Synthesis and Biological Evaluation of Imidazole derivatives against the Metallo-Β-Lactamase IMP-1

 

Bharat Kumar Tyagi, Chandra Kishore Tyagi

Sri Satya Sai University of Technology and Medical Sciences, Village Pachama,

Sehore-466001, Madhya Pradesh.

*Corresponding Author E-mail: kishore198012@gmail.com

 

ABSTRACT:

Mutations in bacteria can result in antibiotic resistance due to the overuse or abuse of β-lactam antibiotics. One strategy which bacteria can become resistance toward antibiotics is secreting of metallo-β-lactamase enzymes that can open the lactam ring of the β-lactam antibiotic and inactivate them. This issue is a threat for human health and one strategy to overcome this situation is co-administration of β-lactam antibiotics with an inhibitor. So far, no clinically available inhibitors of metallo β-lactamases (MBLs) reported and the clinically inhibitors of serine β-lactamase are useless for MBLs. Accordingly, finding a potent inhibitor of the MBLs being very important. In this study, imidazole derivatives primarily were synthesized and their inhibitory activity was measured. Later in silico binding model was used to predict the configuration and conformation of the ligands into the active site of enzyme. Two molecules demonstrated with IC50 of 39 μM and 46 μM against MBL (IMP-1).

 

KEYWORDS: Imidazole, Beta-lactamase, Anti-microbial, In-silico, Inhibition.

 

 

 

1.     INTRODUCTION:

Since their discovery in 1930, β-lactam antibiotics have become the standard treatment for bacterial infections. The use of antibiotics is not monitored strictly in many parts of the world and more than 50% of antibiotics are used without prescription worldwide(1–8). Due to the clinical overuse of antibiotics, many bacteria have become resistance against β-lactam antibiotics with emergence of bacterial pathogens by secreting β-lactamases (enzymes that inactivate these antibiotics by hydrolyzing their β-lactam ring) which cause a matter of great concern. According to the mechanism of action, β-Lactamases are classified into serine-β-lactamases (Classes A, C and D) and MBLs (Class B).

 

MBLs are further divided into three subclasses, B1, B2, and B3, depending on their amino acid sequences and metal occupancies with one or two zinc (II) ions in the active site(1–9). The inactivation of β-lactam antibiotics by MBLs is a significant threat to public health. This issue can be controlled by either discovery of new antibiotics or the use of an inhibitor co-administered with β-lactam antibiotics(10,11). At the current time, none of them are clinically available. Moreover, MBLs are not inhibited by clavulanic acid, an inhibitor commonly co-administered with β-lactam antibiotics for serine β-lactamases. Therefore, there are currently no clinically available inhibitors of MBLs. In addition, MBLs are characterized by αββα quaternary structural fold. The zinc ion(s) containing active site is located at the edge of the ββ sheets in a pocket. The distance between two zinc ions is roughly 3.4–4.4 A for most of the MBLs. There is a bridging water molecule between two zinc ions and the activated water molecule plays an important role in the hydrolysis of antibiotics. In the active site of subclass B1, one of the zinc ions is coordinated by three histidines (His116, His118 and His196) and a water molecule with the arrangement of tetrahedral while the second zinc ion is coordinated by Asp120, Cys221, His263 and two water molecules with the geometry of distorted trigonal bipyramidal (Fig. 1)(12–20). The aim of the research is to introduce a new series of MBLs inhibitors derived from Imidazole and investigate their inhibitory activity.

 

Inhibitors of MBLs have been reported in different categories such as thiols(21–27), sulphates(28), dicarboxylic acids(29–34), trifluoromethylketones and alcohols (35), hydroxamates(36), tetrazoles(37), sulfonamides and sulfonyl hydrazones(38). Furthermore, compounds containing a zinc-binding sulfur atom comprise the first category of MBLs inhibitors(39).

 

Fig. 1. Representative active-site pocket of MBL (IMP-1, subclass B1 of metallo β-lactamase (MBLs), PDB Code: 1JJT). The active site is shown with yellow dash circle and the left picture shows zinc ions and the amino acids of the active site of IMP-1.

 

 

Fig. 2. Lead compounds with IC50 at the concentration of 1mM against IMP-1.

 

2.    CHEMISTRY:

In this study, to find a new series of inhibitors, two imidazole molecules (Fig. 2), reported by Vella et al.(40) with IC50 at the concentration of 1mM against IMP-1, were used as the lead compounds for synthesis of further analogues.

 

Accordingly, a series of imidazole analogues with electron –donor and -acceptor (Fig. 3) were synthesized and their inhibitory activity evaluated against IMP-1. In total, twenty-four molecules and lead compounds were synthesized and 1H NMR and 13C NMR spectra and HRMS were recorded. Some of these compounds are new and were not already reported in the literature. All chemicals required for the process is commercially available with inexpensive price which is an advantage to produce the final compound in a single step. The other advantages of these chemicals are their stability as they are not easily oxidized when access to fresh air or dissolved in water. Furthermore, because of the hydrogen -donor and -acceptor groups, they are expected to be soluble in water at the time of assay. These molecules were synthesized in one step by three different procedures. Compounds 1–18 were synthesized with the general procedure reported by Salvio et al.(41) with the yield of 55–93% and the synthetic pathway of the reaction is shown in Scheme 1. The 1H NMR and 13C NMR spectra were recorded and were in agreement with compounds that already reported. For all known and new compounds, LRMS and HRMS (positive mode) spectra were also recorded to make sure about the purity of these compounds as a key factor at the time of assay. Compounds 19–24 were synthesized in one step with the general procedure reported by Roumen et al.(42) using Pd/C, HCl, H2 in ethanol shown in Scheme 2. These molecules were prepared in a single step by a range yield of 80–92% and their chemical structures were investigated by 1H NMR and 13C NMR spectra as well as recording LRMS and HRMS (positive mode) spectra to investigate the purity of these compounds.

 

The general procedure reported by Vallee et al.(43) was used for the synthesis of compounds 25 and 26 and the synthetic pathway is shown in Scheme 3. The mixture of starting materials was heated up to 160°C for half an hour without addition of solvent to produce the products a range yield of 80–90%. These compounds are known and their 1H NMR and 13C NMR spectra were in agreement with the reference(43). For both molecules LRMS and HRMS (positive mode) were recorded for the purpose of purity assessment.

 

3.    BIOLOGICAL EVALUATION:

3.1. Enzyme expression and purification:

The IMP-1 enzyme, lacking the first 21 signal peptide amino acid residues, was expressed and purified using the protocol of Vella et al.(40). Details of the expression and purification of the enzyme are presented in the Supplementary data.

 

3.2. Kinetic assays:

CENTA (sodium (7R)-3-(((3-carboxylato-4-nitrophenyl) thio) methyl)-8-oxo-7-(2-(thiophen-2-yl) acetamido)-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylate) was used as the substrate for the study of kinetic assay and it was synthesized by a procedure reported by Bebrone et al.(44). Inhibition assays for IMP-1 were performed in 96 well 400μL multi-titre plates using a multi-plate spectrophotometer and the hydrolysis rate of CENTA was measured at λ = 405nm. The initial screening assay was performed in duplicate at concentrations of 1 mM, 500μM, 250μM, 100μM, 50μM and 10μM of inhibitors, with CENTA (a type of cephalosporin) as the substrate and HEPESX (50mM HEPES, 0.1M NaCl, 100mM ZnCl2, pH 7.0) as the buffer at 25°C. At the time of assay, some compounds were insoluble at the concentration of 1mM but were soluble at the other concentrations. The final concentrations of enzyme and CENTA were 5nM and 70μM respectively. Bovine serum albumin (final concentration of 20μg/ml) was added to the enzyme to stability. For each well, 196μL substrate and 4μL inhibitor were added followed by the addition of 200μL of enzyme. The rate of hydrolysis of substrate was recorded for 5 min. As per discussed, MBLs catalyze the hydrolysis of β-lactam antibiotics (Fig. 4) which eventually lead to their inactivation against bacteria. When CENTA is hydrolyzed by MBLs, a yellow chromophore compound (3-carboxy-4-nitrobenzenethiolate, ε=6400M−1 cm−1) is released which is detectable at the wavelength of 405 nm (Fig. 4). The results indicate that nearly 90% of all compounds are at least 5–10-fold more active than reference compounds (Table 1). In addition, more than half of the synthesized molecules show IC50 nearly 100 μM while the reference molecules show IC50 at 1 mM. Furthermore, compounds with R=methyl group are more potent than analogues with hydrogen group. This issue can be explained by the better fitting or locking of these inhibitors into the active site of enzyme.

 

Fig. 3. Two reference compounds and other imidazole derivatives.

 

In-silico modeling shows different configurations and conformations for this series of compounds into the active site. For instance, compounds that have nitro substitution are coordinated into zinc ions via the oxygen of nitro group while the other molecules without electron-donor groups are coordinated into zinc ions via the lone pair of nitrogen of imidazole. Moreover, the molecules with electron-donor groups can create further interactions with amino acids of the active sites. The investigation of computational modeling of ligand 16 (Fig. 5) predicted that one of the oxygen atoms of nitro group is coordinated to both zinc atoms with the predicted distances of 5.10 A (Zn1) and 3.36 A (Zn2) and the other oxygen of nitro group predicted to form hydrogen bonds with Gly232 and Lys224 with the distances of 1.70 A and 2.04 A respectively. The aromatic ring of this ligand can also create a π-π interaction with aromatic ring of TRP64 which predicted to increase the potency of inhibition activity.

 

4.    CONCLUSION:

In order to introduce a new class of inhibitors of IMP-1, twenty-four molecules derived from imidazole were synthesized and their inhibitory activity and IC50 were measured. The results demonstrated that all molecules are more potent than reference molecules against IMP-1. Furthermore, two compounds show the best IC50 with the values of 39μM and 46μM in this series of molecules. The study demonstrated that the addition of the electron-donor group to imidazole derivatives can increase the potency of inhibitory activity against IMP-1 with better coordination to zinc ions of the active site.

 

5.    EXPERIMENTAL

 

Scheme 1. Reagents and conditions: Dry CH3CN, K2CO3, reflux, and yield=55–93%.

 

 

5.1. Synthesis:

All chemicals were purchased from Sigma-Aldrich, Merck and Fluka chemical companies. All NMR experiments were recorded on Bruker AVANCE 500, 400 or 300 MHz spectrometers. Chemical shifts are reported in parts per million (ppm) on a δ scale and referenced to the residual solvent peak (1H, 7.24 ppm, 13C, 77.0 ppm for CDCl3; 1H, 2.49 ppm, 13C, 39.5 ppm for DMSO‑d6; 1H, 3.30 ppm, 13C, 49.5 ppm for CD3OD). Coupling constants (J) are reported in Hertz. Multiplicities of the peaks are abbreviated as follows: s for singlet, bs for broad singlet, d for doublet, t for triplet, and q for quartet. Low- and high- resolution EIMS were measured on a Finnigan MAT 900 XL-Trap mass spectrometer in positive and negative ionization mode. LR-ESI were recorded on a Bruker HCT 3D Ion Trap and HR-ESI were performed on a Bruker MicrO Tof-Q with the DIONEX Ultimate 3000LC in positive and negative electrospray ionization mode, with CH3OH as solvent. 1H NMR and 13C NMR spectra are shown in the Supplementary data.

 

5.2. General procedure 1:

Compounds 1–18 were synthesized using the following general procedure reported by Salvio et al.(41). A mixture of potassium carbonate (2.0g, 14.4 mmol), imidazole derivatives 27–28 (32.9 mmol) and compounds 29–37 (4.7 mmol) in dry acetonitrile (50ml) was heated under reflux and the progress of the reaction were monitored by TLC. Then the solvent was evaporated under the vacuum and the residue was dissolved in DCM (100ml) *. The organic layer was washed with saturated sodium bicarbonate aqueous solution (2×50 ml), passed through diatomaceous earth, dried over sodium sulfate, evaporated under the vacuum, and purified by flash column chromatography (ethyl acetate-hexane 0–100 %) ** to give the products 1–18:

 

*Note 1: Ethyl acetate (200 ml) was used for compounds 17 and 18.

**Note 2: Compounds 17 and 18 (ethyl acetate–methanol 0–100%).

 

5.3. General procedure 2:

The general procedure reported by Roumen et al. (43) was modified and used (HCl 2M was added in the reaction) for the synthesis of hydrochloride salt of the molecules 19–24. A mixture of compounds 13–18 (4.6 mmol), HCl 2M (4 ml), Pd/C 5% (100 mg) in ethanol (20 ml) was hydrogenated under reflux at atmospheric pressure for 24 h. The organic solvent was evaporated under the vacuum and water 50 ml) was added and stirred for 10 min and the solid impurity was filtered off then water phase was washed with ethyl acetate (2×50 ml), passed through diatomaceous earth, and evaporated under the vacuum and dried in oven at 40 °C to give the products 19–24.

 

27 R1 = H                                56                                            25 R = H

28 R1 = CH3                                                                                          26 R = CH3

Scheme 3. Reagents and conditions: 160 °C, 30 min, yield: 80–90%.

 

Table 1: IC50 of imidazole derivatives 1–26 against IMP-1.

Compound

IC50 (μM)

Compound

IC50 (μM)

1

>100

14

84.7

2

>100

15

>100

3

>100

16

39.0

4

89.3

17

>100

5

>100

18

>100

6

88.6

19*

970

7

88.1

20

64.6

8

81.5

21*

962

9

>100

22

64.7

10

92.5

23

>100

11

>100

24

>100

12

46.0

25

>100

13

>100

26

97.6

 

5.4. General procedure 3:

Compounds 25–26 were synthesized using the following general procedure reported by Vallee et al.(43). A mixture of imidazole derivatives 27–28 (40 mmol) and 4-hydroxybenzyl alcohol 56 (1.0g, 8.0 mmol) was heated at 160°C for half an hour which resulted dark brown oil. The mixture of the reaction was then cooled down to 50–80°C and added to a stirring hot water (100 ml) resulted brown solid residue which was filtered off. Then the residue was transferred to a round bottom flask and ethyl acetate (2×50ml) was added and stirred for 10 min and then it was filtered off and dried in the oven at 40 °C to give the products 25–26.

 

5.4.1. 1-Benzyl-1H-imidazole (1):

Pale yellow solid, 0.61 g (82%). 1H NMR (300 MHz, CDCl3): δ 7.51 (1H, s, NCHN), 7.37–7.25 (3H, m, Ph-H), 7.16–7.08 (2H, m, Ph-H), 7.06 (1H, s, NCHCHNCH2), 6.87 (1H, s, NCHCHNCH2), 5.08 (2H, s, CH2). 13C NMR (75 MHz, CDCl3): δ 137.4 (Ar-C), 136.1 (Ar-C), 129.7 (Ar-C), 128.9 (Ar-C), 128.2 (Ar-C), 127.2 (Ar-C), 119.2 (Ar-C), 50.7 (CH2). HRMS calculated for C10H11N2 [M+H] + 159.0922, found 159.0924. m.p. 71–73°C (lit. m.p. 71–72 °C) (41).

 

5.4.2. 1-Benzyl-2-methyl-1H-imidazole (2):

Pale yellow oil, 0.65 g (80%). 1H NMR (400 MHz, CDCl3): δ 7.30–7.17 (3H, m, Ph-H), 6.98 (2H, d, J=1.5 Hz, Ph-H), 6.88 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.76 (1H, d, J=1.4 Hz, NCHCHNCH2), 4.95 (2H, s, CH2), 2.45 (3H, s, CH3). 13C NMR (100 MHz, CDCl3): δ 144.5 (Ar-C), 136.1 (Ar-C), 128.6 (Ar-C), 127.6 (Ar-C), 126.9 (Ar-C), 126.3 (Ar-C), 119.6 (Ar-C), 49.3 (CH2), 12.8 (CH3). HRMS calculated for C11H13N2 [M+H] + 173.1073, found 173.1077.

 

5.4.3. 1-(4-Methylbenzyl)-1H-imidazole (3):

Brown solid, 0.66 g (81%). 1H NMR (300 MHz, CDCl3): δ 7.44 (1H, s, NCHN), 7.08 (2H, d, J=7.9 Hz, Ph-H), 7.04–6.94 (3H, m, Ph-H and NCHCHNCH2), 6.81 (1H, t, J=1.2 Hz, NCHCHNCH2), 4.97 (2H, s, CH2), 2.27 (3H, s, CH3). 13C NMR (75 MHz, CDCl3): δ 137.7 (Ar-C), 137.1 (Ar-C), 132.9 (Ar-C), 129.4 (Ar-C), 129.3 (Ar-C), 127.0 (Ar-C), 118.9 (Ar-C), 50.2 (CH2), 20.8 (CH3). HRMS calculated for C11H13N2 [M+H] + 173.1073, found 173.1076. m.p. 49–50 °C (lit. m.p. 49–50 °C) [46].

 

5.4.4. 2-Methyl-1-(4-methylbenzyl)-1H-imidazole (4):

Brown oil, 0.69 g (79%). 1H NMR (500 MHz, CDCl3): δ 7.09 (2H, d, J=7.9 Hz, Ph-H), 6.94–6.86 (3H, m, Ph-H and NCHCHNCH2), 6.77 (1H, d, J=1.3 Hz, NCHCHNCH2), 4.94 (2H, s, CH2), 2.28 (6H, s, both CH3). 13C NMR (125 MHz, CDCl3): δ 144.7 (Ar-C), 137.5 (Ar-C), 133.2 (Ar-C), 129.4 (Ar-C), 127.1 (Ar-C), 126.5 (Ar-C), 119.7 (Ar-C), 49.3 (CH2), 20.9 (Ar-Me), 13.0 (Imidazole-Me). HRMS calculated for C12H15N2 [M+H] + 187.1230, found 187.1227.

 

5.4.5. 1-(2-Chlorobenzyl)-1H-imidazole (5):

Brown oil, 0.78 g (86%). 1H NMR (300 MHz, CDCl3): δ 7.48 (1H, s, NCHN), 7.35–7.29 (1H, m, Ph-H), 7.25–7.11 (2H, m, Ph-H), 7.01 (1H, t, J=1.1 Hz, NCHCHNCH2), 6.90–6.84 (2H, m, Ph-H and NCHCHNCH2), 5.14 (2H, s, CH2). 13C NMR (75 MHz, CDCl3): δ 137.4 (Ar-C), 133.8 (Ar-C), 132.8 (Ar-C), 129.6 (Ar-C), 129.5 (Ar-C), 129.4 (Ar-C), 128.8 (Ar-C), 127.2 (Ar-C), 119.1 (Ar-C), 48.1 (CH2). HRMS calculated for C10H10ClN2 [M+H] + 193.0527, found 193.0534. Rf = 0.13 (20/80 ethyl acetate/petroleum ether).

 

Fig. 5. Interactions of ligand 16 at the active site of IMP-1 (PDB: 1JJT). Atom colors are as follows: blue–nitrogen, red–oxygen, grey–carbon and yellow-zinc atom (of IMP-1), and red–oxygen, blue–nitrogen, green–carbon, and yellow–sulfur (on inhibitor).

 

5.4.6. 1-(2-Chlorobenzyl)-2-methyl-1H-imidazole (6):

Brown solid, 0.83 g (85%). 1H NMR (300 MHz, CDCl3): δ 7.35 (1H, dd, J=7.3, 1.3 Hz, Ph-H), 7.24–7.10 (2H, m, Ph-H), 6.92 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.77 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.60 (1H, d, J=6.5 Hz, Ph-H), 5.07 (2H, s, CH2), 2.28 (3H, s, CH3). 13C NMR (75 MHz, CDCl3): δ 145.0 (Ar-C), 134.0 (Ar-C), 132.3 (Ar-C), 129.5 (Ar-C), 129.1 (Ar-C), 127.6 (Ar-C), 127.5 (Ar-C), 127.3 (Ar-C), 119.8 (Ar-C), 47.2 (CH2), 12.8 (CH3). HRMS calculated for C11H12ClN2 [M+H] + 207.0684, found 207.0687. m.p =62.5–63.5 °C.

5.4.7. 1-(4-Chlorobenzyl)-1H-imidazole (7):

Pale yellow oil, 0.84 g (93%). 1H NMR (300 MHz, CDCl3): δ 7.30 (1H, s, NCHN), 7.06 (2H, d, J=8.5 Hz, Ph-H), 6.88 (3H, m, Ph-H and NCHCHNCH2), 6.67 (1H, t, J=1.3 Hz, NCHCHNCH2), 4.84 (2H, s, CH2). 13C NMR (75 MHz, CDCl3): δ 136.7 (Ar-C), 134.3 (Ar-C), 133.3 (Ar-C), 129.2 (Ar-C), 128.4 (Ar-C), 128.1 (Ar-C), 118.6 (Ar-C), 49.3 (CH2). HRMS calculated for C10H10ClN2 [M+H] + 193.0527, found 193.0533.

 

5.4.8. 1-(4-Chlorobenzyl)-2-methyl-1H-imidazole (8):

Brown viscous oil, 0.85 g (88%). 1H NMR (500 MHz, CDCl3): δ 7.29 (2H, t, J=13.6 Hz, Ph-H), 6.98–6.92 (3H, m, Ph-H and NCHCHNCH2), 6.80 (1H, d, J=1.4 Hz, NCHCHNCH2), 5.00 (2H, s, CH2), 2.31 (3H, s, CH3). 13C NMR (125 MHz, CDCl3): δ 144.9 (Ar-C), 134.8 (Ar-C), 133.9 (Ar-C), 129.2 (Ar-C), 128.0 (Ar-C), 127.4 (Ar-C), 119.8 (Ar-C), 49.1 (CH2), 13.0 (CH3). HRMS calculated for C11H12ClN2 [M+H] + 207.0684, found 207.0685.

 

5.4.9. 1-(4-Methoxybenzyl)-1H-imidazole (9):

Pale yellow solid, 0.80 g (90%). 1H NMR (300 MHz, CDCl3): δ 7.42 (1H, s, NCHN), 7.03 (3H, t, J=8.5 Hz, Ph-H and NCHCHNCH2), 6.85–6.78 (3H, m, Ph-H and NCHCHNCH2), 4.97 (2H, s, CH2), 3.73 (3H, s, CH3). 13C NMR (75 MHz, CDCl3): δ 159.3 (Ar-C), 137.1 (Ar-C), 129.5 (Ar-C), 128.7 (Ar-C), 128.0 (Ar-C), 119.0 (Ar-C), 114.2 (Ar-C), 55.1 (CH3), 50.1 (CH2). HRMS calculated for C11H12N2NaO [M+Na] + 211.0842, found 211.0846. m.p. 57–59 °C (lit. m.p. 57–58 °C).

 

5.4.10. 1-(4-Methoxybenzyl)-2-methyl-1H-imidazole (10):

Brown viscous oil, 0.85 g (89%). 1H NMR (500 MHz, CDCl3): δ 6.93 (2H, d, J=11.0 Hz, Ph-H), 6.84 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.78 (2H, d, J=11.0 Hz, Ph-H), 6.72 (1H, d, J=1.3 Hz, NCHCHNCH2), 4.87 (2H, s, CH2), 3.69 (3H, s, CH3O), 3.25 (3H, s, CH3). 13C NMR (125 MHz, CDCl3): δ 159.0 (Ar-C), 144.5 (Ar-C), 128.1 (Ar-C), 127.9 (Ar-C), 126.9 (Ar-C), 119.5 (Ar-C), 114.0 (Ar-C), 55.0 (CH3O), 49.0 (CH2), 12.9 (CH3). HRMS calculated for C12H15N2O [M+H] +203.1179, found 203.1179.

 

5.4.11. 1-(Naphthalen-1-ylmethyl)-1H-imidazole (11):

Dark brown viscous oil, 0.88 g (90%). 1H NMR (400 MHz, CDCl3): δ 7.93–7.81 (3H, m, naphthyl), 7.66 (1H, s, NCHN), 7.56–7.47 (2H, m, naphthyl), 7.43 (1H, dd, J=8.2, 7.0 Hz, naphthyl), 7.18 (1H, d, J=7.0 Hz, naphthyl), 7.09 (1H, s, NCHCHNCH2), 6.92 (1H, s, NCHCHNCH2), 5.59 (2H, s, CH2). 13C NMR (100 MHz, CDCl3): δ 137.3 (Ar-C), 133.8 (Ar-C), 131.0 (Ar-C), 130.8 (Ar-C), 129.4 (Ar-C), 129.0 (Ar-C), 128.9 (Ar-C), 127.1 (Ar-C), 126.4 (Ar-C), 126.3 (Ar-C), 125.4 (Ar-C), 122.3 (Ar-C), 119.5 (Ar-C), 48.9 (CH2). HRMS calculated for C14H13N2 [M+H] + 209.1073, found 209.1077.

 

5.4.12. 2-Methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole (12):

Dark brown solid, 0.84 g (80%). 1H NMR (400 MHz, CDCl3): δ 7.90–7.71 (3H, m, naphthyl), 7.56–7.46 (2H, m, naphthyl), 7.33 (1H, dd, J=8.2, 7.2 Hz, naphthyl), 6.94 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.75 (1H, dd, J=7.1, 1.0 Hz, naphthyl), 6.72 (1H, d, J=1.4 Hz, NCHCHNCH2), 5.39 (2H, s, CH2), 2.32 (3H, s, CH3). 13C NMR (100 MHz, CDCl3): δ 144.9 (Ar-C), 133.4 (Ar-C), 131.5 (Ar-C), 130.2 (Ar-C), 128.8 (Ar-C), 128.4 (Ar-C), 127.2 (Ar-C), 126.6 (Ar-C), 126.0 (Ar-C), 125.3 (Ar-C), 124.1 (Ar-C), 122.0 (Ar-C), 119.8 (Ar-C), 47.2 (CH2), 12.8 (CH3). HRMS calculated for C15H15N2 [M+H] + 223.1230, found 223.1234. m.p. 103.5–104.5 °C.

 

5.4.13. 1-(3-Nitrobenzyl)-1H-imidazole (13):

Brown solid, 0.67 g (70%). 1H NMR (300 MHz, DMSO‑d6): δ 8.18–8.08 (2H, m, Ph-H), 7.82 (1H, s, NCHN), 7.73–7.60 (2H, m, Ph-H), 7.25 (1H, t, J=1.4 Hz, NCHCHNCH2), 6.93 (1H, t, J=1.0 Hz, NCHCHNCH2), 5.36 (2H, s, CH2). 13C NMR (75 MHz, DMSO‑d6): δ 147.9 (Ar- C), 140.1 (Ar-C), 137.6 (Ar-C), 134.1 (Ar-C), 130.3 (Ar-C), 129.0 (Ar-C), 122.7 (Ar-C), 122.1 (Ar-C), 119.6 (Ar-C), 48.5 (CH2). HRMS calculated for C10H10N3O2 [M+H] + 204.0768, found 204.0767. m.p. 95–97 °C (lit. m.p. 95–97 °C) [50].

 

5.4.14. 2-Methyl-1-(3-nitrobenzyl)-1H-imidazole (14):

Brown solid, 0.91 g (89%). 1H NMR (500 MHz, CDCl3): δ 8.14 (1H, m, Ph-H), 7.95 (1H, s, Ph-H), 7.51 (1H, t, J=8.0 Hz, Ph-H), 7.29 (1H, d, J=8.0 Hz, Ph-H), 6.97 (1H, s, NCHCHNCH2), 6.84 (1H, s, NCHCHNCH2), 5.14 (2H, s, CH2), 2.31 (3H, s, CH3). 13C NMR (125 MHz, CDCl3): δ 148.6 (Ar-C), 144.8 (Ar-C), 138.6 (Ar-C), 132.3 (Ar-C), 130.1 (Ar-C), 128.1 (Ar-C), 123.0 (Ar-C), 121.5 (Ar-C), 119.7 (Ar-C), 48.9 (CH2), 13.1 (CH3). HRMS calculated for C11H12N3O2 [M+H] +218.0924, found 218.0929. m.p. 82–83 °C.

 

5.4.15. 1-(4-Nitrobenzyl)-1H-imidazole (15):

Brown solid, 0.86 g (90%). 1H NMR (300 MHz, DMSO‑d6): δ 8.19 (2H, d, J=8.5 Hz, Ph-H), 7.55 (1H, s, NCHN), 7.25 (2H, d, J=8.5 Hz, Ph-H), 7.11 (1H, t, J=1.2 Hz, NCHCHNCH2), 6.88 (1H, t, J=1.2 Hz, NCHCHNCH2), 5.23 (2H, s, CH2). 13C NMR (75 MHz, DMSO‑d6): δ 147.8 (Ar-C), 143.4 (Ar-C), 137.5 (Ar-C), 130.4 (Ar-C), 127.7 (Ar-C), 124.2 (Ar-C), 119.2 (Ar-C), 49.9 (CH2). HRMS calculated for C10H10N3O2 [M+H] + 204.0768, found 204.0770. m.p. 55–56 °C (lit. m.p. 55–56 °C) [52].

 

5.4.16. 2-Methyl-1-(4-nitrobenzyl)-1H-imidazole (16):

Black solid, 0.90 g (88%). 1H NMR (300 MHz, CDCl3): δ 8.19 (2H, d, J=8.8 Hz, Ph-H), 7.16 (2H, d, J=8.6 Hz, Ph-H), 7.00 (1H, s, NCHCHNCH2), 6.85 (1H, s, NCHCHNCH2), 5.16 (2H, s, CH2), 2.32 (3H, s, CH3). 13C NMR (75 MHz, CDCl3): δ 147.7 (Ar-C), 143.4 (Ar-C), 127.7 (Ar-C), 127.2 (Ar-C), 124.5 (Ar-C), 124.3 (Ar-C), 119.9 (Ar-C), 49.1 (CH2), 12.9 (CH3). HRMS calculated for C11H12N3O2 [M+H] +218.0924, found 218.0927. m.p. 96–97 °C (lit. m.p. 95–96 °C).

 

5.4.17. 1-(2-Chloro-5-nitrobenzyl)-1H-imidazole (17):

Brown solid, 0.61 g (55%). 1H NMR (500 MHz, CD3OD): δ 8.17 (1H, dd, J=8.8, 2.6 Hz, Ph-H), 7.89 (1H, d, J=2.7 Hz, Ph-H), 7.83 (1H, s, NCHN), 7.70 (1H, d, J=8.8 Hz, Ph-H), 7.19 (1H, t, J=1.3 Hz, NCHCHNCH2), 7.05 (1H, t, J=1.2 Hz, NCHCHNCH2), 5.46 (2H, s, CH2). 13C NMR (125 MHz, CD3OD): δ 148.4 (Ar-C), 140.9 (Ar-C), 139.2 (Ar-C), 138.0 (Ar-C), 132.1 (Ar-C), 129.8 (Ar-C), 125.5 (Ar-C), 125.0 (Ar-C), 121.1 (Ar-C), 48.8 (CH2). HRMS calculated for C10H9ClN3O2 [M+H] + 238.0378, found 238.0386. m.p. 107–109 °C.

 

5.4.18. 1-(2-Chloro-5-nitrobenzyl)-2-methyl-1H-imidazole (18):

Dark brown solid, 0.65 g (55%). 1H NMR (300 MHz, CD3OD): δ 8.16 (1H, dd, J=8.8, 2.7 Hz, Ph-H), 7.72 (1H, d, J=8.7 Hz, Ph-H), 7.56 (1H, d, J=2.6 Hz, Ph-H), 7.06 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.94 (1H, d, J=1.3 Hz, NCHCHNCH2), 5.37 (2H, s, CH2), 2.34 (3H, s, CH3). 13C NMR (75 MHz, CD3OD): δ 148.5 (Ar-C), 146.7 (Ar-C), 140.5 (Ar-C), 137.9 (Ar-C), 132.2 (Ar-C), 127.8 (Ar-C), 125.3 (Ar-C), 123.9 (Ar-C), 121.5 (Ar-C), 48.0 (CH2), 12.5 (CH3). HRMS calculated for C11H11ClN3O2 [M+H] + 252.0534, found 252.0537. m.p. 88–90 °C.

 

5.4.19. 1-(3-Aminobenzyl)-1H-imidazol-3-ium (19):

Pale brown solid, 0.79 g (82%). 1H NMR (400 MHz, DMSO‑d6): δ 9.39 (1H, s, NHCHN), 7.79 (1H, t, J=1.7 Hz, NHCHCHN), 7.72 (1H, t, J=1.7 Hz, NHCHCHN), 7.45 (1H, t, J=7.8 Hz, Ph-H), 7.34–7.23 (3H, m, Ph-H), 5.50 (2H, s, CH2). 13C NMR (100 MHz, DMSO‑d6): δ 136.8 (Ar-C), 135.5 (Ar-C), 134.8 (Ar-C), 130.2 (Ar-C), 126.0 (Ar-C), 122.4 (Ar-C), 122.1 (Ar-C), 121.4 (Ar-C), 120.3 (Ar-C), 51.0 (CH2). HRMS calculated for C10H12N3 [M]+ 174.1031, found 174.1034. m.p. 217–218 °C.

 

5.4.20. 1-(3-Aminobenzyl)-2-methyl-1H-imidazol-3-ium (20):

Pale yellow solid, 0.82 g (80%). 1H NMR (300 MHz, DMSO‑d6): δ 8.28–8.18 (2H, m, Ph-H), 7.81–7.66 (3H, m, Ph-H and NHCHCHN), 7.62 (1H, d J=2.1 Hz, NHCHCHN), 5.56 (2H, s, CH2), 2.63 (3H, s, CH3). 13C NMR (75 MHz, DMSO‑d6): δ 148.0 (Ar-C), 144.6 (Ar-C), 136.7 (Ar-C), 134.6 (Ar-C), 130.6 (Ar-C), 123.4 (Ar-C), 122.9 (Ar-C), 122.2 (Ar-C), 118.3 (Ar-C), 48.9 (CH2), 10.5 (CH3). HRMS calculated for C11H14N3 [M]+ 188.1188, found 188.1191. m.p. 219–220 °C.

 

5.4.21. 1-(4-Aminobenzyl)-1H-imidazol-3-ium (21):

Brown solid, 0.81 g (82%). 1H NMR (300 MHz, DMSO‑d6): δ 9.34 (1H, t, J=1.5 Hz, NHCHN), 7.78 (1H, t, J=1.6 Hz, NHCHCHN), 7.68 (1H, t, J=1.6 Hz, NHCHCHN), 7.45 (2H, d, J=8.5 Hz, Ph-H), 7.27 (2H, d, J=8.5 Hz, Ph-H), 5.43 (2H, s, CH2). 13C NMR (75 MHz, DMSO‑d6): δ 135.3 (Ar-C), 134.0 (Ar-C), 133.6 (Ar-C), 129.5 (Ar-C), 122.9 (Ar-C), 121.9 (Ar-C), 120.2 (Ar-C), 50.9 (CH2). HRMS calculated for C10H12N3 [M]+ 174.1031, found 174.1032. m.p. 209–210 °C.

 

5.4.22. 1-(4-Aminobenzyl)-2-methyl-1H-imidazol-3-ium (22):

Brown solid, 0.84 g (80%). 1H NMR (300 MHz, DMSO‑d6): δ 8.23 (2H, d, J=8.5 Hz, Ph-H), 7.75 (1H, d, J=2.0 Hz, NHCHCHN), 7.61 (1H, d, J=2.0 Hz, NHCHCHN), 7.56 (2H, d, J=8.7 Hz, Ph-H), 5.60 (2H, s, CH2), 2.59 (3H, s, CH3). 13C NMR (75 MHz, DMSO‑d6): δ 147.3 (Ar-C), 144.6 (Ar-C), 142.2 (Ar-C), 128.9 (Ar-C), 124.0 (Ar-C), 122.3 (Ar-C), 118.5 (Ar-C), 49.0 (CH2), 10.4 (CH3). HRMS calculated for C11H14N3 [M]+ 188.1188, found 188.1193. m.p. 183–185 °C.

 

5.4.23. 1-(5-Amino-2-chlorobenzyl)-1H-imidazol-3-ium (23):

Pale yellow solid, 1.06 g (92%). 1H NMR (300 MHz, DMSO‑d6): δ 9.35 (1H, t, J=1.3 Hz, NHCHN), 8.38 (1H, d, J=2.7 Hz, Ph-H), 8.28 (1H, dd, J=8.8, 2.8 Hz, Ph-H), 7.85 (1H, d, J=8.8 Hz, Ph-H), 7.80 (1H, t, J=1.7 Hz, NHCHCHN), 7.74 (1H, t, J=1.7 Hz, NHCHCHN), 5.71 (2H, s, CH2). 13C NMR (75 MHz, DMSO‑d6): δ 146.6 (Ar-C), 140.1 (Ar-C), 136.1 (Ar-C), 134.0 (Ar-C), 131.3 (Ar-C), 126.2 (Ar-C), 125.6 (Ar-C), 122.3 (Ar-C), 120.2 (Ar-C), 49.2 (CH2). HRMS calculated for C10H11ClN3 [M]+ 208.0642, found 208.0645. m.p. 233–234 °C.

 

5.4.24. 1-(5-Amino-2-chlorobenzyl)-2-methyl-1H-imidazol-3-ium (24):

Black solid, 1.12 g (92%). 1H NMR (400 MHz, DMSO‑d6): δ 8.26 (1H, dd, J=8.8, 2.8 Hz, Ph-H), 8.11 (1H, d, J=2.7 Hz, Ph-H), 7.87 (1H, t, J=8.8 Hz, Ph-H), 7.64 (1H, d, J=2.0 Hz, NHCHCHN), 7.58 (1H, d, J=2.0 Hz, NHCHCHN), 5.60 (2H, s, CH2), 2.66 (3H, s, CH3). 13C NMR (100 MHz, DMSO‑d6): δ 146.7 (Ar-C), 145.2 (Ar-C), 139.7 (Ar-C), 133.7 (Ar-C), 131.4 (Ar-C), 125.3 (Ar-C), 125.3 (Ar-C), 122.2 (Ar-C), 118.4 (Ar-C), 47.7 (CH2), 10.6 (CH3). HRMS calculated for C11H13ClN3 [M]+ 222.0798, found 222.0799. m.p. 199–201 °C.

 

5.4.25. 4-((1H-imidazol-1-yl) methyl) phenol (25):

Pale brown solid, 1.12 g (80%). 1H NMR (400 MHz, DMSO‑d6): δ 9.47 (1H, bs, OH), 7.68 (1H, s, NCHN), 7.10–7.01 (3H, m, Ph-H and NCHCHNCH2), 6.86 (1H, t, J=1.0 Hz, NCHCHNCH2), 6.71 (2H, d, J=8.5 Hz, Ph-H), 5.02 (2H, s, CH2). 13C NMR (100 MHz, DMSO‑d6): δ 157.0 (Ar-C), 137.1 (Ar-C), 129.1 (Ar-C), 128.5 (Ar-C), 127.9 (Ar-C), 119.3 (Ar-C), 115.3 (Ar-C), 49.1 (CH2). HRMS calculated for C10H10N2NaO [M+Na] + 197.0685, found 197.0689. m.p. 210–212 °C (lit. m.p. 210–211 °C).

 

5.4.26. 4-((2-Methyl-1H-imidazol-1-yl) methyl) phenol (26):

Brown solid, 1.25 g (90%). 1H NMR (300 MHz, DMSO‑d6): δ 9.46 (1H, bs, OH), 7.05 (1H, d, J=1.3 Hz, NCHCHNCH2), 6.99 (2H, d, J=8.6 Hz, Ph-H), 6.75–6.68 (3H, m, Ph-H and NCHCHNCH2), 4.97 (2H, s, CH2), 2.22 (3H, s, CH3). 13C NMR (75 MHz, DMSO‑d6): δ 156.8 (Ar-C), 143.6 (Ar-C), 128.6 (Ar-C), 127.6 (Ar-C), 126.2 (Ar-C), 120.0 (Ar-C), 115.4 (Ar-C), 48.3 (CH2), 12.8 (CH3). HRMS calculated for C11H13N2O [M+H] + 189.1022, found 189.1022. m.p. 209–210 °C.

 

6. REFERENCES:

1.     Arjomandi O Khalili, Kavoosi M, Adibi H. Synthesis and enzyme-based evaluation of analogues L-tyrosine thiol carboxylic acid inhibitor of metallo-β-lactamase IMP- 1, J. Enzyme Inhib. Med. Chem. 2019; 34 (1): 1414-1425.

2.     Arjomandi O Khalili, Hussein WM, Vella P, Yusof Y, Sidjabat HE, Schenk G, McGeary RP. Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1. Eur. J. Med. Chem., 2016; 114: 318-327.

3.     Yusof Y, Tan DT, Arjomandi OK, Schenk G, McGeary RP. Captopril analogues as metallo-β-lactamase inhibitors. Bioorg. Med. Chem. Lett., 2016; 26 (6): 1589-1593.

4.     McGeary RP, Tan DT, Schenk G. Progress toward inhibitors of metallo-β-lactamases. Future Med. Chem., 2017; 9 (7): 673-691.

5.     King D, Strynadka N. Crystal structure of New Delhi metallo-β-lactamase reveals molecular basis for antibiotic resistance. Protein Sci., 2011; 20 (9): 1484-1491.

6.     Docquier JD, Mangani S. An update on β-lactamase inhibitor discovery and development. Drug. Resist. Update, 2018; 36: 13-29.

7.     Everett M, Sprynski N, Coelho A, Castandet J, Bayet M, Bougnon J, Lozano C, Davies DT, Leiris S, Zalacain M, Morrissey I, Magnet S, Holden K, Warn P, De Luca F, Docquier JD, Lemonnier M. Discovery of a novel metallo-β-lactamase inhibitor that potentiates meropenem activity against carbapenem-resistant enterobacteriaceae antimicrob, Agents Chemother., 2018; 62 (5): e00074-18.

8.     Shi C, Chen J, Kang X, Shen X, Lao X, Zheng H. Approaches for the discovery of metallo‐β‐Lactamase inhibitors: a review. Chem. Biol. Drug Des, 2019.

9.     Page MI, Badarau A. The mechanisms of catalysis by metallo beta-lactamases, Bioinorg. Chem. Appl., 2008.

10.  Diaz N, Suarez D, Merz KM. Zinc metallo-β-lactamase from Bacteroides fragilis: A quantum chemical study on model systems of the active site. J. Am. Chem. Soc., 2000; 122 (17): 4197-4208.

11.  Bebrone C. Metallo-β-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem. Pharmacol. 2007; 74 (12): 1686-1701.

12.  Crowder MW, Spencer J, Vila AJ. Metallo-β-lactamases: Novel weaponry for antibiotic resistance in bacteria, Acc. Chem. Res., 2006; 39: 721-728.

13.  Moran-Barrio J, Gonzalez JM, Lisa MN, Costello AL, Dal PM, Carloni P, Bennett B, Tierney DL, Limansky AS, Viale AM, Vila AJ. The metallo-β-lactamase GOB is a mono-Zn (ii) enzyme with a novel active site. J. Biol. Chem., 2007; 282 (25): 18286-18293.

14.  Paul-Soto R, Bauer R, Frere JM, Galleni M, Mayer-Klaucke W, Nolting H, G.M., Rossolini SD. Hernandez-Valladares M. Zeppezauer M. Adolph HW. Mono and binuclear Zn2+-β-lactamase. Role of the conserved cysteine in the catalytic mechanism, J. Biol. Chem., 1999; 274(19): 13242-13249.

15.  Phelan EK, Miraula M, Selleck C, Ollis DL, Schenk G, Mitić N. Metallo-β-lactamases: a major threat to human health, J. Mol. Biol. 2014; 4 (03): 11-15.

16.  Galleni M, Lamotte-Brasseur J, Rossolini GM, Spencer J, Dideberg O, Frere JM. Standard numbering scheme for class B β-lactamases. Antimicrob. Agents Chemother. 2001; 45 (3): 660-663.

17.  Lienard BMR, Papamicael C, Schofield CJ, Garau G, Dideberg O, Horsfall L, Lassaux P, Galleni M, Frere JM, Karsisiotis AI, Damblon C, Roberts GCK. Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols. Org. Biomol. Chem., 2008; 6 (13): 2282-2294.

18.  Palzkill T. Metallo-β-lactamase structure and function, Ann N.Y Acad Sci, 2013; 1277 (1): 91-104.

19.  Babini GS, Danel F, Munro SD, Micklesen PA, Livermore DM. Unusual tazobactam- sensitive Amp-C β-lactamase from two Escherichia coli isolates, J. Antimicrob. Chemother., 1998; 41: 115-118.

20.  Goto M, Takahashi T, Yamashita F, Koreeda A, Mori H, Ohta M, Arakawa Y. Inhibition of the metallo-β-lactamase produced from serratia marcescens by thiol compounds. Chem. Biol. Drug. Des., 1997; 20: 1136-1140.

21.  Mollard C, Moali C, Papamicael C, Damblon C, Vessilier S, Amicosante G, Schofield CJ, Galleni M, Frere JM, Roberts GCK. Thiomandelic acid, a broad spectrum inhibitor of zinc β-lactamases, J. Biol. Chem., 2001; 276 (48): 45015-45023.

22.  Hammond GG, Huber JL, Greenlee ML, Laub JB, Young K, Silver LL, Balkovec JM, Pryor KD, Wu JK, Leiting B, Pompliano DL, Toney JH. Inhibition of IMP-1 metallo-beta-lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives. FEMS Microbiol. Lett., 1999; 179 (2): 289-296.

23.  Heinz U, Bauer R, Wommer S, Meyer-Klaucke W, Papamichaels C, Bateson J, Adolph HW. Coordination geometries of metal ions in D- or L-captopril-inhibited metallo-β-lactamases. J. Biol. Chem. 2003; 278 (23): 20659-20666.

24.  Hussein WM, Fatahala SS, Mohamed ZM, McGeary RP, Schenk G, Ollis DL, Mohamed MS. Synthesis and Kinetic Testing of Tetrahydropyrimidine-2-thione and Pyrrole Derivatives as Inhibitors of the Metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa, Chem. Biol. Drug. Des., (2012); 80 (4) 500–515.

25.  Hussein WM, Vella P, Islam NU, Ollis DL, Schenk G, McGeary RP. 3- Mercapto-1, 2, 4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors. Bioorg. Med. Chem. Lett. 2012; 22 (1): 380-386.

26.  Mohamed MS, Hussein WM, McGeary RP, Vella P, Schenk G, El-hameed RHA. Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Eur. J. Med. Chem., 2011; 46 (12): 6075-6082.

27.  Simm AM, Loveridge EJ, Crosby J, Avison MB, Walsh TR, Bennett PM. Bulgecin A: a novel inhibitor of binuclear metallo-β-lactamases. Biochem. J. 2005; 387: 585-590.

28.  Hiraiwa Y, Morinaka A, Fukushima T, Kudo T. Metallo-β-lactamase inhibitory activity of phthalic acid derivatives. Bioorg. Med. Chem. Lett., 2009; 19 (17): 5162-5165.

29.  Toney JH, Hammond GG, Fitzgerald PMD, Sharma N, Balkovec JM, Rouen GP, Olson SH, Hammond ML, Greenlee ML, Gao YD. Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-β-lactamase. J. Biol. Chem., 2001; 276 (34): 31913-31918.

30.  Nauton L, Kahn R, Garau G, Hernandez JF, O. Dideberg. Structural insights into the design of inhibitors for the L1 Metallo-β-lactamase from Stenotrophomonas maltophilia, J. Mol. Biol., 2008; 375 (1): 257-269.

31.  Olsen L, S. Jost, HW, Pettersson I. Adolph, Hemmingsen L, Jorgensen FS. New leads of metallo-β-lactamase inhibitors from structure-based pharmacophore design. Bioorg. Med. Chem., 2006; 14: 2627-2635.

32.  Feng L, Yang KW, Zhou LS, Xiao JM, Yang X, Zhai L, Zhang YL, Crowder MW. N-Heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria, Bioorg. Med. Chem. Lett. 2012; 22(16): 5185–5189.

33.  Hiraiwa Y, Saito J, Watanabe T, Yamada M, Morinaka A, Fukushima T, Kudo T. X-ray crystallographic analysis of IMP-1 metallo-β-lactamase complexed with a 3- aminophthalic acid derivative, structure-based drug design, and synthesis of 3, 6- disubstituted phthalic acid derivative inhibitors. Bioorg. Med. Chem. Lett. 2014; 24(20): 4891-4894.

34.  Walter MW, Felici A, Galleni M, Soto RP, Adlington RM, Baldwin JE, Frere JM, Gololobov M, Schofield CJ. Trifluoromethyl alcohol and ketone inhibitors of metallo-β-lactamases, Bioorg. Med. Chem. Lett. 1996; 6 (20): 2455–2458.

35.  Walter MW, Valladares MH, Adlington RM, Amicosante G, Baldwin JE, Frere JM, Galleni M, Rossolini GM, Schofield CJ. Hydroxamate inhibitors of aeromonas hydrophila AE036 metallo-beta-lactamase, Bioorg Chem. 1999; 27(1): 35-40.

36.  Toney JH, Fitzgerald PMD, Grover-Sharma N, Olson SH, May WJ, Sundelof JG, Vanderwall DE, Cleary KA, Grant SK, Wu JK, Kozarich JW, Pompliano DL, Hammond GG. Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of bacteroides fragilis metallo-β-lactamase, Chem. Biol. 1998; 5 (4):185-196.

37.  Siemann S, Evanoff DP, Marrone L, Clarke AJ, Viswanatha T, Dmitrienko GI. N-Arylsulfonyl hydrazones as inhibitors of IMP-1 metallo-β-lactamase. Antimicrob. Agents Chemother. 2002; 46 (8): 2450-2457.

38.  Drawz SM, Bonomo RA. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 2010; 23: 160-201.

39.  Vella P, Hussein WM, Leung EW, Clayton D, Ollis DL, Mitic N, Schenk G, McGeary RP. The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening. Bioorg. Med. Chem. Lett. 2011; 21: 3282–3285.

40.  Salvio R, Cacciapaglia R, Mandolini L. General base–guanidinium cooperation in bifunctional artificial phosphodiesterases. J. Org. Chem. 2011; 76 (13): 5438-5443.

41.  Roumen L, Peeters JW, Emmen JMA, Beugels IPE, Custers EMG, Gooyer de M, R., Plate K, PAJ Pieterse, JFM Hilbers, JAJ Smits, D Vekemans, HCJ Leysen, HM Ottenheijm, JJR Janssen. Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1h-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2), J. Med. Chem. 2010; 53 (4): 1712-1725.

42.  Vallee C, Chauvin Y, Basset JM, Santini CC, Galland JC. Design of ionic phosphites for catalytic hydrocyanation reaction of 3-pentenenitrile in ionic liquids, Adv. Synth. Catal. 2005; 347 (14): 1835-1847.

43.  Bebrone C, Moali C, Mahy F, Rival S, Docquier JD, Rossolini GM, Fastrez J, Pratt RF, Frere JM, Galleni M. CENTA as a chromogenic substrate for studying β- lactamases, Antimicrob. Agents Chemother. 2001; 45: 1868-1871.

44.  Maccallini C, Patruno A, Lannutti F, Ammazzalorso A, Filippis De B, Fantacuzzi M, S. Franceschelli, L. Giampietro, S. Masella, M. Felaco, N. Re, R. Amoroso, N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase, Bioorg. Med. Chem. Lett. 2010; 20(22): 6495–6499.

45.  Hille UE, Zimmer C, Vock CA, Hartmann RW. First selective CYP11B1 inhibitors for the treatment of cortisol-dependent diseases. ACS Med. Chem. Lett. 2010; 2(1): 2-6.

46.  Byun YS, Jung CH, Park YT. Synthesis of 5H-imidazo [5,1-a] isoindole: photocyclization of N, N′ -bis(o-chlorobenzyl) imidazolium chloride and N-(o-chlorobenzyl) imidazole, J. Heterocycl. Chem. 1995; 32(6): 1835–1837.

47.  Nakamura S, Kawasaki I, Yamashita M, Ohta S. 1-Methyl-3-trimethylsilylparabanic acid as an effective reagent for the preparation of N-substituted (1-methyl-2, 5-dioxo-1,2,5h-imidazolin-4-yl)-amines and its application to the total synthesis of isonaamidines A and C, antitumor imidazole alkaloids, Heterocycles, 2003; 60: 583-598.

48.  Lee HM, Lu CY, Chen CY, Chen WL, Lin HC, Chiu PL, Cheng PY. Palladium complexes with ethylene-bridged bis (N-heterocyclic carbene) for C-C coupling reactions, Tetrahedron, 2004; 60(27): 5807-5825.

49.  Porretta GC, Biava M, Cerreto F, Scalzo M, Panico S, Simonetti N, Villa A. Research on anti-bacterial and anti-fungal agents II. Synthesis and anti-fungal activity of new (1H-imidazol-1-ylmethyl)-benzenamine derivatives, Eur. J. Med. Chem 1988; 23(4): 311-317.

50.  O’Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK, Maggs JL. Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4′-fluoro and 4′-chloro analogues of amodiaquine. Identification of a suitable “back-up” compound for n-tert-butyl isoquine, J. Med. Chem. 2009; 52(7): 1828-1844.

51.  Yang H, Li Y, Jiang M, Wang J, Fu H. General copper-catalyzed transformations of functional groups from arylboronic acids in water, Chem. Eur. J. 2011; 17(20): 5652-5660.

52.  Pardo C, Graf S, Ramos M, Sesmilo E, Elguero J. Synthesis of 1-(p-nitrobenzyl) azoles and 1-(p-nitrobenzyl) benzazoles, Org. Prep. Proced. Int. 2000; 32 (4): 385-390.

53.  Street LJ, Baker R, Davey WB, Guiblin AR, Jelley RA, Reeve AJ, Routledge H, Sternfeld F, Watt AP. Synthesis and serotonergic activity of n, ndimethyl- 2-[5-(1,2,4-triazol-1-ylmethyl)-1h-indol-3-yl]ethylamine and analogs: Potent agonists for 5-ht1d receptors, J. Med. Chem. 1995; 38(10): 1799-1810.

 

 

 

Received on 09.04.2020          Modified on 30.04.2020

Accepted on 19.05.2020   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2020; 10(3):140-148.

DOI: 10.5958/2231-5691.2020.00026.X