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Article

Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents

by
Yun-Xin Yao
1,2,
Nan-Nan Jia
1,
Ya-Nan Cao
1,
Xing-Xiu Chen
3,
Feng Gao
1,2,* and
Xiao-Xia Liang
1,*
1
Agronomy College, Sichuan Agriculture University, Chengdu 611130, China
2
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
3
Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway SLSRC, Norman, OK 73019-5251, USA
*
Authors to whom correspondence should be addressed.
Catalysts 2018, 8(10), 433; https://doi.org/10.3390/catal8100433
Submission received: 8 September 2018 / Revised: 27 September 2018 / Accepted: 28 September 2018 / Published: 30 September 2018
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Abstract

:
2-aryl-N-alkylbenzimidazole derivatives synthesized by CuI/PPh3 promoted direct coupling of N-alkylbenzimidazoles with aryl bromides. In vitro neurotoxicities of 20 compounds were evaluated, and the neuroprotective abilities of low-neurotoxic compounds (3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s and 3t) were investigated against toxicity induced by 1-methyl-4-phenylpyridinium ion (MPP+) in SH-SY5Y neuronal cells. In silico studies revealed that compound 3g could have molecule docking with the following proteins: the bone morphogenetic protein receptor type 1B (BMPR1B), human cytochrome P450 1B1(CYP1B1), Metabotropic glutamate receptor 7 (GRM7), histone deacetylase 6 (HDAC6), 5-hydroxytryptamine receptor 5A (HTR5A), human topoisomerase II beta (TOP2B). A molecular docking simulation of model compound 3g and model protein CYP1B1 has been shown.

1. Introduction

Benzimidazole derivatives are known to display a wide range of biological activities [1]. Among them, the neuroprotective activity is significant in the treatment of neurodegenerative diseases including ischemia [2], epilepsy [3], and Alzheimer’s and Parkinson’s disease [4]. For example, two clinically-promising anti-Parkinson’s disease agents, Istradefylline and Preladenant, are both benzimidazole derivatives [5]. In particular, 2-arylbenzimidazole derivatives were evaluated as inhibitors of c-Jun N-terminal kinase 3 (JNK3) in the treatment of neurodegenerative symptoms [6,7]. In addition, a novel cholinesterase (ChE) inhibitor with 2-arylbenzoimidazoles skeleton was helpful in reversing the memory impairments associated with Alzheimer’s disease [8]. 2-arylbenzimidazole derivatives also inhibited the increase of inducible nitric oxide synthase (iNOS) when peripheral nerve injury occurred (Figure 1) [9]. Consequently, there is a great demand for the generation a library of novel 2-arylbenzimidazoles for the evaluation of their neuroprotective activity.
The preparations of 2-arylbenzimidazoles include intermolecular cyclization of aldehydes [10,11,12], intramolecular cyclization of alobenzanilides, and oxidative arylation of enzothiazoles by recyclization [13,14,15,16]. Another approach to synthesizing 2-arylbenzimidazoles is metal-catalyzed direct C–H bond arylation reactions, which have emerged as one of the most efficient protocols for the synthesis of diverse 2-arylbenzimidazoles. The classical cross-coupling of benzimidazoles with aryl electrophiles catalyzed by a noble metal such as Palladium has yielded various 2-arylbenzimidazoles [17,18,19,20,21,22]. However, the high cost limits the scale-up development of Pd-catalyzed cross coupling reaction. Fortunately, cheap copper is an efficient counterpart of palladium in the direct arylation of benzoheterocyclic compounds [23,24,25,26,27,28]. Previously, we have reported that Cu/PPh3 directly catalyzed the 2-arylation of benzoxazoles with economical aryl bromides [29], and the same catalysis system has been used in our further research. In this work, a series of 2-aryl-N-alkylbenzimidazole derivatives were prepared via copper-catalyzed direct arylation of N-alkylbenzimidazoles with aryl bromides, and their in vitro neuroprotective activities were evaluated.

2. Results and Discussion

2.1. Copper-Catalyzed Synthesis of 2-Aryl-N-alkylbenzimidazoles

We investigated the best reaction conditions of the Cu-catalyzed direct arylation of 1-methyl-benzimidazole (1a) with 1-bromo-4-tert-butylbenzene (2d) (Table 1). Initially, the screening of various bases was carried out under the CuI/ PPh3 (10 mol %/30 mol %) catalytic system at 140 °C in DMF for 24 h. There was small quantity of 2-[4-(1,1-Dimethylethyl)phenyl]-1-methyl-1H-benzimidazole (3d) when KOH, NaOH and t-BuOK (Table 1, entry 1–3) was used as base. In contrast, a mild base such as K2CO3, Na2CO3 or KH2PO4 (Table 1, entry 4–6) promoted the arylation reaction dramatically. Next, we examined the effect of temperatures ranging from 120 °C to 150 °C (Table 1, entries 4, 7–8). When the temperature decreased to 120 °C, the yield dropped to 45%. After the temperature screening, the selection of a high boiling-point solvent drew our attention. DMF and xylene positively affected this arylation reaction. We also studied the reasons why, as the temperature changed from 140 °C to 130 °C (Table 1, entries 9 and 10), the solvent became xylene. The yield increased as the temperature rose to 140 °C. The reaction-time difference of group 1 (Table 1, entries 11 and 8) and group 2 (Table 1, entries 9 and 12) revealed that increasing time benefits the yield. Therefore, optimized conditions (Table 1, entry 12) were obtained by following the scope of aryl bromides. In a study of 2-arylations of 1-methyl-benzimidazole (Table 2), compared with optimized conditions using 40 h, the majority of products could be produced in the same yield with a shorter reaction time (24 h).
The use of the aryl bromides in the 2-arylation of 1-methyl-benzoimidazole is presented in Table 2. Under optimized reaction conditions, the yields of aryl bromides with electron neutral groups, 2-bromonaphthalene (2a), 1-bromonaphthalene (2e), and1-bromo-4-tert-butylbenzene (2d), were 72%, 85%, and 78% respectively. The aryl bromides bearing electron-donating methoxy (2g) groups and electron-withdrawing fluoric (2c) and trifluoromethyl (2f) groups were well tolerated in moderate yields. In addition, the direct arylation of 1-methyl-benzimidazole with heteroaryl bromides including 3-bromoquinoline (2b), 2-bromothiophene (2h), and 2-bromopyridine (2i) proceeded well to produce yields of 80%, 70%, and 54%, respectively.
With respect to 2-arylation of 1-ethyl-benzimidazole (Table 3), the scope could be extended when it reacted with 1-bromo-4-fluorobenzene (2c), 2-bromothiophene (2h), 2-bromonaphthalene (2a) and 3-bromoquinoline (2b), which delivered the arylated products (3j, 3k, 3n and 3m) in 40–46% yields. 4-Bromobenzotrifluoride (3l) was less tolerated in 20%. The arylation scope of 1-benzyl-benzimidazole was also shown in Table 3. In most cases, 1-benzyl-benzimidazoles (3o, 3p, 3q, 3s and 3t) were arylated at yield rates 40–54%. The challenging product, 1-(phenylmethyl)-2-(2-pyridinyl)-1H-benzimidazole (3r), was produced at a yield rate of 35%. Although yields of heterocyclic structures (Table 3. 3k and 3m, Table 4. 3r, 3s and 3t) were moderate, the economical Cu-catalyzed protocol helped to meet the demands of the activity tests.

2.2. Neuroprotective Performances of 2-Aryl-N-alkylbenzimidazoles against MPP+

The ability to prevent SH-SY5Y cells from MPP+-induced damage is shown in Table 4 and Figure 1. Unfortunately, our results indicated that the protective capcities of compounds (3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s, 3t) under 10 and 50 μM were low. We chose these compounds for the aforementioned experiment based on the fact that they did not show appreciable neurotoxicities on SH-SY5Y cells under 50 μM. (The inhibition rates of 20 compounds are illustrated in the supplementary materials).

2.3. The Computer Anaysis of Neuroprotective Targets Metablising 3g and Docking Analysis

In order to gain some insights into the neuroprotective potential of 2-aryl-N-alkylbenzimidazoles, we prepared proteins with neuroprotective functions and performed molecular docking studies to identify the neuroprotective enzymes that play a key role in metablising 2-aryl-N- alkylbenzimidazoles. Compound 3g was listed as a model to select enzymes.

2.3.1. The Preparation of Neuroprotective Targets

The preparation began by searching for protein targets using a similarity ensemble approach (SEA) [30]. Only proteins from human and mouse samples were saved for subsequent analyses. Gene ontology (GO) annotation and cluster analysis were used as a filter for proteins with neuroprotective functions [31]. Then, 19 targets were selected for further discussion of potential targets of compound 3g. There were 14 proteins whose crystal structures were available in the Protein Data Bank (PDB) at the time of the work: APP, BMPR1B, CXCL8, CYP1B1, GLRA1, GRIK2, GRM7, HDAC6, NR4A2, PRKCG, RELA, TLR8, TOP2B, TSHR. As no crystallographic structures were available for the other five targets, CCKAR, FPR2, GABRB3, HTR5A, NPBWR1, a homology modeling methodology was used to build 3D structures of these enzymes. The appropriate template structures corresponded to proteins with PDB accession codes 5ZBH, 3ODU, 4COF, 4IAR, 4N6H, respectively [32,33,34,35,36].

2.3.2. The Molecular Docking Simulation of 3g and Neuroprotective Targets

After the preparation of 19 neuroprotective targets, molecular docking simulations between compound 3g and neuroprotective targets were performed by use of Discovery Studio. The CHARMm force field was applied to the molecules, and CDOCKER module was used in a molecular docking simulation [37]. The final binding results were determined by -CDOCKING ENERAGE, which means that six proteins (BMPR1B, CYP1B1, GRM7, HDAC6, HTR5A, and TOP2B) whose -CDOCKING ENERAGE is above zero are much more likely to interact with compound 3g (Figure 2a). The score of -CDOCKING ENERAGE cannot illustrate actual levels of interactions between compound 3g and the six targets. During the preliminary docking study, the major 3g-binding sites on cytochromes P450 1B1 (CYP1B1) were analyzed through comparison with the docking study of interaction between polycyclic aromatic compounds and CYP1B1. Polycyclic aromatic compounds and 2-aryl-N-alkylbenzimidazoles were found to bind to the same site (Phe231) [38]. There is no discussion about the binding mode between 2-aryl-N-alkylbenzimidazoles and CYP1B1 in the litterature. As such, a molecular docking study between protein CYP1B1 and 3g was listed as a model to obtain more insight into the binding sites (Figure 2). The binding site was mainly delimitated by Phe 231 through π-π interaction. The 2-naphthalenyl group also interacted with Ala330 and Ala133 residues through CH-π interaction. In addition, the naphthalene moiety in compound 3g could form a hydrogen bond with the Gly329 residue of protein CYP1B1. For the benzimidazole moiety of 3g, Val395, Ile399 and Cys470 residues were implicated in Pi bonds. The van der Waals interactions are also shown in Figure 2d. These interactions contributed to the binding affinity of 2-naphthalenyl-alkylbenzimidazole, compound 3g, and model protein CYP1B1. (Figure 2b–d) The polycyclic aromatic rings at 2-position of N-alkylbenzimidazoles seems to be important for ligands to dock into CYP1B1 through π-π interactions.

3. Materials and Methods

3.1. General Methods

All reactions were carried out under a nitrogen atmosphere with ovendried glassware. Unless otherwise stated, reagents were commercially available and used as purchased. The tetrahydrofuran (THF) was steamed through sodium to remove the aqueous part when using as a solvent, and N,N-Dimethylformamide (DMF) and xylene were dried through activated 4 Å Molecular Sieves under argon. TLC was performed with silica gel plates (GF 254) with detection under UV light at 254 nm. The NMR spectra were recorded by a Brüker 400 MHz Fourier-transform NMR spectrometer (Swiss Brüker, Chengdu, China). Chemical shifts (δ) are reported in units of parts per million (ppm) downfield from tetramethylsilane (TMS).

3.2. A Typical Procedure for the Cu-Catalyzed Arylation of Benzoimidazoles

A Schlenk 15 mL flask equipped with a magnetic bar was loaded with the benzoimidazoles with substituents at the nitrogen position (0.2 mmol) and K2CO3 (69.1 mg, 2.5 equiv), while CuI (10 mol %) and PPh3 (30 mol %) were prepared in another flask. Then, the vessels were purged by a sequence of seven vacuum-argon refill-evacuation cycles. A solution of catalytic Cu/PPh3 system was prepared through the addition of 1 mL dry DMF (or xylene) with a syringe. Preparation of the stock solution of CuI and PPh3 was stirred for 2 h at 45 °C under argon. The catalytic solution and aryl bromide (0.3 mmol, 1.5 equiv) were added to the reaction mixture by syringe, but the solid aryl bromides were added to the reaction at the beginning. The reaction mixture was stirred for 20–44 h at 140 or 150 °C, and quenched with two drops of H2O. The crude products were filtered over Na2SO4 and silica to remove salts, and rinsed with additional ethyl acetate. Finally, the solution was concentrated in vacuo. The arylated products were obtained by flash chromatography.

3.3. Preparation of Compounds 3a–3t

1-methyl-2-(naphthalen-2-yl)-1H-benzoimidazole (3a) Compound 1a (26.4 mg, 0.2 mmol) and 2-bromonaphthalene (2a, 49.6 mg, 0.24 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 24 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3a (37.3 mg), with a 72% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.29 (1H, s), 8.00 (1H, d, J = 8.5 Hz), 7.98–7.84 (4H, m), 7.62–7.54 (2H, m), 7.46–7.41 (1H, m), 7.37–7.32 (2H, m), 3.97 (3H, s); 13C-NMR (400 MHz, CDCl3) δ: 154.02, 143.32, 136.94, 133.86, 133.20, 129.58, 128.75, 128.70, 128.07, 127.79, 127.44, 127.00, 126.58, 123.08, 122.75, 120.13, 109.85, 32.09. The spectroscopic data match the previously reported data [39].
3-(1-methyl-1H-benzoimidazol-2-yl)quinoline (3b) Compound 1a (16 mg, 0.1 mmol) and 3-Bromoquinoline (2b, 16 μL, 25.0 mg, 0.12 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 24 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3b (24.9 mg), with an 80% yield rate, as a pale yellow powder; 1H-NMR (400 MHz, CDCl3) δ: 9.34 (1H, d, J = 2.2 Hz), 8.59 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.5 Hz,), 7.98–7.79 (3H, m), 7.70–7.61 (1H, m), 7.45 (1H, dd, J = 6.2, 2.5 Hz), 7.42–7.33 (2H, m), 3.97 (3H, s); 13C-NMR (400 MHz, CDCl3) δ: 151.12, 150.22, 148.39, 143.36, 137.08, 136.91, 131.03, 129.74, 128.56, 127.80, 127.49, 123.80, 123.60, 123.10, 120.32, 110.00, 32.09; HRMS (ESI) [M + H]+calcd for C17H14N3: 260.1188; found 260.1164.
2-(4-fluorophenyl)-1-methyl-benzoimidazole (3c) Compound 1a (16 mg, 0.12 mmol) and 4-Bromofluorobenzene (2c, 11 μL, 17.4 mg, 0.1 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 20 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3c (18.7 mg), with a 69% yield rate, as a pale yellow powder; 1H-NMR (400 MHz, CDCl3) δ: 7.87–7.82 (1H, m), 7.81–7.75 (2H, m), 7.42 (1H, dt, J = 4.6, 2.8 Hz), 7.39–7.32 (2H, m), 7.25(2H, ddd, J = 11.6, 5.7, 3.6 Hz), 3.89 (3H, s); 13C-NMR (400 MHz, CDCl3) δ: 165.11, 162.62, 153.01, 143.01, 136.73, 131.68, 131.60, 129.40, 123.14, 122.81, 120.04, 116.23, 116.02, 109.85, 31.88. The spectroscopic data match the previously reported data [40].
2-(4-(tert-butyl)phenyl)-1-methyl-benzoimidazole (3d) Compound 1a (16 mg, 0.12 mmol) and 1-Bromo-4-tert-butylbenzene (2d, 17.5 μL, 21.2 mg, 0.1 mmol) were dissolved in anhydrous xylene. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3d (24.8 mg), with a 78% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 7.89–7.79 (1H, m), 7.65 (4H, dd, J = 66.3, 8.4 Hz), 7.44–7.38 (m, 1H), 7.37–7.30 (2H, m), 3.90 (3H, s) 1.40 (9H, s). 13C-NMR (400 MHz, CDCl3) δ: 154.15, 153.21, 143.25, 136.83, 129.37, 127.51, 125.85, 122.80, 122.54, 119.98, 109.74, 35.08, 31.92, 31.46. The spectroscopic data match the previously reported data [39].
1-methyl-2-(naphthalen-1-yl)-benzoimidazole (3e) Compound 1a (16 mg, 0.12 mmol) and 1-bromonaphthalene (2e, 42.0 μL, 61.8 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3e (26.4 mg), with an 85% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.02 (1H, d, J = 8.2 Hz), 7.98–7.86 (2H, m), 7.73 (1H, d, J = 8.3 Hz), 7.69 (1H, dd, J = 7.0, 1.1 Hz), 7.64–7.58 (1H, m), 7.57–7.51 (1H, m), 7.48 (2H, ddd, J = 9.2, 7.5, 3.0 Hz), 7.42–7.34 (2H, m), 3.62 (3H, s). 13C-NMR (400 MHz, CDCl3) δ: 153.12, 143.39, 136.11, 133.75, 132.36, 130.51, 129.09, 128.64, 128.03, 127.41, 126.58, 125.65, 125.22, 123.02, 122.60, 120.25, 109.78, 31.26. The spectroscopic data match the previously reported data [41].
1-methyl-2-(4-(trifluoromethyl) phenyl)-benzoimidazole (3f) Compound 1a (16 mg, 0.12 mmol) and 4-Bromobenzotrifluoride (2f, 39.0 μL, 67.2 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 140 °C for 44 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3f (23.3 mg), with a 70% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 7.91 (2H, d, J = 8.2 Hz), 7.85 (1H, dd, J = 6.4, 2.5 Hz), 7.80 (2H, d, J = 8.2 Hz), 7.42 (1H, dd, J = 6.5, 2.6 Hz), 7.39–7.33 (2H, m), 3.89 (3H, s). 13C-NMR (400 MHz, CDCl3) δ: 152.30, 143.13, 136.86, 134.01, 132.01, 130.01, 125.91, 125.88, 123.59, 123.05, 120.35, 109.99, 31.97. The spectroscopic data match the previously reported data [39].
2-(4-methoxyphenyl)-1-methyl-benzoimidazole (3g) Compound 1a (16 mg, 0.12 mmol) and 2-Bromo-6-methoxynaphthalene (2g, 71.7 mg, 0.3 mmol) were dissolved in anhydrous xylene. The solution was stirred at 140 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3g (25.0 mg), with a 72% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.17 (1H, s), 7.91–7.80 (4H, m), 7.44–7.37 (1H, m), 7.35–7.28 (2H, m), 7.25–7.16 (2H, m), 3.93 (6H, d, J = 16.2 Hz). 13C-NMR (400 MHz, CDCl3) δ: 158.92, 154.21, 143.27, 136.90, 135.23, 130.24, 129.32, 128.64, 127.42, 127.09, 125.46, 122.89, 122.62, 119.95, 119.89, 109.77, 105.93, 55.59, 32.04; HRMS (ESI) [M + H]+ calcd for C19H17N2O: 289.1341; found 289.1344.
1-methyl-2-(thiophen-2-yl)-benzoimidazole (3h) Compound 1a (1 6 mg, 0.12 mmol) and 2-Bromothiophene (2h, 29.0 μL, 49.0 mg, 0.3 mmol) were dissolved in anhydrous xylene. The solution was stirred at 140 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3h (18.2 mg), with a 70% yield rate, as a green and yellow powder; 1H-NMR (400 MHz, CDCl3) δ: 7.80 (1H, dd, J = 6.2, 2.7 Hz), 7.53 (2H, dd, J = 17.8, 4.1 Hz), 7.36–7.27 (3H, m), 7.18 (1H, dd, J = 4.8, 3.9 Hz), 3.95 (3H, s). 13C-NMR (400 MHz, CDCl3) δ: 148.03, 143.00, 136.72, 132.68, 128.68, 128.10, 127.97, 123.09, 122.79, 119.86, 109.55, 31.78. The spectroscopic data match the previously reported data [39].
1-methyl-2-(pyridin-2-yl)-benzoimidazole (3i) Compound 1a (16 mg, 0.12 mmol) and 2-Bromopyridine (2i, 33.0 μL, 69.1 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3i (13.6 mg), with a 54% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.69 (1H, d, J = 4.3 Hz), 8.38 (1H, d, J = 8.0 Hz), 7.88–7.80 (2H, m), 7.43 (1H, d, J = 7.3 Hz), 7.38–7.28 (3H, m), 4.27 (3H, s). 13C-NMR (400 MHz, CDCl3) δ: 150.83, 150.50, 148.75, 142.73, 137.48, 137.00, 124.91, 123.89, 123.50, 122.77, 120.21, 114.48, 110.09, 32.87. The spectroscopic data match the previously reported data [42].
2-(4-fluorophenyl)-1-ethyl-benzoimidazole (3j) Compound 1b (35.4 mg, 0.2 mmol) and 4-Bromofluorobenzene (2j, 33.0 μL, 52.2 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3j (20.1 mg), with a 42% yield rate, as a yellow powder; 1H-NMR (400 MHz, CDCl3) δ: 7.85 (1H, dd, J = 5.1, 3.9 Hz), 7.78–7.71 (2H, m), 7.49–7.42 (1H, m), 7.39–7.30 (2H, m), 7.26 (2H, dd, J = 15.8, 7.2 Hz), 4.30 (2H, q, J = 7.2 Hz), 1.48 (3H, dd, J = 15.5, 8.2 Hz). 13C-NMR (400 MHz, CDCl3) δ: 165.09, 162.60, 152.67, 143.30, 135.54, 131.48, 131.39, 129.48, 126.96, 126.93, 123.04, 122.69, 120.20, 116.25, 116.03, 110.13, 92.63 39.81, 29.90; HRMS (ESI) [M + H]+ calcd for C15H14FN2: 241.1141; found 241.1119.
1-ethyl-2-(thiophen-2-yl)-benzoimidazole (3k) Compound 1b (35.4 mg, 0.2 mmol) and 2-Bromothiophene (2h, 29.0 μL, 49.0 mg, 0.3 mmol) were dissolved in anhydrous xylene. The solution was stirred at 140 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3k (18.2 mg), with a 40% yield rate, as a yellow and green powder; 1H-NMR (400 MHz, CDCl3) δ: 7.84–7.78 (1H, m), 7.54 (2H, ddd, J = 5.9, 4.4, 0.8 Hz), 7.42–7.36 (1H, m), 7.32–7.27 (2H, m), 7.20 (1H, dd, J = 5.1, 3.7 Hz), 4.44 (2H, q, J = 7.3 Hz), 1.54 (3H, t, J = 7.3 Hz). 13C-NMR (400 MHz, CDCl3) δ: 147.38, 143.26, 135.79, 132.66, 128.64, 128.01, 127.73, 123.10, 122.79, 120.06, 109.68, 39.77, 15.40; HRMS (ESI) [M + H]+ calcd for C13H13N2S: 229.0766; found 229.0778.
1-ethyl-2-(4-(trifluoromethyl)phenyl)-1H-benzoimidazole (3l) Compound 1b (35.4 mg, 0.2 mmol) and 4-Bromobenzotrifluoride (2l, 39.0 μL, 67.2 mg, 0.3 mmol) were dissolved in anhydrous xylene. The solution was stirred at 140 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3l (12.0 mg), with a 20% yield rate, as a yellow and green powder; 1H-NMR (400 MHz, CDCl3) δ: 7.84–7.78 (3H, m), 7.54 (2H, ddd, J = 5.9, 4.4, 0.8 Hz), 7.39 (1H, dt, J = 4.5, 2.6 Hz), 7.33–7.27 (2H, m), 7.20 (1H, dd, J = 5.1, 3.7 Hz), 4.44 (2H, q, J = 7.3 Hz), 1.54 (3H, t, J = 7.3 Hz). 13C-NMR (400 MHz, CDCl3) δ: 151.98, 143.40, 135.68, 134.39, 129.87, 126.01, 125.98, 125.94, 125.90, 123.49, 122.96, 110.28, 39.95, 15.55; HRMS (ESI) [M + H]+ calcd for C16H14F3N2: 291.1109; found 291.1130.
3-(1-ethyl-1H-benzoimidazol-2-yl)-quinoline (3m) Compound 1b (35.4 mg, 0.2 mmol) and 4-Bromobe 3-Bromoquinolinenzotrifluoride (2b, 41.0 μL, 62.1 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3m (25.3 mg), with a 46% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 9.29 (1H, d, J = 2.1 Hz), 8.20 (1H, d, J = 8.5 Hz), 7.99–7.77 (3H, m), 7.64 (1H, t, J = 7.5 Hz), 7.48 (1H, dd, J = 5.7, 3.2 Hz), 7.56–7.30 (3H, m), 4.37 (2H, q, J = 7.2 Hz), 1.53 (3H, t, J = 7.2 Hz). 13C-NMR (400 MHz, CDCl3) δ: 150.66, 149.96, 148.41, 143.60, 137.01, 135.73, 131.00, 129.69, 128.56, 127.78, 127.52, 124.13, 123.49, 122.98, 120.42, 110.27, 40.10, 27.10, 15.64; HRMS (ESI) [M + H]+ calcd for C17H16N3: 274.1344; found 274.1305.
1-ethyl-2-(naphthalen-2-yl)-1H-benzoimidazole (3n) Compound 1b (35.4 mg, 0.2 mmol) and 2-bromonaphthalene (2a, 62.3 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3n (21.6 mg), with a 40% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.24 (1H, s), 8.00 (1H, d, J = 8.5 Hz), 7.94 (2H, t, J = 8.7 Hz), 7.90–7.81 (2H, m), 7.62–7.54 (2H, m), 7.50–7.43 (1H, m), 7.38–7.30 (2H, m), 4.37 (2H, q, J = 7.2 Hz), 1.51 (3H, t, J = 7.2 Hz). 13C-NMR (400 MHz, CDCl3) δ: 153.69, 143.57, 135.73, 133.87, 133.23, 129.37, 128.75, 128.72, 128.15, 128.06, 127.40, 126.98, 126.41, 122.98, 122.64, 120.26, 110.15, 39.96, 15.54; HRMS (ESI) [M + H]+ calcd for C19H17N2: 273.1392; found 273.1344.
1-benzyl-2-(naphthalen-2-yl)-benzoimidazole (3o) Compound 1c (44.4 mg, 0.2 mmol) and 2-bromonaphthalene (2a, 62.3 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3o (33.2 mg), with a 50% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.16 (1H, s), 7.97–7.86 (3H, m), 7.85–7.75 (2H, m), 7.54 (2H, tt, J = 13.9, 3.5 Hz), 7.42–7.31 (4H, m), 7.28 (2H, d, J = 4.0 Hz), 7.16 (2H, d, J = 6.7 Hz), 5.53 (s, 2H).13C-NMR (400 MHz, CDCl3) δ: 154.40, 143.50, 136.76, 136.52, 133.93, 133.12, 129.47, 129.33, 128.78, 128.77, 128.06, 128.00, 127.57, 127.45, 126.91, 126.39, 126.26, 123.36, 122.98, 120.25, 110.70, 48.79. The spectroscopic data match the previously reported data [43].
1-benzyl-2-(4-(trifluoromethyl)phenyl)-benzoimidazole (3p) Compound 1c (44.4 mg, 0.2 mmol) and 4-Bromobenzotrifluoride (2l, 39.0 μL, 67.2 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3p (30.3 mg), with a 43% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 7.93 (1H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.2 Hz), 7.41–7.29 (6H, m), 7.13 (2H, dd, J = 9.3, 7.8 Hz), 5.49 (2H, s). 13C-NMR (400 MHz, CDCl3) δ: 152.64, 143.27, 136.42, 136.22, 133.79, 129.82, 129.43, 128.22, 126.02, 125.99, 125.95, 125.91, 125.88, 123.88, 123.29, 120.50, 110.80, 48.63; HRMS (ESI) [M + H]+ calcd for C21H16F3N2: 353.1266; found 353.1244.
1-benzyl-2-(4-fluorophenyl)-benzoimidazole (3q) Compound 1c (44.4 mg, 0.2 mmol) and 4-Bromofluorobenzene (2c, 33.0 μL, 152.2 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3q (32.5 mg) with a 54% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 7.89 (1H, d, J = 8.0 Hz), 7.74–7.66 (2H, m), 7.38–7.32 (4H, m), 7.31–7.25 (2H, m), 7.16 (4H, ddd, J = 15.5, 9.2, 4.7 Hz), 5.46 (2H, s); 13C-NMR (400 MHz, CDCl3) δ: 165.18, 162.69, 153.37, 143.27, 136.45, 136.29, 131.50, 131.41, 129.33, 128.08, 126.08, 123.38, 122.99, 120.19, 116.24, 116.03, 110.66, 48.54. The spectroscopic data match the previously reported data [43].
1-benzyl-2-(pyridin-2-yl)-benzoimidazole (3r) Compound 1c (44.4 mg, 0.2 mmol) and 2-Bromopyridine (2i, 33.0 μL, 69.1 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3r (20.0 mg), with a 35% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.62 (1H, dd, J = 4.8, 0.8 Hz), 8.44 (1H, d, J = 8.0 Hz), 7.90–7.79 (2H, m), 7.38–7.27 (4H, m), 7.25–7.12 (5H, m), 6.20 (2H, s); 13C-NMR (400 MHz, CDCl3) δ: 150.78, 150.17, 148.82, 142.95, 137.67, 137.04, 137.02, 128.76, 127.53, 127.00, 124.90, 124.04, 123.76, 122.99, 120.34, 110.96, 49.11. The spectroscopic data match the previously reported data [44].
3-(1-benzyl-1H-benzo[d]imidazol-2-yl)quinoline (3s) Compound 1c (44.4 mg, 0.2 mmol) and 3-Bromoquinoline (2b, 32 μL, 50.2 mg, 0.24 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3s (35.7 mg), with a 53% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 9.26 (1H, d, J = 2.2 Hz), 8.46 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.4, 0.7 Hz), 7.94 (1H, d, J = 8.0 Hz), 7.80 (2H, ddd, J = 9.2, 5.4, 2.0 Hz), 7.60 (1H, ddd, J = 8.1, 6.9, 1.1 Hz), 7.40–7.31 (6H, m), 7.14 (2H, d, J = 6.9 Hz), 5.54 (2H, s). 13C-NMR (400 MHz, CDCl3) δ: 151.48, 150.09, 148.46, 143.51, 136.96, 136.58, 136.28, 131.05, 129.66, 129.50, 128.60, 128.32, 127.72, 127.36, 126.08, 123.90, 123.62, 123.33, 120.46, 110.73, 48.76; HRMS (ESI) [M + H]+ calcd for C23H18N3: 336.1501; found 336.1470.
3-(1-benzyl-benzoimidazol-2-yl)isoquinoline (3t) Compound 1c (44.4 mg, 0.2 mmol) and 2-Bromoquinoline (2t, 62.0 mg, 0.3 mmol) were dissolved in anhydrous DMF. The solution was stirred at 150 °C for 40 h. The residue was purified by column chromatography (hexane/EtOAc = 5:1) to afford 3t (34.0 mg), with a 50% yield rate, as a white powder; 1H-NMR (400 MHz, CDCl3) δ: 1H-NMR (400 MHz, CDCl3) δ 8.61 (1H, d, J = 8.6 Hz), 8.27 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.4 Hz), 7.93 (1H, d, J = 7.0 Hz), 7.83 (1H, d, J = 7.9 Hz), 7.70 (1H, t, J = 7.6 Hz), 7.56 (1H, t, J = 7.5 Hz), 7.43 (1H, d, J = 7.1 Hz), 7.37–7.19 (7H, m), 6.37 (2H, s). 13C-NMR (400 MHz, CDCl3) δ: 150.50, 149.94, 147.40, 143.00, 137.92, 137.41, 136.81, 129.96, 129.84, 128.78, 127.98, 127.87, 127.50, 127.06, 124.15, 123.12, 121.99, 120.57, 110.95, 49.49; HRMS (ESI) [M + H]+ calcd for C23H18N3: 336.1501; found 336.1549.

3.4. Determination of Protective Rate by MTT Assay

Cells were cultured in 96-well plates with a density of 5 × 103 edia for one day, and then pre-treated at 37 °C for 4 h with compounds 3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s and 3t (10 and 50 μM, n = 3). The cells were treated with 1mm MPP+ in the continued presence of low-neurotoxicity compounds for 24 h, and then assessed for cell viability. Cell viability was determined by a mitochondrial enzymedependent reaction of MTT assay. In brief, 10 μL of MTT 5 mg/mL was added directly to each culture media with SH-SY5Y cells. Following a two-hour incubation at 37 °C, the supernatants were removed, and then 150 μL solubilizing agent was added to dissolve the purple formazan crystals formed by metabolism of the yellow MTT tetrazolium salt. The plate was then incubated for 1 h or overnight, and the absorbance was measured using a microplate reader (Wellscan MK3, Labsystems Dragon) at a wavelength of 570 nm. Cell death following MPP+ treatment was shown by the inhibition rate of untreated cells. Microsoft®Excel 2010 was used to analyze data. The neuroprotective effects by the compounds were expressed as the protective rate, and it was calculated according to the following formulas:
Inhibition rate = (mean OD control − mean OD drug reated)/(mean OD control − mean OD vacuity) × 100%
Cell viability = 1 − Inhibition rate
Protective rate = (Cell viability drug reated − Cell viability MPP+)/Cell viability MPP+ × 100%
And Cell viability MPP+ = 46.35%

3.5. A Procedure for the Preparation of Neuroprotective Targets

Relying on the structural similarity, possible targets related to 3g were predicted by the similarity ensemble approach (SEA) (http://sea.bkslab.org/) [30]. After the screening of targets, only proteins from human and mouse were continuously analyzed through gene ontology (GO) annotation and cluster analysis. According to the results from GO annotation and cluster analysis, the following six results related to neuroprotective function (inhibitory postsynaptic potential, cellular response to hydrogen peroxide, chemical synaptic transmission, inflammatory response, adult locomotory behavior, and axonogenesis) were obtained, and 19 targets were selected [31]. Among them, the 3D crystal structures of 14 targets were retrieved from the Protein Data Bank (PDB); their names and PDB codes were APP (PDB ID: 3KTM), BMPR1B (PDB ID: 3MDY), CXCL8 (PDB ID: 5D14), CYP1B1 (PDB ID: 3PM0), GLRA1 (PDB ID: 3JAF), GRIK2 (PDB ID: 5CMM), GRM7 (PDB ID: 3MP4), HDAC6 (PDB ID: 6CE6), NR4A2 (PDB ID: 1OVL), PRKCG (PDB ID: 2UZP), RELA (PDB ID: 3GUT), TLR8 (PDB ID: 3W3J), TOP2B (PDB ID: 4G0W), TSHR (PDB ID: 3G04). The 3D structures of another 5 proteins, CCKAR, FPR2, GABRB3, HTR5A, NPBWR1, that were absent from this study were constructed by homology modeling using SWISS-MODEL. This protein structure homology-modeling server is one of the most accurate computational methods (https://swissmodel.expasy.org/workspace/) [33,34,35,36,37]. The template structures for CCKAR, FPR2, GABRB3, HTR5A, and NPBWR1 were downloaded from PDB for the homology methodology; their template codes are 5ZBH, 3ODU, 4COF, 4IAR, 4N6H, respectively (The results of SEA, GO annotation, cluster analysis, homology modeling and the summarizing scheme of in silico studies are shown in the Supplementary Materials).

3.6. A Procedure for Molecular Docking Simulation

The Accelrys Discovery Studio docking program (version 3.5, Accelrys Inc., Bedminster Township, NJ, USA) was adopted here [32]. For the module, CDOCKER is a molecular dynamics (MD) simulated-annealing-based algorithm, and ligand conformations are generated using a high-temperature molecular dynamics methodology and energy minimized into the protein active site using simulated annealing molecular dynamics [45]. Although the docking accuracy decreases when ligands with eight or more rotatable bonds, low-flexible 2-aryl-N-alkylbenzimidazoles could have appropriate docking accuracy rates [37,46]. In this program, the preparations of protein structures included adding hydrogen atoms, removing water molecules, and assigning a CHARMm forcefield. After clicking the CDOCKER module, the input receptors were set up as the corresponding targets, and the input ligand was set up as compound 3g. Top hits were selected as 10, and the other parameters were set as default.

4. Conclusions

We demonstrated a copper-catalyzed direct arylation of N-alkylbenzimidazoles with diverse aryl bromides to furnish the corresponding 2-aryl-N-alkylbenzimidazoles. All these compounds were evaluated for their in vitro neurotoxicities, but low-neurotoxic compounds (3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s and 3t) were found to exert a low neuroprotective effect. This preliminary study provided basic research about 2-aryl-N-alkylbenzimidazoles based on neurodegenerative diseases. Six targets, BMPR1B, CYP1B1, GRM7, HDAC6, HTR5A, and TOP2B, could be potential goals for the study of 2-aryl-N-alkylbenzimidazoles as neuroprotective agents. The dicyclic aromatic rings at the 2-position of N-alkylbenzimidazoles could be important structure moieties for the interaction with CYP1B1, according to our atomic-level study of the interaction between 3g and CYP1B1. This work generated a series of compounds for the 2-arylbenzimidazoles library using a direct protocol, and provided a basic evaluation of 2-aryl-N-alkylbenzimidazoles as neuroprotective agents. Six potential targets and suggestions about the structure of 2-aryl-N-alkyl benzimidazoles as a ligand for CYP1B1 were provided in terms of atomic level.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/8/10/433/s1.

Author Contributions

Conceptualization, F.G. and X.-X.L.; methodology, Y.-X.Y.; software, Y.-X.Y.; validation, N.-N.J., Y.-N.C. and X.-X.C.; formal analysis, Y.-X.Y.; investigation, N.-N.J.; resources, Y.-N.C.; data curation, Y.-X.Y.; writing—original draft preparation, Y.-X.Y.; writing—review and editing, F.G.; visualization, Y.-X.Y.; supervision, F.G.; project administration, F.G.; funding acquisition, F.G.

Funding

This research was funded from NSFC (grant number 31570341) and Key Technology Program from Sichuan Province, China (grant number 2015SZ0105).

Acknowledgments

I acknowledge the support of Key Technology Program from Sichuan Province and help of Guangchuan Wang and Shuangmei Zhao.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Briguglio, I.; Piras, S.; Corona, P.; Gavini, E.; Nieddu, M.; Boatto, G.; Carta, A. Benzotriazole: An overview on its versatile biological behavior. Eur. J. Med. Chem. 2015, 97, 612–648. [Google Scholar] [CrossRef] [PubMed]
  2. Barrett, T.D.; Palomino, H.L.; Brondstetter, T.I.; Kanelakis, K.C.; Wu, X.; Haug, P.V.; Yan, W.; Young, A.; Hua, H.; Hart, J.C.; et al. Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor. Mol. Pharmacol. 2011, 79, 910–920. [Google Scholar] [CrossRef] [PubMed]
  3. Conn, J.P.; Lindsley, C.W.; Hopkins, C.R.; Weaver, C.D.; Niswender, C.M.; Cheung, Y. Substituted Benzoimidazolesulfonamides and Substituted Indolesulfonamides as mGluR4 Potentiators. U.S. Patent 13/386,651, 19 July 2012. [Google Scholar]
  4. Duroux, R.; Renault, N.; Cuelho, J.E.; Agouridas, L.; Blum, D.; Lopes, L.V.; Melnyk, P.; Yous, S. Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A2A receptor. J. Enzyme Inhib. Med. Chem. 2017, 32, 850–864. [Google Scholar] [CrossRef] [PubMed]
  5. Pinna, A. Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Dscontinued. CNS Drugs 2014, 28, 455–474. [Google Scholar] [CrossRef] [PubMed]
  6. Kim, M.; Lee, J.; Jung, K.; Kim, M.; Park, Y.; Ahn, H.; Kwon, Y.H.; Hah, J. Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1H-benzimidazole. Bioorg. Med. Chem. 2013, 21, 2271–2285. [Google Scholar] [CrossRef] [PubMed]
  7. Kim, M.; Ryu, J.-S.; Hah, J.-M. 3D-QSAR studies of 1, 2-diaryl-1H-benzimidazole derivatives as JNK3 inhibitors with protective effects in neuronal cells. Bioorg. Med. Chem. 2013, 23, 1639–1642. [Google Scholar] [CrossRef] [PubMed]
  8. Ozadali-Sari, K.; Küçükkılınç, T.T.; Ayazgok, B.; Balkan, A.; Unsal-Tan, O. Novel multi-targeted agents for alzheimer’s disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. Bioorg. Chem. 2017, 72, 208–214. [Google Scholar] [CrossRef] [PubMed]
  9. Payne, J.E.; Bonnefous, C.; Symons, K.T.; Nguyen, P.M.; Sablad, M.; Rozenkrants, N.; Zhang, Y.; Wang, L.; Yazdani, N.; Shiau, A.K.; et al. Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) part 2: Identification of a novel, potent, and selectives. J. Med. Chem. 2010, 53, 7739–7755. [Google Scholar] [CrossRef] [PubMed]
  10. Xiao, T.; Xiong, S.; Xie, Y.; Dong, X.; Zhou, L. Copper-catalyzed synthesis of benzazoles via aerobic oxidative condensation of o-amino/mercaptan/hydroxyanilines with benzylamines. RSC Adv. 2013, 3, 15592. [Google Scholar] [CrossRef]
  11. Sharma, H.; Singh, N.; Jang, D.O. A ball-milling strategy for the synthesis of benzothiazole, benzimidazole and benzoxazole derivatives under solvent-free conditions. Green Chem. 2014, 16, 4922–4930. [Google Scholar] [CrossRef]
  12. Yang, D.; Zhu, X.; Wei, W.; Sun, N.; Yuan, L.; Jiang, M.; You, J.; Wang, H. Magnetically recoverable and reusable CuFe2O4 nanoparticle-catalyzed synthesis of benzoxazoles, benzothiazoles and benzimidazoles using dioxygen as oxidant. RSC Adv. 2014, 45, 17832–17839. [Google Scholar] [CrossRef]
  13. Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, X.; Wang, Y.; Chen, C. Copper-catalyzed intramolecular C−N bond formation: A straightforward synthesis of benzimidazole derivatives in water. J. Org. Chem. 2011, 76, 716–719. [Google Scholar] [CrossRef] [PubMed]
  14. Peng, J.; Zong, C.; Ye, M.; Chen, T.; Gao, D.; Wang, Y.; Chen, C. Direct transition-metal-free intramolecular C–O bond formation: Synthesis of benzoxazole derivatives. Org. Biomol. Chem. 2011, 4, 1225–1230. [Google Scholar] [CrossRef] [PubMed]
  15. Khemnar, A.B.; Bhanage, B.M. Iron catalyzed efficient synthesis of 2-arylbenzothiazoles from benzothiazole and olefins using environmentally benign molecular oxygen as oxidant. RSC Adv. 2014, 4, 8939–8942. [Google Scholar] [CrossRef]
  16. Gao, Y.; Song, Q.; Cheng, G.; Cui, X. KI-catalyzed arylation of benzothiazoles from the boupling of aryl aldehydes with benzothiazoles in neat water. Org. Biomol. Chem. 2014, 7, 1044–1047. [Google Scholar] [CrossRef] [PubMed]
  17. Kawano, T.; Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M. Copper-mediated direct arylation of 1, 3, 4-oxadiazoles and 1, 2, 4-triazoles with aryl iodides. Org. Lett. 2009, 11, 3072–3075. [Google Scholar] [CrossRef] [PubMed]
  18. Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. Palladium-catalyzed desulfitative C-H arylation of heteroarenes with sodium sulfinates. Chem. Eur. J. 2011, 17, 13415–13419. [Google Scholar] [CrossRef] [PubMed]
  19. Tabuchi, S.; Hirano, K.; Satoh, T.; Miura, M. Synthesis of triarylmethanes by palladium-catalyzed C–H/C–O coupling of oxazoles and diarylmethanol derivatives. J. Org. Chem. 2014, 79, 5401–5411. [Google Scholar] [CrossRef] [PubMed]
  20. Shen, X.-B.; Zhang, Y.; Chen, W.-X.; Xiao, Z.-K.; Hu, T.-T.; Shao, L.-X. Direct C–H bond arylation of (benzo)oxazoles with aryl chlorides catalyzed by N-heterocyclic carbene–palladium(II)–1-methylimidazole complex. Org. Lett. 2014, 16, 1984–1987. [Google Scholar] [CrossRef] [PubMed]
  21. Zhu, F.; Wang, Z.-X. Palladium-catalyzed coupling of azoles or thiazoles with aryl thioethers via C–H/C–S activation. Org. Lett. 2015, 17, 1601–1604. [Google Scholar] [CrossRef] [PubMed]
  22. Zhu, F.; Tao, J.-L.; Wang, Z.-X. Palladium-catalyzed C–H arylation of (benzo)oxazoles or (benzo)thiazoles with aryltrimethylammonium triflates. Org. Lett. 2015, 17, 4926–4929. [Google Scholar] [CrossRef] [PubMed]
  23. Do, H.Q.; Daugulis, O. Copper-catalyzed arylation of heterocycle C-H bonds. J. Am. Chem. Soc. 2007, 41, 12404–12405. [Google Scholar] [CrossRef] [PubMed]
  24. Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M. Copper-mediated direct arylation of benzoazoles with aryl iodides. Tetrahedron Lett. 2008, 49, 1598–1600. [Google Scholar] [CrossRef]
  25. Phipps, R.J.; Grimster, N.P.; Gaunt, M.J. Cu (II)-catalyzed direct and site-selective arylation of indoles under mild conditions. J. Am. Chem. Soc. 2008, 130, 8172–8174. [Google Scholar] [CrossRef] [PubMed]
  26. Zhang, W.; Tian, Y.; Zhao, N.; Wang, Y.; Li, J.; Wang, Z. Nano CuO-catalyzed C–H functionalization of 1,3-azoles with bromoarenes and bromoalken es. Tetrahedron 2014, 70, 6120–6126. [Google Scholar] [CrossRef]
  27. Kim, D.; Yoo, K.; Kim, S.E.; Cho, H.J.; Lee, J.; Kim, Y.; Kim, M. Copper-catalyzed selective arylations of benzoxazoles with aryl iodides. J. Org. Chem. 2015, 80, 3670–3676. [Google Scholar] [CrossRef] [PubMed]
  28. Yang, F.; Koeller, J.; Ackermann, L. Photoinduced copper-catalyzed C−H arylation at room temperature. Angew. Chem. Int. Ed. 2016, 55, 4759–4762. [Google Scholar] [CrossRef] [PubMed]
  29. Jia, N.; Tian, X.; Qu, X.; Chen, X.; Cao, Y.; Yao, Y.; Gao, F.; Zhou, X. Copper-catalyzed direct 2-arylation of benzoxazoles and benzoimidazoles with aryl bromides and cytotoxicity of products. Sci. Rep. 2017, 7, 43758. [Google Scholar] [CrossRef] [PubMed]
  30. Keiser, M.J.; Roth, B.L.; Armbruster, B.N.; Ernsberger, P.; Irwin, J.J.; Shoichet, B.K. Relating protein pharmacology by ligand chemistry. Nat. Biotech. 2007, 25, 197–206. [Google Scholar] [CrossRef] [PubMed]
  31. Ashburner, M.; Ball, C.A.; Blake, J.A.; Botstein, D.; Butler, H.; Cherry, J.M.; Davis, A.P.; Dolinski, K.; Dwight, S.S.; Eppig, J.T.; et al. Gene ontology: Tool for the unification of biology. Nat. Genet. 2000, 25, 25–29. [Google Scholar] [CrossRef] [PubMed]
  32. Arnold, K.; Bordoli, L.; Kopp, J.; Schwede, T. The SWISS-MODEL workspace: A web-based environment for protein structure homology modeling. Bioinformatics 2006, 22, 195–201. [Google Scholar] [CrossRef] [PubMed]
  33. Kiefer, F.; Arnold, K.; Künzli, M.; Bordoli, L.; Schwede, T. The SWISS-MODEL repository and associated resources. Nucleic Acids Res. 2009, 37, D387–D392. [Google Scholar] [CrossRef] [PubMed]
  34. Schwede, T.; Kopp, J.; Guex, N.; Peitsch, M.C. Swiss-model: An automated protein homology-modeling server. Nucleic Acids Res. 2003, 31, 3381–3385. [Google Scholar] [CrossRef] [PubMed]
  35. Guex, N.; Peitsch, M.C. SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling. Electrophoresis 1997, 18, 2714–2723. [Google Scholar] [CrossRef] [PubMed]
  36. Peitsch, M.C. Protein Modeling by E-mail. Biotechnology 1995, 13, 658–660. [Google Scholar] [CrossRef]
  37. Wu, G.; Robertson, D.H.; Brooks III, C.L.; Vieth, M. Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm. J. Comput. Chem. 2003, 24, 1549–1562. [Google Scholar] [CrossRef] [PubMed]
  38. Gonzalez, J.; Marchand-Geneste, N.; Giraudel, J.L.; Shimada, T. Docking and QSAR comparative studies of polycyclic aromatic hydrocarbons and other procarcinogen interactions with cytochromes P450 1A1 and 1B1. SAR QSAR Environ. Res. 2012, 23, 87–109. [Google Scholar] [CrossRef] [PubMed]
  39. Nguyen, K.M.H.; Largeron, M. Catalytic oxidative coupling of primary amines under air: A flexible route to benzimidazole derivatives. Eur. J. Org. Chem. 2016, 2016, 1025–1032. [Google Scholar] [CrossRef]
  40. Liao, L.-Y.; Liu, K.-M.; Duan, X.-F. Unified protocol for cobalt-catalyzed oxidative assembly of two aryl metal reagents using oxygen as an oxidant. J. Org. Chem. 2015, 80, 9856–9867. [Google Scholar] [CrossRef] [PubMed]
  41. Liu, K.M.; Liao, L.Y.; Duan, X.F. Iron catalyzed oxidative assembly of N-heteroaryl and aryl metal reagents using oxygen as an oxidant. Chem. Commun. 2015, 51, 1124–1127. [Google Scholar] [CrossRef] [PubMed]
  42. Haneda, S.; Gan, Z.; Eda, K.; Hayashi, M. Ligand effects of 2-(2-pyridyl)benzazole−pd complexes on the X-ray crystallographic structures, 1 h nmr spectra, and catalytic activities in mizoroki-heck reactions. Organometallics 2007, 26, 6551–6555. [Google Scholar] [CrossRef]
  43. Guru, M.M.; Ali, M.A.; Punniyamurthy, T. Copper-mediated synthesis of substituted 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles via C–H functionalization/C–N/C–O bond formation. J. Org. Chem. 2011, 76, 5295–5308. [Google Scholar] [CrossRef] [PubMed]
  44. Michel, B.W.; Steffens, L.D.; Sigman, M.S. On the mechanism of the palladium-catalyzed tert-butylhydroperoxide-mediated wacker-type oxidation of alkenes using quinoline-2-oxazoline ligands. J. Am. Chem. Soc. 2011, 133, 8317–8325. [Google Scholar] [CrossRef] [PubMed]
  45. Kim, S.J.; Joo, J.C.; Song, B.K.; Yoo, Y.J.; Kim, Y.H. Engineering a horseradish peroxidase C stable to radical attacks by mutating multiple radical coupling sites. Biotechnol. Bioeng. 2015, 112, 668–676. [Google Scholar] [CrossRef] [PubMed]
  46. Erickson, J.A.; Jalaie, M.; Robertson, D.H.; Lewis, R.A.; Vieth, M. Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy. J. Med. Chem. 2004, 47, 45–55. [Google Scholar] [CrossRef] [PubMed]
Catalysts 08 00433 g001 550
Figure 1. Protective rate (%) under MPP + treatment.
Figure 1. Protective rate (%) under MPP + treatment.
Catalysts 08 00433 g001
Catalysts 08 00433 g002 550
Figure 2. Molecular docking simulations. (a) CDOCKER ENERGY of potential targets; (b) Molecular docking of compound 3g into CYP1B1 protein; (c) Three-dimensional representation of the complex (CYP1B1 protein and 3g compound); (d) Two-dimensional interactions diagram of the complex.
Figure 2. Molecular docking simulations. (a) CDOCKER ENERGY of potential targets; (b) Molecular docking of compound 3g into CYP1B1 protein; (c) Three-dimensional representation of the complex (CYP1B1 protein and 3g compound); (d) Two-dimensional interactions diagram of the complex.
Catalysts 08 00433 g002
Table
Table 1. Optimization of direct 2-arylation of 1-methyl-benzimidazole 1a with 1-bromo-4-tert-butylbenzene 2d a.
Table 1. Optimization of direct 2-arylation of 1-methyl-benzimidazole 1a with 1-bromo-4-tert-butylbenzene 2d a.
Catalysts 08 00433 i001
EntryBaseSolventTem. (°C)Time (h)Yield (%) b
1KOHDMF14024Trace
2NaOHDMF14024Trace
3t-BuOKDMF14024Trace
4K2CO3DMF1402460
5Na2CO3DMF1402438
6KH2PO4DMF1402430
7K2CO3DMF1202445
8K2CO3DMF1502464
9K2CO3Xylene1302440
10K2CO3Xylene1402475
11K2CO3DMF1504069
12 cK2CO3Xylene1504078
a The reactions performed using 1.0 equiv.of 1a, 1.2 equiv. of 2d and 2.0 equiv. of base on a 0.1 mmol scale. b This is NMR assay yield. c Isolated yield.
Table
Table 2. Scope of aryl bromides in direct 2-arylation of 1-methyl-benzimidazole 1a.
Table 2. Scope of aryl bromides in direct 2-arylation of 1-methyl-benzimidazole 1a.
Catalysts 08 00433 i002
Catalysts 08 00433 i003
Table
Table 3. Scope of aryl bromides in direct 2-arylation of 1-ethyl-benzoimidazole 1b and 1-benzyl-benzimidazole 1c.
Table 3. Scope of aryl bromides in direct 2-arylation of 1-ethyl-benzoimidazole 1b and 1-benzyl-benzimidazole 1c.
Catalysts 08 00433 i004
Catalysts 08 00433 i005
a 1b was recovered from 50% to 60% yield. b 1b was recovered in 78% yield. c 1c was recovered from 55% yield. d 1c was recovered in 62% yield.
Table
Table 4. The protective rate of compounds on MPP+-induced SH-SY5Y cells.
Table 4. The protective rate of compounds on MPP+-induced SH-SY5Y cells.
Conc. (μM)3b3g3h3i3j3k3o3q3s3t
Protective rate (%)50−42.99−10.20.792.23−2.231.97−17.82−2.722.040.95
10−4.7216.190.130.92−4.195.640.410.442.993.13

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Yao, Y.-X.; Jia, N.-N.; Cao, Y.-N.; Chen, X.-X.; Gao, F.; Liang, X.-X. Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents. Catalysts 2018, 8, 433. https://doi.org/10.3390/catal8100433

AMA Style

Yao Y-X, Jia N-N, Cao Y-N, Chen X-X, Gao F, Liang X-X. Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents. Catalysts. 2018; 8(10):433. https://doi.org/10.3390/catal8100433

Chicago/Turabian Style

Yao, Yun-Xin, Nan-Nan Jia, Ya-Nan Cao, Xing-Xiu Chen, Feng Gao, and Xiao-Xia Liang. 2018. "Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents" Catalysts 8, no. 10: 433. https://doi.org/10.3390/catal8100433

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