Design, synthesis, and evaluation of metronidazole-1,2,3-triazole derivatives as potent urease inhibitors

Article abstract of DOI:10.1007/s11696-021-01653-4

A new series of metronidazole-1,2,3-triazole derivatives 6a–o was synthesized and evaluated as Helicobacter pylori urease inhibitors. All the synthesized compounds were more potent than standard inhibitor thiourea against urease. Among the synthesized compounds, compound 6f (IC₅₀ = 1.975 ± 0.25?μM) with inhibitory activity around 11-fols more than thiourea (IC₅₀ = 22.00 ± 0.14?μM) was the most potent compound. Kinetic study of this compound revealed that compound 6f inhibited urease in an uncompetitive mode. Based on molecular modeling study, compound 6f pointed toward the bi-nickel center and stabilized by H-bond and T-shape π–π hydrophobic interactions with the critical residues His492 and Asp633. Moreover, it anchored to the helix-turn-helix motif in the active site cavity through interaction with His593 and Arg609. Consequently, it proposed that compound 6f through stabilization of active site flap inhibited urease activity.

Full text of DOI:10.1007/s11696-021-01653-4

Chemical Papers
https://doi.org/10.1007/s11696-021-01653-4
ORIGINAL PAPER
Design, synthesis, and evaluation of metronidazole‑1,2,3‑triazole
derivatives as potent urease inhibitors
Elham Babazadeh Rezaei1 · Fahimeh Abedinifar1 · Homa Azizian2 · Mohammad Nazari Montazer3 · Mehdi Asadi3 ·
Samanesadat Hosseini4 · Saghi Sepehri5 · Maryam Mohammadi‑Khanaposhtani6 · Mahmood Biglar1 ·
Bagher Larijani1 · Massoud Amanlou3 · Mohammad Mahdavi1
Received: 9 September 2020 / Accepted: 12 April 2021
© Institute of Chemistry, Slovak Academy of Sciences 2021
Abstract
A new series of metronidazole-1,2,3-triazole derivatives 6a–o was synthesized and evaluated as Helicobacter pylori urease
inhibitors. All the synthesized compounds were more potent than standard inhibitor thiourea against urease. Among the
synthesized compounds, compound 6f (IC50 =1.975 0.25 µM) with inhibitory activity around 11-fols more than thiourea
(IC50 =22.00 0.14 µM) was the most potent compound. Kinetic study of this compound revealed that compound 6f inhibited
urease in an uncompetitive mode. Based on molecular modeling study, compound 6f pointed toward the bi-nickel center and
stabilized by H-bond and T-shape π–π hydrophobic interactions with the critical residues His492 and Asp633. Moreover, it
anchored to the helix-turn-helix motif in the active site cavity through interaction with His593 and Arg609. Consequently,
it proposed that compound 6f through stabilization of active site fap inhibited urease activity.
Keywords Urease inhibitors · 1,2,3-Triazole · Metronidazole · Kinetic study · Molecular modeling
Introduction
Urease is a very potent target in the clinically important
complications related to Helicobacter pylori (H. pylori)
(Follmer 2010; Suerbaum and Michetti 2002; Malfertheiner
et al. 2017). Urease by providing nitrogen for the growth
of H. pylori, plays a signifcant role in the survival of this
bacteria (Amtul et al. 2002). H. pylori infection is responsi-
ble for gastrointestinal diseases such as gastritis, ulceration,
gastric carcinomas, and primary gastric lymphomas (Kusters
et al. 2006). A very promising strategy for controlling and
treating H. pylori infection is the use of urease inhibitors
(Modolo et al. 2015; Rego et al. 2018; Hameed et al. 2019).
Over the last decade, diferent derivatives of urea, barbitu-
ric, thiobarbituric acid, triazole, coumarin, semicarbazone,
Schif bases, and oxadiazoles have been introduced as potent
urease inhibitors (Upadhyay 2012; Salar et al. 2019; Arshia
et al. 2016; de Fátima et al. 2018; Akhtar et al. 2010; Ullah
et al. 2018).
* Mahmood Biglar
Mbiglar@tums.ac.ir
* Mohammad Mahdavi
Momahdavi@sina.tums.ac.ir
1
Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran, Iran
2
Department of Medicinal Chemistry, School
of Pharmacy-International Campus, Iran University
of Medical Sciences, Tehran, Iran
3
Department of Medicinal Chemistry, Faculty of Pharmacy
and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, Tehran, Iran
4
Department of Pharmaceutical Chemistry, School
of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
Nitroimidazole scafold is an attractive pharmacophore
for design of biological active compounds with properties
such as antimicrobial, antitubercular, and anti-urease (Günay
et al. 1999; Kim et al. 2009; Huang et al. 2011). One of the
most popular derivatives of nitroimidazole is metronidazole
5
Department of Medicinal Chemistry, School of Pharmacy,
Ardabil University of Medical Sciences, Ardabil, Iran
6
Cellular and Molecular Biology Research Center, Health
Research Institute, Babol University of Medical Sciences,
Babol, Iran
Vol.:(0123456789)
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Chemical Papers
that is a potent antibiotic (Finegold 1980). This drug formed
of a 2-methyl-5-nitro-1H-imidazol moiety and a hydroxy-
ethyl moiety (Fig. 1). Recently, the structure modifcation
in the metronidazole structure especially in alcoholic moi-
ety of this compound has received much attention (Mallia
et al. 2005; Mao et al. 2009). For example, metronidazole
by a modifcation in the pendant hydroxyl group converted
to urease inhibitors A (Fig. 1) (Mao et al. 2009). On the
other hand, the 1,2,3-triazole ring has received much atten-
tion in medicinal chemistry due to its high dipole moment,
capability to form hydrogen bonds, and metabolic stabil-
ity (Lauria et al. 2014). Given that a valuable method for
the construction of the 1,2,3-triazole was reported by Sharp
et al., numerous 1,2,3-triazole derivatives with diverse bio-
logical efects have been reported (Hou et al. 2012; Lewis
et al. 2002; Kharb et al. 2011; H Zhou and Wang 2012; Hof-
man et al. 2000; Zhang et al. 2017). Furthermore, recently,
our research group has been reported aryl urea-1,2,3-triazole
derivatives B and 1,2,3‐triazole–(thio)barbituric acid deriva-
tives C with high inhibitory activity against urease (Fig. 1)
(Moghimi et al. 2018; Asgari et al. 2020).
Experimental
All the organic reagents were commercial products from
Sigma-Aldrich with the highest purity available (98%) and
were used without further purifcation. Melting points of the
synthesized compounds 6a–o were measured on a Kofer
hot stage apparatus and were uncorrected. 1H and 13C NMR
spectra of the title compounds were recorded on a Bruker
FT-500, using TMS as an internal standard. FT-IR spec-
tra of these compounds were obtained on a Nicolet Magna
FTIR 550 spectrophotometer (KBr disks). Mass spectrom-
etry (MS) was done by an Agilent Technology (HP) mass
spectrometer performing at ionization potential=70 eV. The
elemental analysis of the compounds 6a–o for C, H, and N
was carried out with an Elementar Analysen system GmbH
VarioEL.
General procedure for the synthesis
of 2‑methyl‑5‑nitro‑1‑(prop‑2‑yn‑1‑yl)‑1H‑imidazole
(3)
Therefore, in our continuous efort to introduce novel
urease inhibitors, we attached 2-methyl-5-nitro-1H-imida-
zole moiety of metronidazole to 1,2,3-triazole derivatives
in order to design metronidazole-1,2,3-triazole derivatives
6a–o as new urease inhibitor (Fig. 1) (Biglar et al. 2020).
These compounds were synthesized by click reaction and
evaluated against Jack bean urease (JBU). Furthermore, in
silico induced-ft docking of the most active compound was
performed to investigate interaction mode, orientation, and
conformation of this compound over the active site of JBU.
A typical process for preparation of 2-methyl-5-nitro-1-
(prop-2-yn-1-yl)-1H-imidazole; 30 mmol of 2-methyl-
5-nitro-1H-imidazole, 36 mmol potassium carbonate
(1.2 eq) was stirred in DMF (30 mL) at room temperature
while 36 mmol propargyl bromide (1.2 eq) was added to
the solution dropwise. The reaction completed within 48 h,
controlled by thin-layer chromatography (TLC, 50% petro-
leum ether/50% ethyl acetate). After fltering the solvent
to reduce potassium carbonate, the solvent was evapo-
rated, and the residue was washed by hexane to afford
2-methyl-5-nitro-1-(prop-2-yn-1-yl)-1H-imidazole.
Fig. 1 The design strategy for metronidazole-1,2,3-triazole derivatives 6 as new urease inhibitors
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Chemical Papers
1301, 1244, 1178, 1117, 1035, 931, 831, 776, 744. 1H NMR
(DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s, CH3), 3.74
(3H, s, O–CH3), 5.37 (2H, s, CH2), 5.58 (2H, s, CH2–Bn),
6.86–6.92 (3H, m, H3, H4, H6), 7.27–7.33 (1H, dd,, J=7.8,
8.7 Hz, H5), 8.25 (1H, s, H-triazole), 8.36 (1H, s, H-imida-
zole). 13C NMR (125 MHz, DMSO-d6), δ ppm: 13.2, 42.0,
53.3, 55.5, 114.0, 114.2, 120.5, 122.6, 124.4, 130.4, 137.6,
142.5, 145.5, 145.8, 159.9. Anal. Calcd for C15H16N6O3: C,
54.87; H, 4.91; N, 25.60; Found C, 54.38; H, 4.92; N, 24.84.
General procedure for the synthesis of 1‑ben‑
zyl‑4‑((2‑methyl‑5‑nitro‑1H‑imidazole‑1‑yl)
methyl)‑1H‑1,2,3‑triazole derivatives (6a‑o)
1-((1-substituted benzyl)-4-((2-methyl-5-nitro-1H-imidazole-
1-yl)methyl)-1H-1,2,3-triazole derivatives 6a–o were prepared
through a click reaction procedure. 1.1 mmol benzyl bromide
derivatives, triethylamine (1.1 mmol), and 1.1 mmol sodium
azide were stirred at room temperature for 1 h in 5 mL water/
tert-butyl alcohol (1:1) as the solvent. Afterward, 0.25 mmol
copper sulfate, 0.5 mmol sodium ascorbate, and 1 mmol
2-methyl-5-nitro-1-(prop-2-yn-1-yl)-1H-imidazole were added
to the solution and pursued by TLC (25% petroleum ether/75%
ethyl acetate). After reaction completion through 48 h, water
was added to the reaction mixture and fltered. The precipitate
was recrystallized in Ethanol to yield 6a–o.
1‑(2‑Fluorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imida‑
zol‑1‑yl)methyl)‑1H‑1,2,3‑triazole (6d)
White solid, Yield: 66%, m.p.: 143–145 °C; IR (KBr) ν
(cm−1): 3102, 3067, 2896, 1510, 1420, 1362, 1312, 1289,
1245, 1198, 1126, 1096, 1054, 974, 912, 841, 777, 727,
659. 1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.39 (2H, s, CH2), 5.80 (2H, s, CH2–Bn), 7.67–7.73
(1H, dd, J=7.8, 8.4 Hz, 1H, H5), 7.79 (1H, d, J=7.8 Hz,
1‑Benzyl‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6a)
3
H6), 8.20–8.23(2H, m, JHF = 9.5 Hz H3,4) 8.34 (1H, s,
H-triazole), 8.36 (1H, s, H-imidazole). 13C NMR (125 MHz,
DMSO-d6), δ ppm: 13.2, 42.0, 52.3, 122.6, 123.5, 123.6,
124.7, 130.8, 135.2, 138.3, 142.6, 145.5, 145.8, 148.3.
EI-MS m/z: 316.10 (Calcd for C14H13FN6O2: 316.13). Anal.
Calcd for C14H13FN6O2: C, 53.16; H, 4.14; N, 26.57; Found
C, 53.38; H, 4.12; N, 26.44.
White solid, Yield: 79%, m.p.:144–146 °C. IR (KBr) ν
(cm−1): 3300, 3102, 3054, 2951, 1590, 1512, 1440, 1325,
1284, 1215, 1173, 1053, 921, 862, 820, 753, 710, 626.
1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.37 (2H, s, CH2), 5.62 (2H, s, CH2-Bn), 7.32–7.42
(5H, m, H 2, H3, H4, H5, H6), 8.25 (1H, s, H-triazole),
8.36(1H, s, H-imidazole). 13C NMR (DMSO-d6) δ (ppm)
(125 MHz): 13.2, 42.0, 53.4, 122.6, 124.4, 128.4, 128.6,
129.2, 136.2, 142.5, 145.5, 145.8. EI-MS m/z: 298.10 (Calcd
for: C14H14N6O2: 298.12). Anal. Calcd for C14H14N6O2: C,
56.37; H, 4.73; N, 28.17; Found C, 56.18; H, 4.72; N, 28.14.
1‑(3‑Fluorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imida‑
zol‑1‑yl)methyl)‑1H‑1,2,3‑triazole (6e)
White solid, Yield: 85%, m.p: 141.2–146.1 °C. IR (KBr) ν
(cm−1): 3112, 3064, 2996, 1510, 1430, 1372, 1322, 1282,
1245, 1197, 1136, 1096, 1054, 974, 912, 841, 777, 727,
659. 1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.38 (2H, s, CH2), 5.66 (2H, s, CH2–Bn), 7.14–7.21
(3H, m, H2, H4, H6), 7.42–7.48(1H, m, H5), 8.28 (1H, s,
H-triazole), 8.36(1H, s, H-imidazole). 13C NMR (125 MHz,
DMSO-d6), δ ppm: 13.2, 42.0, 52.7, 115.2, 115.5(d,
2JC–F =23 Hz), 115.6, 122.6, 124.5(d, 4JC–F =5 Hz), 124.6,
131.2 (d, 3JC–F =14 Hz), 138.8, 138.9, 142.5, 145.5, 145.8,
160.9, 164.2. Anal. Calcd for C14H13FN6O2: C, 53.16; H,
4.14; N, 26.57; Found C, 53.18; H, 4.13; N, 26.44.
4‑((2‑Methyl‑5‑nitro‑1H‑imidazol‑1‑yl)methyl)‑1‑(2‑
methylbenzyl)‑1H‑1,2,3‑triazole (6b)
White solid, Yield: 86%, m.p: 147–150 °C. IR (KBr) ν
(cm−1): 3381, 3280, 2957, 2327, 2049, 1516, 1448, 1301,
1
1244, 1178, 1117, 1035, 931, 831, 776, 744. H NMR
(DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s, CH3), 5.36
(2H, s, CH2), 5.63( s, 2H, CH2–Bn), 7.12(1H, d, J=7.2 Hz,
H3), 7.18–7.26(1H, m, H4,H5,H6), 8.16 (1H, s, H-triazole),
8.36 (1H, s, H-imidazole). 13C NMR (125 MHz, DMSO-d6),
δ ppm: 13.2, 19.0, 42.0, 51.6, 122.6, 124.4, 126.7, 128.9,
129.2, 130.9, 134.3, 136.8, 142.4, 145.5, 145.8. EI-MS m/z:
312.10 (Calcd for: C15H16N6O2: 312.13). Anal. Calcd for
C15H16N6O2: 57.68; H, 5.16; N, 26.91; Found C, 57.38; H,
4.92; N, 26.84.
1‑(4‑Fluorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imida‑
zol‑1‑yl)methyl)‑1H‑1,2,3‑triazole (6f)
White solid, Yield: 86%, m.p.: 173–175 °C. IR (KBr) ν
(cm−1): 3112, 3064, 2996, 1510, 1430, 1372, 1322, 1282,
1245, 1197, 1136, 1096, 1054, 974, 912, 841, 777, 727,
659. 1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.38 (2H, s, CH2), 5.64 (2H, s, CH2–Bn), 7.25–7.30
(1H, m, H-aromatic), 7.42–7.43 (3H, m, H-aromatic), 8.29
(1H, s, H-triazole), 8.36 (1H, s, H-imidazole). 13C NMR
1‑(2‑Methoxybenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imi‑
dazol‑1‑yl)methyl)‑1H‑1,2,3‑triazole (6c)
White solid, Yield: 86%, m.p.: 126.9–128 °C. IR (KBr) ν
(cm−1): 3462, 3381, 3280, 2957, 2327, 2049, 1516, 1448,
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Chemical Papers
(DMSO-d6) δ (ppm) (125 MHz): 13.2, 42.0, 52.6, 122.6,
124.6, 127.2, 128.4, 128.7, 131.1, 133.7, 138.6, 142.6,
145.5, 145.8. Anal. Calcd for C14H13FN6O2: C, 53.16; H,
4.14; N, 26.57; Found C, 53.17; H, 4.13; N, 26.54.
1‑(2‑Bromobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6j)
White solid, Yield: 82%, m.p.: 141.2–146.1 °C. IR (KBr)
ν (cm−1): 3248, 3102, 3057, 2983, 1513, 1440, 1330,
1283, 1223, 1174, 1114, 1050, 922, 873, 824, 750, 687.
1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.38 (2H, s, CH2), 5.71 (2H, s, CH2-Bn), 7.23 (1H,
d, J = 6.6 Hz, H6), 7.30–7.36(1H, dd, J = 7.5 Hz, 7.8 Hz,
H4), 7.41–7.45(1H, dd, J = 6.9 Hz, 7.2 Hz, H5), 7.70(1H,
d, J = 7.5 Hz, H3), 8.23 (1H, s, H-triazole), 8.36 (1H, s,
H-imidazole). 13C NMR (DMSO-d6) δ (ppm) (125 MHz):
13.3, 42.0, 53.5, 122.6, 123.4, 124.9, 128.7, 130.9, 131.1,
133.4, 135.0, 142.3, 145.5, 145.7. EI-MS m/z: 376 (Calcd for
C14H13BrN6O2: 376.03). Anal. Calcd for C14H13BrN6O2: C,
44.58; H, 3.47; N, 22.28; Found C, 44.48; H, 3.42; N, 22.24.
1‑(2‑Chlorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imida‑
zol‑1‑yl)methyl)‑1H‑1,2,3‑triazole (6g)
White powder, Yield: 87%, m.p.: 149–152 °C. IR (KBr)
ν (cm−1): 3417, 3248, 3102, 3057, 2983, 1590, 1513,
1440, 1330, 1283, 1223, 1174, 1114, 1050, 922, 873,
824, 750, 687. 1H NMR (DMSO-d6) δ (ppm) (300 MHz):
2.41 (3H, s, CH3), 5.37 (2H, s, CH2), 5.72 (2H, s, CH2-
Bn), 7.27–7.30(1H, m, H6), 7.36–7.45(2H, m, H4, H5),
7.52–7.55(1H, m, H3), 8. 24(1H, s, H-triazole), 8.35 (1H,
s, H-imidazole). 13C NMR (125 MHz, DMSO-d6), δ ppm:
13.3, 42.0, 51.2, 122.6, 124.8, 128.2, 130.1, 131.1, 133.2,
133.4, 142.3, 145.5, 145.7. EI-MS m/z: 332.10 (Calcd for
C14H13ClN6O2: 332.08). Anal. Calcd for C14H13ClN6O2: C,
50.53; H, 3.94; N, 25.26; Found C, 50.48; H, 3.92; N, 25.24.
1‑(3‑Bromobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6k)
White solid, Yield: 88%, m.p: 157–160 °C, IR (KBr) ν
(cm−1): 3281, 3270, 2967, 2227, 2149, 1536, 1428, 1311,
1
1254, 1278, 1107, 1235, 936, 837, 786, 734. H NMR
1‑(3‑Chlorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6h)
(DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s, CH3), 5.37
(2H, s, CH2), 5.63 (2H, s, CH2-Bn), 7.31–7.39(2H, m,
H5,6), 7.54–7.56 (2H, m, H2,4), 8.29 (1H, s, H-triazole),
8.36 (1H, s, H-imidazole). 13C NMR (125 MHz, DMSO-d6),
δ ppm: 13.2, 42.0, 52.5, 122.3, 122.6, 124.6, 127.6, 131.2,
131.4, 131.5, 138.8, 142.6, 145.5, 145.8. Anal. Calcd for
C14H13BrN6O2: C, 44.58; H, 3.47; N, 22.28; Found C, 44.58;
H, 3.46; N, 22.27.
White solid, Yield: 86%, m.p.:126.9–128 °C. IR (KBr) ν
(cm−1): 3240, 3002, 2983, 1587, 1510, 1460, 1320, 1283,
1213, 1178, 1114, 1050, 922, 888, 828, 759, 688. 1H NMR
(DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s, CH3), 5.37
(2H, s, CH2), 5.61 (2H, s, CH2–Bn), 7.19–7.27(2H, m,
H4,6), 7.39–7.43(2H, m, H2,5), 8.25 (1H, s, H-triazole),
8.36 (1H, s, H-imidazole). 13C NMR (DMSO-d6) δ (ppm)
(125 MHz): 13.2, 42.0, 52.6, 122.6, 124.6, 127.2, 128.4,
128.6, 131.1, 133.7, 138.6, 142.6, 145.5, 145.8. Anal. Calcd
for C14H13ClN6O2: C, 50.53; H, 3.94; N, 25.26; Found C,
50.51; H, 3.92; N, 25.24.
1‑(4‑Bromobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6l)
White solid, Yield: 81%, m.p: 179–181 °C. IR (KBr) ν
(cm−1): 3281, 3270, 2967, 2227, 2149, 1536, 1428, 1311,
1
1254, 1278, 1107, 1235, 936, 837, 786, 734. H NMR
(DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s, CH3), 5.37
(2H, s, CH2), 5.61 (2H, s, CH2–Bn),7.29 (2H, d, J=8.4 Hz,
H2,6), 7.60 (2H, d, J = 8.4 Hz, H3,5), 8.25(1H, s, H-tria-
zole), 8.36 (1H, s, H-imidazole). 13C NMR (125 MHz,
DMSO-d6), δ ppm: 13.2, 42.0, 52.5, 122.0, 122.6, 124.5,
127.6, 130.7, 132.1, 135.6, 142.5, 145.5, 145.8. Anal. Calcd
for C14H13BrN6O2: C, 44.58; H, 3.47; N, 22.28; Found C,
44.56; H, 3.46; N, 22.28.
1‑(4‑Chlorobenzyl)‑4‑((2‑methyl‑5‑nitro‑1H‑imidazol‑1‑yl)
methyl)‑1H‑1,2,3‑triazole (6i)
White solid, Yield: 74%, m.p.:184.4–185.9 °C. IR (KBr) ν
(cm−1): 3248, 3102, 3057, 2983, 1590, 1513, 1440, 1330,
1283, 1223, 1174, 1114, 1050, 922, 873, 824, 750, 687.
1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.37 (2H, s, CH2), 5.62 (2H, s, CH2–Bn),7.36 (2H,
d, J = 8.7 Hz, H2,6), 7.46 (2H, d, J = 8.7 Hz, H3,5), 8.25
(1H, s, H-triazole), 8.36 (1H, s, H-imidazole). 13C NMR
(DMSO-d6) δ (ppm) (125 MHz): 13.2, 42.0, 52.6, 122.6,
124.4, 129.2, 130.4, 133.4, 135.2, 142.5, 145.5, 145.8. Anal.
Calcd for C14H13ClN6O2: C, 50.53; H, 3.94; N, 25.26; Found
C, 50.51; H, 3.92; N, 25.24.
4‑((2‑Methyl‑5‑nitro‑1H‑imidazol‑1‑yl)methyl)‑1‑(2‑nitrobe
nzyl)‑1H‑1,2,3‑triazole (6m)
White solid, Yield: 87%, m.p.: 149–152 °C. IR (KBr) ν
(cm−1): 3112, 3064, 2996, 1510, 1430, 1372, 1322, 1282,
1245, 1197, 1136, 1096, 1054, 974, 912, 841, 777, 727,
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659. 1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.42 (3H,
s, CH3), 5.40 (2H, s, CH2), 5.98 ( s, 2H, CH2–Bn), 7.15
(1H, d, J=7.8 Hz, H6), 7.63–7.68(1H, dd, J=7.8, 7.5 Hz,
H4), 7.74–7.79 (1H, t, 7.5 Hz, H5), 8.16 (1H, d, J=8.1 Hz,
H3), 8. 27 (1H, s, H-triazole), 8.37 (1H, s, H-imidazole).
13C NMR (125 MHz, DMSO-d6), δ ppm: 13.2, 42.0, 50.61,
122.6, 125.3, 125.5, 130.2, 130.8, 130.9, 134.8, 142.4,
145.5, 145.8, 148.1. EI-MS m/z: 343 (Calcd for C14H13N7O4:
343.10). Anal. Calcd for C14H13N7O4: C, 48.98; H, 3.82; N,
28.56; Found C, 48.78; H, 3.82; N, 28.54.
to literature (Tan et al. 2017). Urease inhibition mode was
determined by varying the concentrations of substrate (urea,
1–4 mM) in the presence of diferent concentrations of com-
pound 6f (0, 1, 2, 4 μM) as most potent inhibitor. The inhibi-
tory constant (Ki) was obtained from secondary replotting of
Lineweaver–Burk plots. All the experiments were conducted
in triplicate.
Molecular modeling
Maestro Molecular Modeling platform (version10.5) by
Schrödinger, LLC was performed in order to fnd out the
interactions mode of the most active molecule over urease
enzyme active site. The X-ray crystallographic structure of
Jack bean urease (JBU) (in complex with acetohydroxamic
acid, AHA) was downloaded from the Protein Data Bank
(PDB ID; 4h9m) (www.rcsb.org). As urease is reported to
be functionally active in monomeric state, all the docking
studies were performed on single monomer. Also, prosthetic
groups and co-factors are not directly involved in urease
inhibition, so they removed before docking investigation.
Water molecules and co-crystallized ligands were removed
from the enzyme crystallographic structure. The 3D struc-
ture of the most active synthesized compound was drawn
in Marvin 15.10.12.0 program (http://www.chemaxon.com)
and converted into pdb fle. The Protein Preparation Wizard
and the LigPrep module were used to prepare protein and
ligand structure properly. The missing side chains of the pro-
teins were flled using the Prime tool, and missing residues
were updated.
4‑((2‑Methyl‑5‑nitro‑1H‑imidazol‑1‑yl)methyl)‑1‑(3‑nitrobe
nzyl)‑1H‑1,2,3‑triazole (6n)
White solid, Yield: 82%, m.p.: 174.5–176.3 °C. IR (KBr) ν
(cm−1): 3112, 3064, 2996, 1510, 1430, 1372, 1322, 1282,
1245, 1197, 1136, 1096, 1054, 974, 912, 841, 777, 727,
659. 1H NMR (DMSO-d6) δ (ppm) (300 MHz): 2.41 (3H, s,
CH3), 5.39 (2H, s, CH2), 5.80 (2H, s, CH2–Bn), 7.67–7.73
(1H, dd, J=7.8, 8.4 Hz, H5), 7.79(1H, d, J=7.8 Hz, H6),
7.80(1H, s, H2), 8. 22(1H, d, J = 7.2 Hz, H4), 8.34(1H, s,
H-triazole), 8.36(1H, s, H-imidazole). 13C NMR (125 MHz,
DMSO-d6), δ ppm: 13.2, 42.0, 52.3, 122.6, 123.3, 123.6,
124.7, 130.8, 135.2, 138.3, 142.6, 145.5, 145.8, 148.3. Anal.
Calcd for C14H13N7O4: C, 48.98; H, 3.82; N, 28.56; Found
C, 48.98; H, 3.83; N, 28.54.
4‑((2‑Methyl‑5‑nitro‑1H‑imidazol‑1‑yl)methyl)‑1‑(4‑nitrobe
nzyl)‑1H‑1,2,3‑triazole (6o)
White solid, Yield: 93%, m.p.:185–186 °C. IR (KBr) ν
(cm−1): 3366, 3112, 3064, 2996, 1645, 1591, 1510, 1430,
1372, 1322, 1282, 1245, 1197, 1136, 1096, 1054, 974,
Induced ft docking (IFD) protocol
1
912, 841, 777, 727, 659. H NMR (DMSO-d6) δ (ppm)
The accurate side-chain and backbone fexibility during
ligand binding at the active site of urease enzyme was pre-
dicted by IFD method using Glide software (Schrödinger
LLC 2018, USA). As the kinetic study revealed competitive-
type inhibition mechanism against the enzyme, the urease
active site was used to generate the grid for IFD calculation.
The maximum 20 poses with receptor and ligand van der
Waals radii of 0.7 and 0.5, respectively, considered. Resi-
dues within 5 Å of the AHA at the active site were refned,
followed by side-chain optimization. Structures whose Prime
energy is more than 30 kcal/mol are eliminated based on
extra precious Glide docking.
(300 MHz): 2.42 (3H, s, CH3), 5.39 (2H, s, CH2), 5.80 (2H,
s, CH2–Bn), 7.55 (2H, d, J = 8.7 Hz, H2,6), 8.25, (2H, d,
J = 8.7 Hz, H3,5), 8.32 (1H, s, H-triazole), 8.37 (1H, s,
H-imidazole). 13C NMR (DMSO-d6) δ (ppm) (125 MHz):
13.2, 42.0, 52.5, 122.6, 124.4, 124.9, 129.5, 142.6, 143.6,
145.5, 145.8, 147.5. Anal. Calcd for C14H13N7O4: C, 48.98;
H, 3.82; N, 28.56; Found C, 48.88; H, 3.81; N, 28.55.
Urease inhibitory activity
Urease inhibitory activity of the synthesized compounds
6a-o was evaluated exactly according to our pervious paper
(Moghimi et al. 2018). Results are expressed as mean SEM
(n=3 experiments).
Results and discussion
Kinetic study
Chemistry
To fnd the type of urease inhibition of the newly synthesized
The synthesis of 1-substituted benzyl-4-((2-methyl-5-nitro-
compounds, Lineweaver–Burk plots were applied according
1H-imidazole-1-yl) methyl)-1H-1,2,3-triazole derivatives
1 3

Chemical Papers
6a–o was carried out by the synthetic route outlined in
Scheme 1. This procedure was carried out in three steps.
The mentioned procedure started of reaction between
2-methyl-5-nitro-1H-imidazole 1 and propargyl bromide
2 in the presence of potassium carbonate in DMF to give
2-methyl-5-nitro-1-(prop-2-yn-1-yl)-1H-imidazole 3. Then,
benzyl bromide derivatives 4a–o, triethylamine, and sodium
azide in water/tert-butyl alcohol as solvent reacted at room
temperature to give azide derivatives 5a–o. Finally, sodium
ascorbate, copper sulfate, and 2-methyl-5-nitro-1-(prop-2-
yn-1-yl)-1H-imidazole 3 were added to azide derivatives
5a–o to aford 1-substituted benzyl-4-((2-methyl-5-nitro-
1H-imidazole-1-yl)methyl)-1H-1,2,3-triazole derivatives
6a–o.
on pendant phenyl group attached to 1,2,3-triazole ring (IC50
values≤2.712 0.16).
The inhibitory activity of metronidazole-1,2,3-tria-
zole derivatives 6a–o against urease showed that 4-fuoro
derivative 6f (IC50 value=1.975 0.25 µM) was the most
potent compound, while 3-chloro and 3-bromo deriva-
tives 6h and 6k were less active halogenated derivatives
(IC50 values = 6.602 0.27–6.336 0.15 µM). As can be
seen in Table 1, remaining halogenated derivatives with
2-fluoro, 3-fluoro, 2-chloro, 4-chloro, 2-bromo, and or
4-bromo substituent had good anti-urease activity (IC50
values=3.30 0.12–5.523 0.24 µM) as observed in com-
pounds 6d-e, 6g, 6i–j, and 6l.
The structures of target compounds were afrmed by 1H
1
NMR, 13C NMR, and elemental analyses. In the H NMR
Table 1 The urease inhibitory activity of metronidazole, compound
3, and the synthesized compounds 6a–o
spectra of the title compounds, a singlet at 2.41 reveals
the CH3 group on the imidazole ring. Two singlet peaks in
5.37 ppm and 5.62 ppm are related to CH2 protons between
imidazole and triazole ring, and another is attributed to the
benzylic group, respectively. The single proton of triazole
moiety appears at 8.25 ppm, and one singlet at 8.30 ppm is
considered one proton of the imidazole ring. In the 13C NMR
spectra, the typical shifts at 130–132 ppm are related to the
triazole ring, which is observed in all spectra.
Com-
pound
R
–
IC50 (µM)a
Com-
pound
R
IC50 (µM)a
Metroni-
dazole
3
>25
>25
4.473 0.17 6j
9.647 0.21 6k
6h
3-Cl
6.602 0.27
In vitro inhibition of urease
–
H
2-CH3
6i
4-Cl
2-Br
3-Br
4-Br
3.742 0.31
5.523 0.24
6.336 0.15
4.017 0.26
6a
6b
6c
6d
6e
6f
Metronidazole, the parent molecule 3, and all the newly
synthesized compounds 6a–o were screened against H.
pylori urease (Table 1). The obtained results demonstrated
that all the synthesized compounds were more potent than
standard inhibitor thiourea while metronidazole and com-
pound 3 were inactive against H. pylori urease in compari-
son with thiourea. The most active compounds among the
new compounds 6a–o were compounds 6f, 6n, 6m, and 6c
with substituents 4-fuoro, 3-nitro, 2-nitro, and 2-methoxy
2-OCH3 2.712 0.16 6l
2-F
3-F
4-F
2-Cl
4.395 0.32 6m
3.30 0.12
1.975 0.25 6o
4.113 0.11 Thiourea
2-NO2 2.625 0.09
3-NO2 2.058 0.18
4-NO2 8.069 0.25
6n
6g
–
22.00 0.14
aValues are the mean standard error of mean. All experiments were
performed at least three times
Scheme 1 Synthetic route of the title compounds 6a–o
1 3

Chemical Papers
The second potent compound among the title syn-
thesized compound was 3-nitro derivative 6n (IC50
value = 2.058 0.18 µM). Changing the position of the
nitro group in the pendant phenyl ring from C-3 to C-2,
producing compound 6m (IC50 value = 2.625 0.09 µM)
slightly diminished the inhibitory activity while move-
ment nitro group of 3-position to 4-position, as in com-
pound 6o (IC50 value = 2.058 0.18 µM), led to a signifi-
cant decrease in the inhibitory activity.
Kinetic study
To study inhibition mode of the synthesized compounds
against urease, the kinetic study was performed on the
most active compound 6f. In this regard, urea was selected
as a substrate for urease. As can be seen in Fig. 4a,
Lineweaver–Burk plots revealed that compound 6f inhibited
target enzyme urease in an uncompetitive mode because in
the presence of this compound both Vmax and Km values were
decreased. Moreover, the value of Ki (inhibition constant) for
compound 6f was 1.21 0.12 μM (Fig. 4b).
The fourth most potent compound among the syn-
thesized compounds was 2-methoxy derivative 6c (IC50
value = 2.712 0.16 µM). Replacement of methoxy group
of compound 6c with methyl group, as in compound 6b
(IC50 value = 9.647 0.21 µM), decreased inhibitory
activity to one-third.
Molecular docking studies
The performed docking procedure was applied based on our
previous docking validity study, to evaluate the interaction
of the compound 6f with the best inhibition activity over the
urease (JBU form) active site in comparison with thiourea
as a reference urease inhibitor and metronidazole as a parent
molecule for design new compounds 6 (Azizian et al. 2020).
Figure 5a–c represents the molecular interactions of the best
conformational pose and energy valued docked complex of
compound 6f, thiourea, and metronidazole over the active
site of urease.
The comparison of anti-urease activity of the metro-
nidazole-1,2,3-triazole derivatives 6 with metronidazole
derivatives A revealed that new compounds 6 were more
active than compounds A (Mao et al. 2009). Moreover, as
can be seen in Fig. 2, the comparison of IC50 values of the
newly synthesized metronidazole-1,2,3-triazole deriva-
tives 6 with their corresponding aryl urea-1,2,3-triazole
analogs against urease revealed that our new compounds
6 significantly were more potent than their analogs of aryl
urea-1,2,3-triazole derivatives B (Moghimi et al. 2018).
As can be seen in Fig. 3, our newly synthesized com-
pounds with the exception of 2-methel derivative, were
also more potent than their corresponding analogs of
1,2,3‐triazole-(thio)barbituric acid derivatives C (Asgari
et al. 2020).
Figure 5a depicts that the 5-nitro group of compound 6f
tightly coordinated along the metal bi-nickel center and fur-
ther stabilized by H-bond and electrostatic interactions with
His492 and Asp633, respectively, which are belong to the
catalytic active site. Also, the 2-methyl-5-nitro-1H-imida-
zole formed π-cation interaction with Arg609. Moreover, the
1,2,3-triazole ring provides several important interactions at
the heart of the active site. It provides H-bond and T-shape
π–π hydrophobic interaction with Arg609 and His593,
Fig. 2 Comparison between aryl urea-1,2,3-triazole derivatives B with new compounds 6
1 3

Chemical Papers
Fig. 3 Comparison between 1,2,3‐triazole–(thio)barbituric acid derivatives C with new compounds 6
Fig. 4 a Lineweaver–Burk plots for the inhibition of urease by compound 6f; b secondary replotting of Lineweaver–Burk plots for determination
of Ki value of compound 6f
respectively, which located at both sides of active site mobile
fap and stabilized the compound in front of the mobile fap
entrance (represent in a yellow cartoon). In addition, the
1,2,3-triazole ring interacts with His492 and His519 around
the bi-nickel center through T-shape π–π hydrophobic. Com-
paring the bond-state of thiourea (Fig. 5b) revealed only
metal coordination, which consequently explains the higher
inhibition activity of compound 6f rather than thiourea.
On the other hand, Fig. 5c depicts the interaction
mode of metronidazole as a parent for design of synthe-
sized compounds 6. The nitro and 2-hydroxyethyl group
ligated to the bi-nickel center and interacted with Asp633
and His492 through H-bond and Asp494 by electrostatic
interaction. Additionally, metronidazole interacts with
Arg609 at one side of the mobile flap through H-bond
and electrostatic interactions. Comparison of the interac-
tion mode of compound 6f and metronidazole reveals that
the introduction of the 1,2,3-triazol derivatives instead of
2-hydroxyethyl was responsible for higher inhibition activ-
ity of the new synthesized compounds as it not only ori-
ented toward the bi-nickel active site and block deposition
of the substrate, but also strongly interacted with the both
side of the mobile active site fap which is important for
urease inhibition activity. Finally, the consequence of this
hybridization is lower binding energy of compound 6f (glide
energy=− 64.56 kcal/mol) in comparison with metronida-
zole (glide energy=− 34.58 kcal/mol).
Based on crystal structures of the ureases, besides the
conserved residues in the active site, including bi-nickel
ions, His492, His519, and Asp633, are of the key catalytic
1 3

Chemical Papers
Fig. 5 Docked representation of the synthesized compound 6f (a), thiourea (b), and metronidazole (c) over the JBU active site. The active site
fap is colored in yellow. H-bond, π–π stacking, π-cation, and electrostatic interactions are in yellow, blue, green, and pink color, respectively
residues in the urease active site most of the ureases share
conserved residues that make up the mobile fap which cov-
ers the active site (Balasubramanian and Ponnuraj 2010). In
JBU, the residues comprising the mobile fap are 590–606
on the α subunit part of the enzyme in a helix-turn-helix
motif structure, in which His593 and Arg609 residues
belong to each side of active site fap. These residues are
the most important residues for urease inhibition because of
their role in the fexibility of mobile fap covering the active
site entrance, followed by inhibiting the ureolytic activity.
active site, which signifcantly reduces the catalytic activity
of urease.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11696-021-01653-4.
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Malfertheiner P, Megraud F, Omorain CA, Gisbert JP, Kuipers EJ,
Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt
R (2017) Management of Helicobacter pylori infection—the
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