO-d ):
3
6
δ 155.77, 154.50, 146.22, 133.94, 123.19, 119.96, 114.36, 55.62, 47.07, 35.35, 30.81.
+
HRMS: m/z (M+H) cacld. for C H N O : 535.2530 found: 535.2111.
25 31 10 4
1
,1′‑((1,1′‑(Butane‑1,4‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑ꢀuorophenyl)urea) (4d) Yield 77%; White solid; mp: 274–278 °C;
−
1
1
IR (KBr, ν /cm ): 3308 (NH str), 3128 (C–H str, triazole), 1633 (C=O str),
max
1
465 (C=C str). H NMR (400 MHz, DMSO-d ): δ 8.63 (s, 2H, 2NH), 7.94 (s,
6
2
H, triazolyl-2H), 7.40 (dd, J=8.6, 4.9 Hz, 4H, Ar–H), 7.06 (t, J=8.8 Hz, 4H,
1
3
Ar–H), 6.59 (t, J=5.1 Hz, 2H, 2NH), 4.38–4.30 (m, 8H), 1.77 (s, 4H). C NMR
(
101 MHz, DMSO-d ): δ 158.56, 156.20, 155.59, 145.94, 137.21, 123.04, 119.78,
6
+
1
19.70, 115.65, 115.44, 49.02, 35.33, 27.35. HRMS: m/z (M+H) cacld. for
C H F N O : 525.2287 found: 525.2884.
2
4
27
2
10
2
1
,1′‑((1,1′‑(Butane‑1,4‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑chlorophenyl)urea) (4e) Yield 72%; White solid; mp: 265–268 °C; IR
−1
(
(
KBr, ν /cm ): 3305 (NH str), 3134 (C–H str, triazole), 1635 (C=O str), 1595
max
1
C=C str). H NMR (400 MHz, DMSO-d ): δ 8.71 (s, 2H, 2NH), 7.95 (s, 2H, tri-
6
azolyl-2H), 7.42 (d, J=8.4 Hz, 4H, Ar–H), 7.26 (d, J=8.4 Hz, 4H, Ar–H), 6.63
1
3
(
broad triplet, 2H, 2NH), 4.40–4.30 (m, 8H), 1.76 (s, 4H). C NMR (101 MHz,
DMSO-d ): δ 155.36, 145.84, 139.84, 128.93, 125.12, 123.06, 119.62, 49.03, 35.32,
6
+
2
7.35. HRMS: m/z (M+H) cacld. for C H Cl N O : 557.1695 found: 557.2104.
2
4
27
2
10
2
1
,1′‑((1,1′‑(Butane‑1,4‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑methoxyphenyl)urea) (4f) Yield 78%; White solid; mp: 266–270 °C; IR (KBr,
−1
ν
/cm ): 3311 (NH str), 3128 (C–H str, triazole), 1635 (C=O str), 1563 (C=C str).
max
1
H NMR (400 MHz, DMSO-d ): δ 8.33 (s, 2H. 2NH), 7.93 (s, 2H, triazolyl-2H), 7.29
6
(
d, J=8.6 Hz, 4H, Ar–H), 6.81 (d, J=8.4 Hz, 4H, Ar–H), 6.48–6.42 (m, 2H, 2NH),
13
4
.40–4.28 (m, 8H), 3.69 (s, 6H, OCH ), 1.77 (s, 4H). C NMR (101 MHz, DMSO-
6
7.35. HRMS: m/z (M+H) cacld. for C H N O : 549.2686 found: 549.2913.
3
d ): δ 155.82, 154.48, 141.71, 133.93, 123.01, 119.90, 114.29, 55.60, 49.02, 35.34,
+
2
26
33 10
4
1
,1′‑((1,1′‑(Pentane‑1,5‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑ꢀuorophenyl)urea) (4g) Yield 71%; White solid; mp: 270–273 °C; IR
−1
(
(
KBr, ν /cm ): 3314 (NH str), 3128 (C–H str, triazole), 1631 (C=O str), 1509
max
1
C=C str). H NMR (400 MHz, DMSO-d ): δ 8.59 (s, 2H, 2NH), 7.94 (s, 2H, tri-
6
azolyl-2H), 7.40 (dd, J=7.7, 4.9 Hz, 4H, Ar–H), 7.06 (t, J=8.6 Hz, 4H, Ar–H),
1
3

N. Poonia et al.
6
.56 (s, 2H, 2NH), 4.32 (d, J=5.6 Hz, 8H), 1.87–1.78 (m, 4H), 1.25–1.15 (m, 2H).
1
3
C NMR (101 MHz, DMSO-d ): δ 158.61, 156.21, 155.57, 145.86, 137.18, 122.93,
6
+
1
19.79, 119.71, 115.66, 115.44, 49.44, 35.34, 29.57, 23.29. HRMS: m/z (M+H)
cacld. for C H F N O : 539.2443 found: 539.2440.
2
5
29
2
10
2
1
,1′‑((1,1′‑(Pentane‑1,5‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑chlorophenyl)urea) (4h) Yield 77%; White solid; mp: 265–270 °C; IR
−1
(
(
KBr, ν /cm ): 3318 (NH str), 3126 (C–H str, triazole), 1634 (C=O str), 1504
max
1
C=C str). H NMR (400 MHz, DMSO-d ): δ 8.71 (s, 2H, 2NH), 7.94 (s, 2H, tri-
6
azolyl-2H), 7.42 (d, J=8.9 Hz, 4H, Ar–H), 7.26 (d, J=8.9 Hz, 4H, Ar–H), 6.62
(
t, J=5.6 Hz, 2H, 2NH), 4.31 (dd, J=7.6, 6.7 Hz, 8H), 1.87–1.77 (m, 4H), 1.25–
1
3
1
.15 (m, 2H). C NMR (101 MHz, DMSO-d ): δ 155.36, 145.81, 139.84, 128.93,
6
+
1
25.06, 122.96, 119.62, 49.45, 35.33, 29.56, 23.28. HRMS: m/z (M+H) cacld. for
C H Cl N O : 571.1852 found: 571.1857.
2
5
29
2
10
2
1
,1′‑((1,1′‑(Pentane‑1,5‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑methoxyphenyl)urea) (4i) Yield 79%; White solid; mp: 260–262 °C; IR
−1
(
(
KBr, ν /cm ): 3311 (NH str), 3128 (C–H str, triazole), 1635 (C=O str), 1563
max
1
C=C str). H NMR (400 MHz, DMSO-d ): δ 8.34 (s, 2H, 2NH), 7.93 (s, 2H, tria-
6
zolyl-2H), 7.29 (d, J=8.9 Hz, 4H, Ar–H), 6.81 (d, J=9.0 Hz, 4H, Ar–H), 6.46 (t,
J=5.6 Hz, 2H, 2NH), 4.31 (dd, J=9.2, 4.8 Hz, 8H), 3.69 (s, 6H, 2OCH ), 1.86–
3
1
3
1
1
2
.78 (m, 4H), 1.20 (dt, J=15.3, 7.8 Hz, 2H). C NMR (101 MHz, DMSO-d ): δ
6
55.73, 154.45, 146.00, 133.94, 122.91, 119.90, 114.34, 55.60, 49.44, 35.34, 29.57,
+
3.29. HRMS: m/z (M+H) cacld. for C H N O : 563.2843 found: 563.2815.
2
7
35 10
4
1
,1′‑((1,1′‑(Hexane‑1,6‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑ꢀuorophenyl)urea) (4j) Yield 76%; White solid; mp: 260–264 °C; IR (KBr,
−1
ν
/cm ): 3305 (NH str), 3131 (C–H str, triazole), 1630 (C=O str), 1561 (C=C str).
max
1
H NMR (400 MHz, DMSO-d ): δ 8.59 (s, 2H, 2NH), 7.94 (s, 2H, triazolyl-2H), 7.39
6
(
s, 4H, Ar–H), 7.06 (t, J=8.4 Hz, 4H, Ar–H), 6.56 (s, 2H, 2NH), 4.31 (s, 8H), 1.77
13
(
s, 4H), 1.24 (s, 4H). C NMR (101 MHz, DMSO-d ): δ 158.57, 156.21, 155.57,
6
1
45.85, 137.19, 122.91, 119.78, 119.70, 115.66, 115.44, 49.58, 35.34, 29.99, 25.68.
+
HRMS: m/z (M+H) cacld. for C H F N O : 553.2600 found: 553.2591.
26
31
2
10
2
1
,1′‑((1,1′‑(Hexane‑1,6‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))bis(3‑(4‑chlo‑
−1
rophenyl)urea) (4k) Yield 74%; White solid; mp: 268–272 °C; IR (KBr, ν /cm ):
max
1
3
309 (NH str), 3102 (C–H str, triazole), 1636 (C=O str), 1596 (C=C str). H NMR
(
400 MHz, DMSO-d ): δ 8.71 (s, 2H, 2NH), 7.94 (s, 2H, triazolyl-2H), 7.42 (d,
6
J=8.8 Hz, 4H, Ar–H), 7.26 (d, J=8.8 Hz, 4H, Ar–H), 6.62 (t, J=5.3 Hz, 2H, 2NH),
13
4
.30 (dd, J=12.7, 6.1 Hz, 8H), 1.76 (s, 4H), 1.23 (s, 4H). C NMR (101 MHz, DMSO-
d ): δ 155.36, 145.73, 139.82, 128.93, 125.06, 122.93, 119.61, 49.58, 35.33, 29.98,
6
+
25.68. HRMS: m/z (M+H) cacld. for C H Cl N O : 585.2008 found: 585.2013.
26
31
2 10 2
1
,1′‑((1,1′‑(Hexane‑1,6‑diyl)bis(1H‑1,2,3‑triazole‑4,1‑diyl))bis(methylene))
bis(3‑(4‑methoxyphenyl)urea) (4l) Yield 76%; White solid; mp: 267–270 °C; IR (KBr,
1
3

Design, synthesis, antimicrobial evaluation and in silico…
−
1
ν
/cm ): 3310 (NH str), 3134 (C–H str, triazole), 1628 (C=O str), 1516 (C=C str).
max
1
H NMR (400 MHz, DMSO-d ): δ 8.34 (s, 2H, 2NH), 7.94 (d, J=5.5 Hz, 2H, triazolyl-
6
2
H), 7.29 (d, J=8.6 Hz, 4H, Ar–H), 6.81 (d, J=8.6 Hz, 4H, Ar–H), 6.45 (t, J=5.1 Hz,
2
4
1
H, 2NH), 4.30 (d, J=5.4 Hz, 8H), 3.69 (s, 6H, 2OCH ), 1.79 (dd, J=12.3, 5.2 Hz,
3
13
H), 1.24 (s, 4H). C NMR (101 MHz, DMSO): δ 155.76, 154.45, 145.95, 133.91,
22.90, 119.89, 114.34, 55.60, 50.97, 49.58, 35.34, 29.99, 28.53, 25.96, 25.87, 25.69.
+
HRMS: m/z (M+H) cacld. for C H N O : 577.2999 found: 577.2960.
28 37 10 4
1
,1′‑((1,1′‑(1,3‑Phenylenebis(methylene))bis(1H‑1,2,3‑triazole‑4,1‑diyl))
bis(methylene))bis(3‑(4‑ꢀuorophenyl)urea) (4m) Yield 79%; White solid; mp:
−1
2
64–268 °C; IR (KBr, ν /cm ): 3317 (NH str), 3128 (C–H str, triazole), 1633
max
1
(
C=O str), 1509 (C=C str). H NMR (400 MHz, DMSO): δ 8.57 (s, 2H, 2NH),
8
.00 (s, 2H, triazolyl-2H), 7.39 (dd, J=9.0, 5.1 Hz, 5H, Ar–H), 7.35 (d, J=2.8 Hz,
H, Ar–H), 7.25 (d, J=7.7 Hz, 2H, Ar–H), 7.05 (t, J=8.9 Hz, 4H, Ar–H), 6.56 (t,
1
1
3
J=5.5 Hz, 2H, 2NH), 5.56 (s, 4H), 4.32 (d, J=5.5 Hz, 4H). C NMR (101 MHz,
DMSO): δ 158.58, 156.22, 155.57, 146.33, 137.18, 129.69, 128.19, 128.09, 123.24,
+
1
19.81, 119.74, 115.65, 115.43, 52.94, 35.35. HRMS: m/z (M+H) cacld. for
C H F N O : 573.2287 found: 573.2290.
2
8
27
2
10
2
1
,1′‑((1,1′‑(1,3‑Phenylenebis(methylene))bis(1H‑1,2,3‑triazole‑4,1‑diyl))
bis(methylene))bis(3‑(4‑chlorophenyl)urea) (4n) Yield 72%; White solid; mp:
−1
2
80–282 °C; IR (KBr, ν /cm ): 3316 (NH str), 3134 (C–H str, triazole), 1635
max
1
(
C=O str), 1511 (C=C str). H NMR (400 MHz, DMSO-d ): δ 8.71 (s, 2H, 2NH),
6
8
.01 (s, 2H, triazolyl-2H), 7.42 (d, J=8.9 Hz, 4H, Ar–H), 7.38 (d, J=7.7 Hz, 1H,
Ar–H), 7.34 (d, J=2.4 Hz, 1H, Ar–H), 7.26 (d, J=8.8 Hz, 5H, Ar–H), 7.24 (s, 1H,
1
3
Ar–H), 6.63 (t, J=5.5 Hz, 2H, 2NH), 5.56 (s, 4H), 4.32 (d, J=5.5 Hz, 4H).
C
NMR (101 MHz, DMSO-d ): δ 155.38, 146.23, 139.83, 137.14, 129.70, 128.93,
6
+
1
28.21, 128.11, 125.08, 123.28, 119.64, 52.95, 35.33. HRMS: m/z (M+H) cacld.
for C H Cl N O : 605.1695 found: 605.1700.
2
8
27
2
10
2
1
,1′‑((1,1′‑(1,3‑Phenylenebis(methylene))bis(1H‑1,2,3‑triazole‑4,1‑diyl))
bis(methylene))bis(3‑(4‑methoxyphenyl)urea) (4o) Yield 76%; White solid; mp:
−1
2
62–268 °C; IR (KBr, ν /cm ): 3322 (NH str), 3128 (C–H str, triazole), 1630
max
1
(
C=O str), 1534 (C=C str). H NMR (400 MHz, DMSO-d ): δ 8.33 (s, 2H, 2NH),
6
7
.99 (s, 2H, triazolyl-2H), 7.38 (d, J=7.8 Hz, 1H, Ar–H), 7.35 (d, J=3.8 Hz, 1H,
Ar–H), 7.30–7.27 (m, 4H, Ar–H), 7.25 (dd, J=7.5, 1.3 Hz, 2H, Ar–H), 6.83–6.79
(
m, 4H, Ar–H), 6.47 (t, J=5.6 Hz, 2H, 2NH), 5.56 (s, 4H), 4.31 (d, J=5.6 Hz, 4H),
1
3
3
1
3
.69 (s, 6H, 2OCH ). C NMR (101 MHz, DMSO-d ): δ 155.74, 154.46, 146.47,
3
6
37.15, 133.92, 129.69, 128.19, 128.08, 123.22, 119.93, 114.34, 55.60, 52.93,
+
5.35. HRMS: m/z (M+H) cacld. for C H N O : 597.2686 found: 597.2653.
3
0
33 10
4
Pharmacology
Already reported procedure by Kaushik et al. was used to study the antimicrobial
activities [55].
1
3

N. Poonia et al.
Docking details
The crystal structure of protein C. albicans sterol 14-α-demethylase was retrieved
from the protein data bank with PDB ID: 5TZ1. The preparation of protein and
compounds was carried out according to the procedure reported by us in previ-
ous studies [55–57]. The docking simulations were accomplished with Autodock
Vina software [58] using search box with dimensions center_x=72.0224738378,
center_y=63.8191053546,
center_z=5.24372711084,
size_x=25.0,
size_y=28.2139473943 and size_z=25.0 and visualization work was performed
with discovery studio visualizer [59] and PyMOL [60].
Results and discussion
Chemistry
Symmetrical bis(urea-1,2,3-triazole) hybrids have been synthesized in two steps
starting from the commercially available dibromides (1a–1e) which on reaction
with sodium azide in dimethylformamide at 70 °C generated diazides (2a–2e).
Then, without isolating, these diazides were subjected to CuACC reaction with
other precursors, i.e., urea-linked terminal alkynes (3a–3c) using sodium ascorbate
and catalytic amount of copper sulfate pentahydrate to yield the hybrid compounds
(
4a–4o; Scheme 1). The urea-linked alkynes (3a–3c) were synthesized via reacting
phenyl isocyanate derivatives with propargyl amine in the presence of triethylamine
in dichloromethane by a well-known method reported previously [61]. A possible
mechanism for the click synthesis of symmetrical bis(urea-1,2,3-triazole) hybrids is
depicted in Scheme 2.
Spectroscopic techniques like FTIR, H NMR, 13C NMR and HRMS were used
1
for analyzing the structures of all the products.
IR analysis
−
1
For instance, in the IR spectrum of 4 h, the presence of a band at 3129 cm due
to C–H stretching of triazole conꢂrmed the formation of a triazole ring. A band at
−
1
1
3
318 cm was due to the N–H stretching of the urea group, and a strong band at
634 cm− was observed due to the C=O stretching vibrations of urea functionality.
1
1H NMR analysis
A sharp singlet conꢂrming the triazole ring formation was observed at δ 7.94 in the
1
H NMR spectrum of the synthesized compound 4 h. The signal due to two pro-
tons (NH) of bis-urea-triazole appeared as a singlet at δ 8.71. The other–NH–pro-
tons of urea moiety observed as a triplet signal at δ 6.62 with a coupling constant of
5
.6 Hz. The eight–NCH –protons observed as a doublet of doublet signal at δ 4.31
2
(
J=7.6, 6.7 Hz). Methylene protons adjacent to nitrogen of triazole ring appeared as
1
3

Design, synthesis, antimicrobial evaluation and in silico…
Scheme 1 i Sodium azide, DMF, 70 °C; 8 h; ii CuSO .5H O, sodium ascorbate, Water:DMF (1:3);
4
2
4
5 °C; 4–5 h
NaN3
Br
N
N+ N-
Br
-N N+
N
A
N
N+
N
+
N
O
O
N
N
Cu
Cu
HN
N
H
HN
N
HN
HN
NH
NH
H
Cu
O
O
Cu+
R1
R1
R1
R1
N
N
N
N
N
N
Cu
Cu
N
N
H O
2
N
NH
HN
HN
HN
HN
N
N
N
O
NH
NH
O
O
O
N
N
NH
N
N
N
N
Cu
Cu
C
NH
NH
HN
HN
R1
R1
B
R1
R1
O
O
R1
R1
Scheme 2 Plausible mechanism for synthesis of symmetrical bis(urea-1,2,3-triazole) hybrids
1
3

N. Poonia et al.
a multiplet of eight protons at δ 1.82. The other methylene protons attached present
at the central carbon atom of the pentyl group appeared as a multiplet at δ 1.20.
13C NMR analysis
13
On analyzing the C NMR spectra of compound 4 h, diꢀerent peaks were allocated
1
3
to the carbon atoms of the compound by means of techniques like DEPT-135,
C
NMR and the previous literature. The carbonyl carbon atom observed at δ 155.36
and those of the triazole ring appeared at δ values 122.96 (C–5) and 145.81 (C–4),
respectively. The chemical shift values to the carbon atoms of the n-pentyl group can
1
be assigned on the basis of the deshielding of protons in the H NMR spectra of com-
pound 4 h.
1.82
1
.20
N
N
N
N
N
HN
7.94
O
N
HN
6
.62
.71
NH
NH
O
Cl
8
Cl
Important chemical shift values (δ ppm) in 13C NMR and H NMR spectrum of
1
compound 4 h.
1
3

Design, synthesis, antimicrobial evaluation and in silico…
HRMS analysis
The structures of synthesized hybrids were further conꢂrmed on the basis of their
HRMS spectra, e.g., compound 4 h demonstrated a signal at m/z 571.1857 analo-
+
gous to [M+H] which closely resembles the calculated value (m/z=571.1852).
Antimicrobial activity
In vitro screening for antimicrobial activity of the synthesized compounds against
gram-positive bacteria (Staphylococcus epidermidis and Bacillus subtilis MTCC
4
41), gram-negative bacterium (Escherichia coli MTCC 16,521) and fungal strains
(
Aspergillus niger MTCC 8189 and Candida albicans MTCC 227) was done using
the standard serial dilution method. The reference drugs Ciproꢃoxacin and Flucona-
zole were taken for comparing the values of antibacterial and antifungal activity of
bis(urea-1,2,3-triazole) hybrids. Minimum inhibitory concentrations (MIC in µmol/
mL) evaluated for all the synthesized hybrids along with the reference drugs are
listed in Table 1. Only a few of the synthesized hybrids, in antibacterial screening,
Table 1 Biological activity results of the synthesized bis(urea-1,2,3-triazole) hybrids
S. No Compounds
R1
E. coli B. subtilis S. epider-
midis
C. albicans A. niger
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
3a
3b
3c
4a
4b
4c
4d
4e
4f
–
–
–
F
Cl
0.1301 0.1301
0.1198 0.1198
0.1301
0.1198
0.1224
0.0245
0.0470
0.0117
0.0238
0.0458
0.0465
0.0232
0.0219
0.0222
0.0462
0.0437
0.0442
0.0218
0.1301
0.1198
0.1224
0.0245
0.0115
0.0234
0.0238
0.0112
0.0228
0.0232
0.0219
0.0222
0.0227
0.0214
0.0217
0.0218
0.1301
0.1198
0.1224
0.0122
0.0231
0.0234
0.0238
0.0225
0.0057
0.0116
0.0110
0.0111
0.0227
0.0214
0.0217
0.0218
OMe 0.1224 0.1224
F
Cl
OMe 0.0234 0.0234
F
Cl
OMe 0.0228 0.0228
F
Cl
OMe 0.0222 0.0454
F
Cl
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
(–CH –)
0.0245 0.0245
0.0231 0.0231
2
3
3
3
4
4
4
5
5
5
6
6
6
2
2
0.0238 0.0238
0.0225 0.0225
2
2
2
0
1
2
3
4
5
6
4 g
4 h
4i
0.0232 0.0232
0.0110 0.0447
2
2
2
4j
0.0226 0.0226
0.0214 0.0214
2
4 k
4 l
4 m
2
OMe 0.0217 0.0217
F
2
m–CH –
0.0218 0.0218
2
C H –CH –
6
4
2
1
1
7
8
4n
4o
m–CH –
Cl
0.0207 0.0422
0.0207
0.0207
0.0207
0.0105
0.0207
0.0207
2
4
C H –CH –
6
2
m–CH –
OMe 0.0428 0.0207
2
C H –CH –
6
4
2
1
2
9
0
Ciproꢃoxacin
Fluconazole
–
–
–
–
0.0094 0.0094
0.0094
–
–
–
–
–
0.0408
0.0408
1
3

N. Poonia et al.
were found to have comparable activity to that of the standard drug Ciproꢃoxacin.
Activity results showed that compound 4c owing an MIC value of 0.0117 µmol/mL
was signiꢂcantly potent against S. epidermidis. Compound 4 h with an MIC value
of 0.0110 µmol/mL also displayed good biological activity against E. coli. The anti-
fungal screening results revealed that all the synthesized compounds showed better
activity than that of the standard drug Fluconazole. Compound 4b, 4e and 4o with
MIC values of 0.0115 µmol/mL, 0.0112 µmol/mL and 0.0105 µmol/mL, respectively
were more potent than other compounds against C. albicans. Also, compounds 4a,
4
g, 4 h and 4i were observed to be more active against A. niger with MIC values
ranging in between 0.0110 µmol/mL to 0.0122 µmol/mL. Among all the synthesized
bis(1,2,3-triazole)urea hybrids, 4f was the most potent compound against A. niger
with MIC value of 0.0057 µmol/mL.
Structure–activity relationship
On analyzing the data for antimicrobial evaluation of the synthesized hybrids, the
following structure–activity relationship was established:
1
. All the synthesized symmetrical bis(urea-1,2,3-triazole) hybrids (4a–4o) showed
better activity than their alkyne precursors (3a–3c) [60]. The synergistic eꢀect
of enhanced pharmacophoric activity was clearly shown by the hybrid bis-urea-
triazoles.
2
. Substitution by methoxy group in some of the compounds like 4c led to an
increase in the results of antibacterial activity of the synthesized symmetrical
bis(urea-1,2,3-triazole) hybrids against S. epidermidis bacterial strain.
. Compounds bearing the Cl substituent were found to be signiꢂcantly active
against all the tested microorganisms except S. epidermidis.
3
4
. Compound 4f with para methoxy group showed the highest potency against all
the tested strains, and it was also found to be even more potent against A. niger
than the reference drug Fluconazole.
5
. Compound 4o bearing the methoxy group at the para position and benzene ring as
the spacer linker showed high activity than the standard drug Fluconazole against
C. albicans.
Docking Studies
The antimicrobial evaluation data of target compounds shows that the bistriazoles
exhibited excellent antifungal activity even higher than the standard drug ꢃucona-
zole. Azole drugs act on sterol 14-α-demethylase (CYP51) and block the synthesis
of ergosterol in fungi [62]. Therefore, to study the binding proꢂle of the most active
compounds and to ꢂnd out the reason for enhancement in antifungal activity after
conversion of alkynes to triazole, target molecules 4e and 4o along with alkynes 3b
and 3c were docked into the active site of sterol 14-α-demethylase of C. albicans.
1
3

Design, synthesis, antimicrobial evaluation and in silico…
Fig. 2 Interactions of compound 4o with active site of fungal sterol 14-α-demethylase
Fig. 3 Interactions of compound 4e with active site of fungal sterol 14-α-demethylase
As shown in Figs. 2 and 3, one of the terminal p-substituted phenyl rings of
both the compounds 4e and 4o entered deep into the binding site and created pi–pi
stacked interactions with pi electrons of one ring of the heme molecule as well as
hydrophobic interactions with Ile131 and Ile304. One nitrogen atom of the urea moi-
ety attached to this deeply residing phenyl ring lie close to the heme iron. The dis-
tance between the heme iron and nitrogen of compound 4e was 3.83 Å while that of
compound 4o was 3.86 Å although these nitrogen atoms did not form coordination
1
3

N. Poonia et al.
bond with heme due to less basicity. The other part of the molecules extends through
the substrate entrance channel and stretches up to the channel gate.
The compound protein complex was mainly stabilized by the hydrophobic inter-
actions as the environment of the substrate channel is also hydrophobic as exhibited
in Fig. 1. The surface on the compound 4o clearly indicates the more hydrophobic
nature of the channel. The diꢀerent types of binding interactions of docked com-
pounds along with the residues involved and interaction distance are grouped in
Table 2.
The docked conformations of both molecules 4e and 4o are presented in the mesh
diagram of protein in Fig. 4.
The binding aꢁnity values for compounds 4e, 4o, 3b and 3c were − 12.1, − 12.2,
−
7.6 and − 7.5 kcal/mol, respectively. Observed activity trend among these com-
pounds was also in the same order, i.e., 4o>4e>3b>3c. Therefore, as hypothe-
sized by us, the antimicrobial activity got enhanced after conversion into triazole.
The in silico trends also conꢂrm the observed activity trend. The binding score of
the co-crystallized ligand VT-1161 was − 12.0, which was less than that of our com-
pounds. This ligand showed 98% inhibition of C. albicans sterol 14-α-demethylase
as compared to 54% by ꢃuconazole as reported by Hargrove et al. [62]. The experi-
mental outcomes of our study are also in the same direction. All the above facts
have proved the compounds synthesized in the present study to be very inꢃuential
antifungal agents.
Table 2 Details of interactions of compounds 4e and 4o
Compound 4o
Compound 4e
Distance Residue Type of interaction Distance
Carbon Hydrogen Bond 3.34599 LYS90
Sr. No Residue
Type of interaction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
SER507
LYS90
LEU87
LEU376
HEM601 Pi-Sigma
PHE380 Pi-Sigma
HEM601 Pi-Pi Stacked
HIS377
HIS377
Pi-Cation
Pi-Sigma
Pi-Sigma
4.10628
3.98529
3.99243
3.69331
4.29618
4.88989
3.89546
4.89884
4.80931
3.74549
4.7695
Pi-Cation
Pi-Sigma
Pi-Sigma
4.04607 LEU87
3.93789 LEU376
3.72739 HEM601 Pi-Pi Stacked
3.78227 HIS377 Pi-Pi T-shaped
3.83015 TYR118 Pi-Pi T-shaped
3.83183 HEM601 Alkyl
Pi-Pi T-shaped
Pi-Pi T-shaped
5.24277 LYS90
4.30204 MET92
4.83527 ILE131
4.63474 ILE304
5.48695 PHE380
4.32584 TYR401 Pi-Alkyl
5.38273 PRO230
LYS90
Alkyl
Alkyl
Alkyl
Alkyl
Pi-Alkyl
0
1
2
3
4
5
6
TYR118 Pi-Pi T-shaped
LEU376
ILE131
PRO230
LYS90
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
4.10363
4.188
Pi-Alkyl
Pi-Alkyl
4.35868
5.43881
4.05739
HEM601 Pi-Alkyl
1
3

Design, synthesis, antimicrobial evaluation and in silico…
Fig. 4 Docked conformation of compounds 4e (light pink) and 4o (yellow) along with co-crystallized
ligand (green) in the substrate channel of C. albicans sterol 14-α-demethylase. (Color ꢂgure online)
Conclusion
In summary, various bis-urea-triazoles have been synthesized by click chemistry and
their antimicrobial evaluation is reported. The bioactivity studies of the synthesized
compounds revealed that some of the tested compounds exhibited comparable activ-
ity to the standard drug Ciproꢃoxacin against all the tested bacteria. Also, all the
compounds (4a-4o) showed superior antifungal potency than Fluconazole. Com-
pound 4f was the most potent compound of the series toward A. niger with an MIC
value of 0.0057 µmol/mL. Also, the compounds 4e and 4o showed better activity
against C. albicans than reference drug taken, which have been supported by dock-
ing simulation into active sites of sterol 14-α-demethylase. So, the synthesized com-
pound 4e, 4o and 4f may be used for further studies in the ꢂeld of drug discovery.
Acknowledgements One of the authors (NP) thanks Haryana State Council for Science & Technology
(
HSCST) for Senior Research Fellowship (Nisha Poonia). Also, the authors are gratiꢂed to APJ Abdul
Kalam Central instrumentation laboratory, Guru Jambheshwar University of Science & Technology,
Hisar, India for providing the spectral analysis of the compounds.
Compliance with ethical standard
Conꢀict of interest The authors declare that they have no conꢃict of interest.
References
1
2
.
.
H. Nikaido, Semin. Cell Dev. Biol. 12, 215 (2001)
P. Nordmann, T. Naas, N. Fortineau, L. Poirel, Curr. Opin. Microbiol. 10, 436 (2007)
1
3

N. Poonia et al.
3
.
R. Wakieć, R. Prasad, J. Morschhäuser, F. Barchiesi, E. Borowski, S. Milewski, Mycoses 50, 109
(
2007)
4
5
6
.
.
.
M.N. Alekshun, S.B. Levy, Cell 128, 1037 (2007)
N.J. Agard, J.A. Prescher, C.R. Bertozzi, J. Am. Chem. Soc. 126, 15046 (2004)
R. Manetsch, A. Krasiński, Z. Radić, J. Raushel, P. Taylor, K.B. Sharpless, H.C. Kolb, J. Am.
Chem. Soc. 126, 12809 (2004)
7
.
M. Taddei, S. Ferrini, L. Giannotti, M. Corsi, F. Manetti, G. Giannini, L. Vesci, F.M. Milazzo,
D. Alloatti, M.B. Guglielmi, M. Castorina, M.L. Cervoni, M. Barbarino, R. Fodera, V. Carollo,
C. Pisano, S. Armaroli, W. Cabri, J. Med. Chem. 57, 2258 (2014)
8
9
.
.
C.G. Parker, M.R. Pratt, Cell 180, 605 (2020)
M. Schunack, M. Gragert, D. Döhler, P. Michael, W.H. Binder, Macromol. Chem. Phys. 213, 205
(
2012)
1
1
1
1
1
1
0. N. Ma, Y. Wang, B.X. Zhao, W.C. Ye, S. Jiang, Drug Des. Dev. Ther. 9, 1585 (2015)
1. J.E. Moses, A.D. Moorhouse, Chem. Soc. Rev. 36, 1249 (2007)
2. K. Bozorov, J. Zhao, H.A. Aisa, Bioorg. Med. Chem. 27, 3511 (2019)
3. A. Rani, G. Singh, A. Singh, U. Maqbool, G. Kaur, J. Singh, RSC Adv. 10, 5610 (2020)
4. K. Nwe, M.W. Brechbiel, Cancer Biother. Radio 24, 289 (2009)
5. W. Yan, X. Wang, K. Li, T.X. Li, J.J. Wang, K.C. Yao, L.L. Cao, S.S. Zhao, Y.H. Ye, Pestic. Bio-
chem. Physiol. 156, 160 (2019)
1
6. L. Romero-Azogil, J.M. Benito, I.M. Pinilla, K. Hakkou, M.B. Martínez, I. Cantón, P. López-
Cornejo, C.B. García-Calderón, I.V. Rosado, M.G. García-Martín, E. Benito, Eur. Polym. J. 123,
1
09458 (2020)
1
1
7. M. Chemama, M. Fonvielle, M. Arthur, J.M. Valéry, M. Etheve-Quelquejeu, Chem. Eur. J. 15,
929 (2009)
8. P. Yadav, K. Lal, A. Kumar, S. Bhushan, S.K. Guru, S. Jaglan, Eur. J. Med. Chem. 126, 944
1
(
2017)
1
2
9. K. Lal, P. Yadav, Anti-Cancer Agents Med. Chem. 18, 21 (2018)
0. Z. Jaafar, S. Chniti, A.B. Sassi, H. Dziri, S. Marque, M. Lecouvey, R. Gharbi, M. Msaddek, J.
Mol. Struct. 1195, 689 (2019)
2
2
1. Naveen, R.K. Tittal, P. Yadav, K. Lal, V.D. Ghule, A. Kumar, New J. Chem. 43, 8052 (2019)
2. V.S. Dofe, A.P. Sarkate, D.K. Lokwani, S.H. Kathwate, C.H. Gill, Res. Chem. Intermed. 43, 15
(
2017)
2
2
3. S.K. Avula, A. Khan, N.U. Rehman, M.U. Anwar, Z. Al-Abri, A. Wadood, M. Riaz, R. Csuk, A.
Al-Harrasi, Bioorg. Chem. 81, 98 (2018)
4. L. Deswal, V. Verma, D. Kumar, C.P. Kaushik, A. Kumar, Y. Deswal, S. Punia, Arch. Pharm.
3
53, 2000090 (2020)
2
2
5. L. Kumar, K. Lal, P. Yadav, A. Kumar, A.K. Paul, J. Mol. Struct. 1216, 128253 (2020)
6. A.N. Boshra, H.H.M. Abdu-Allah, A.F. Mohammed, A.M. Hayallah, Bioorg. Chem. 95, 103505
(
2020)
2
2
7. S. Sharma, D. Kumar, G. Singh, V. Monga, B. Kumar, Eur. J. Med. Chem. 200, 112438 (2020)
8. S.P. Kharei, T.R. Deshmukh, S.V. Akolkar, J.N. Sangshetti, V.M. Khedkar, B.B. Shingate, Res.
Chem. Intermed. 45, 5159 (2019)
2
3
9. T.O. Olomola, R. Klein, K.A. Lobb, Y. Sayed, P.T. Kaye, Tetrahedron Lett. 51, 6325 (2010)
0. A.B. Danne, A.S. Choudhari, D. Sarkar, J.N. Sangshetti, V.M. Khedkar, B.B. Shingate, Res.
Chem. Intermed. 44, 6283 (2018)
3
3
3
3
3
3
1. S. Srinivasarao, A. Nandikolla, A. Suresh, A.K. Ewa, A. Glogowska, B. Ghosh, B.K. Kumar, S.
Murugesan, S. Pulya, H. Aggarwal, K.V.G.C. Sekhar, Bioorg. Chem. 100, 103955 (2020)
2. A. Vartak, C. Goins, V.C.N. de Moura, C.M. Schreidah, A.D. Landgraf, B. Lin, J. Du, M. Jack-
son, D.R. Ronning, S.J. Sucheck, Med. Chem. Comm. 10, 1197 (2019)
3. K. Bojorov, J.Y. Zhao, L.F. Nie, H.R. Ma, K. Bobakulov, R. Hu, N. Rustamova, G. Huang, T.
Eꢀerth, H.A. Aisa, RSC Adv. 50, 31417 (2017)
4. P.K. Ambre, R.R.S. Pissurlenkar, R.D. Wavhale, M.S. Shaikh, V.M. Khedkar, B. Wan, S.G.
Franzblau, E.C. Coutinho, Med. Chem. Res. 23, 2564 (2014)
5. S.K. Mohanvel, V. Ravichandran, C. Kamalanathan, A.S. Satish, S. Ramesh, J. Lee, S.K.
Rajasekharan, Microb. Pathog. 130, 104 (2019)
6. H.M. Faidallah, M.M. Al-Mohammadi, K.A. Alamry, K.A. Khan, J. Enzyme Inhib. Med. Chem.
3
1, 157 (2016)
1
3

Design, synthesis, antimicrobial evaluation and in silico…
3
7. C. Zhao, H.L. Sham, M. Sun, V.S. Stoll, K.D. Stewart, S. Lin, H. Mo, S. Vasavanonda, A. Saldivar,
C. Park, E.J. McDonald, K.C. Marsh, L.L. Klein, D.J. Kempf, D.W. Norbeck, Bioorg. Med. Chem.
Lett. 15, 5499 (2005)
3
3
8. K. Lal, L. Kumar, A. Kumar, A. Kumar, Curr. Top. Med. Chem. 18, 1506 (2018)
9. I.E. Głowacka, P. Grzonkowski, P. Lisiecki, Ł Kalinowski, D.G. Piotrowska, Arch. Pharm. 352,
1
800302 (2019)
4
4
4
0. Z.J. Zheng, D. Wang, Z. Xu, L.W. Xu, Beilstein J. Org. Chem. 11, 2557 (2015)
1. P. Wei, X. Yan, J. Li, Y. Ma, Y. Yao, F. Huang, Tetrahedron 68, 9179 (2012)
2. B. Westermann, S. Dörner, S. Brauch, A. Schaks, R. Heinke, S. Stark, F.L. Van Delft, S.S. van
Berkel, Carbohydr. Res. 371, 61 (2013)
4
3. P.J. Jervis, M. Moulis, J.P. Jukes, H. Ghadbane, L.R. Cox, V. Cerundolo, G.S. Besra, Carbohydr.
Res. 356, 152 (2012)
4
4
4
4
4
4
5
5
5
5
4. M.J. Isaacman, E.M. Corigliano, L.S. Theogarajan, Biomacromol 14, 2996 (2013)
5. K. Lal, A. Kumar, M.S. Pavan, C.P. Kaushik, Bioorg. Med. Chem. Lett. 22, 4353 (2012)
6. Z. Yuan, G.C. Kuang, R.J. Clark, L. Zhu, Org. Lett. 14, 2590 (2012)
7. A.I. Mohammed, Z.H. Abboud, A.H.O. Alghanimi, Tetrahedron Lett. 53, 5081 (2012)
8. M.K. Singh, R. Tilak, G. Nath, S.K. Awasthi, A. Agarwal, Eur. J. Med. Chem. 63, 635 (2013)
9. Y. Li, J.C. Huꢀman, A.H. Flood, Chem. Commun. 26, 2692 (2007)
0. P. Anthony, N. Bashir, R. Parveen, Asian J. Pharm. Sci. 4, 9 (2014)
1. M.C. Nielsen, A.F. Larsen, F.H. Abdikadir, T. Ulven, Eur. J. Med. Chem. 72, 119 (2014)
2. A.M. Hoyo, A. Latorre, R. Diaz, A. Urbano, M.C. Carreño, Adv. Synth. Catal. 357, 1154 (2015)
3. M. Jurášek, P. Džubák, D. Sedlák, H. Dvořáková, M. Hajdúch, P. Bartůněk, P. Drašar, Steroids 78,
3
56 (2013)
5
5
5
5
4. H.J. Huang, H.Y. Fang, J.L. Chir, A.T. Wu, Luminescence 26, 518 (2011)
5. C.P. Kaushik, K. Lal, A. Kumar, S. Kumar, Med. Chem. Res. 23, 2995 (2014)
6. MarvinSketch 19.19.0 ChemAxon (2019)
7. E.F. Pettersen, T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblatt, E.C. Meng, T.E. Ferrin, J.
Comput. Chem. 25, 1605 (2004)
5
5
8. O. Trott, A.J. Olson, J. Comput. Chem. 31, 455 (2010)
9. Dassault Systèmes BIOVIA, Discovery studio visualizer v17.2.0.16349, San Diego: Dassault Sys-
tèmes, 2016
6
0. Open Source PyMOL (TM) Molecular Graphics System, Version 1.7.2.1. Copyright © 2009–2014,
Schrodinger, LLC
6
6
1. K. Lal, N. Poonia, P. Rani, A. Kumar, A. Kumar, J. Mol. Struct. 1215, 128234 (2020)
2. T.Y. Hargrove, L. Friggeri, Z. Wawrzak, A. Qi, W.J. Hoekstra, R.J. Schotzinger, J.D. York, F.P.
Guengerich, G.I. Lepesheva, J. Biol. Chem. 292, 6728 (2017)
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional aꢁliations.
Aꢀliations
1
1
2
Nisha Poonia · Kashmiri Lal · Ashwani Kumar
*
Kashmiri Lal
klal_iitd@yahoo.com
1
2
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar,
Haryana 125001, India
Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science
and Technology, Hisar, Haryana 125001, India
1
3