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Original article
32 (
2
); 1544-1554
doi:
10.1016/j.jksus.2019.12.010

Synthesis, structural characterization of silver(I)-NHC complexes and their antimicrobial, antioxidant and antitumor activities

, , , , , , ,
a Research Laboratory of Environmental Sciences and Technologies, LR16ES09, Higher Institute of Environmental Sciences and Technology, University of Carthage, Hammam-Lif, Tunisia
b Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
c İnönü University, Faculty of Science and Art, Department of Chemistry, Malatya, Turkey
d Department of Chemistry, College of Sciences and Arts at Al-Rass, Qassim University, P.O. Box 53, Saudi Arabia

⁎Corresponding author. lmansour@ksu.edu.sa (Lamjed Mansour)

Received: , Accepted: ,
© The Author(s) 2019
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

To prepare a novel series of silver (I) complexes, the interaction of benzimidazolium salts having their two nitrogen atoms substituted by bulky groups with Ag2O in DMF has been carried out. Their structures were characterized by elemental analyses, 1H NMR, 13C NMR and IR spectroscopy techniques. Further, the antibacterial properties of both the salts and their silver(I)-NHC complexes were tested against positive and negative bacteria using the agar dilution procedure. The results show that silver complexes are effective against Salmonella Typhimurium, Listeria monocytogenes, and Micrococcus luteus with moderate to high activity, and their minimum inhibitory concentrations ranging from 0.0024 to 1.25 mg/ml. Moreover, the antioxidant activity determination of these compounds were studied with the DPPH, and compared with (gallic acid “GA“and butylatedhydroxytoluene “BHT “). They exhibited significant antioxidant activities. In addition, the of benzimidazoles salts 2a-j and silver-NHC complexes 3a-j were screened for their antitumor activity. The highest antitumor activity was observed for 3e and 3d Complexes and they exhibited IC50 values 6.85 μg/mL against MCF-7 and 10.75 μg/mL against T47D, respectively.

Keywords

N-heterocyclic carbene
Benzimidazolium salts
Silver(I)-NHC complexes
Antimicrobial
Antioxidant activities and antitumor activities
1

1 Introduction

In organometallic chemistry, N-heterocyclic carbene (NHC) ligands have generated a great interest (ArduengoIII and Harlow, 1991). They can form stable metal complexes with strong metal-carbon bonds. Silver complexes are of considerable importance among the NHC-metal complex. The reaction of AgO Tf and a free carbene led to the first NHC-Ag(I) complex isolated in 1993 by ArduengoIII et al. (1993). The most common method reported fot synthesis has been the deprotonation with a silver base such as Ag2O, Ag2CO3 and AgOAc (Xia et al., 2017; Patil et al., 2010a,b; Gok et al., 2013). NHC-Ag(I) complexes have been widely used as sources of different metal complexes via transmetallation (Nakamura et al., 2016; Baquero et al.,2013; Deng et al., 2013; Hameury et al., 2014; Iwasaki et al., 2016; Monticelli et al., 2016; Wan et al., 2016; Chardon et al., 2017). These compounds have antimicrobial and anticancer properties (Shahini et al., 2017a,b; Haque et al., 2015; Karatas et al., 2016; Iqbal et al., 2015; Anchez et al., 2016). Also, they have been studied as luminescent materials (Syu et al.,2017; Adhikary et al., 2012; Seth et al., 2013; Lin et al., 2013). There have been limited number of reports related to the use of NHC-Ag(I) complexes in catalysis (Yoshida et al., 2014; Fu et al., 2011; Kilincarslan et al., 2016; Li et al., 2013; Samantaray et al., 2006; Balcan et al.,2013; Fujii et al.,2009; Tasci et al., 2017; Avinash et al., 2008; Datani et al., 2012). The biological interest of benzimidazole derivatives structure comes from their similarity with naturally occurring nucleotides (Cavallo et al.,2005). For this reason, we synthesized a series of new Ag(I) complexes. The study was conducted with two primary objectives. The first objective was to synthetize a series of new Ag(I) complexes and the second objective was to evaluate the antimicrobial, antioxidant and antitumor activities of these compounds. All new benzimidazoles and silver complexes were characterized by elemental analysis including 13C NMR, 1H NMR and FT-IR spectroscopy

2

2 Experimental

2.1

2.1 Preparation of benzimidazolium salts

Reaction of 1-isobutyl-benzimidazole (1 mmol) (1) with various alkyl chloride(1,1mmol) in dimethylformamide (DMF; 5 mL) at 80 °C for 24 h afford benzimidazole salts 2a-j. A white crystalline solid was obtained after adding Diethyl ether (15 mL), which was subsequently filtered off. After washing with diethyl ether (3*10 mL) the solid was dried under vacuum, and the crude product was recrystallized from Dichloromethane/diethyl ether (1:3 ratio).

2.2

2.2 1-(isobutyl)-3-(benzyl) benzimidazolium chloride, 2a

Yield 89%, Mp: 128.3 °C, ν(CN) = 1650.9 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.06 (d, 6H, CH3 (a,b), J = 4 Hz), 2.44 (Hep, 1H, H2′, J = 8 Hz), 4.44 (d, 2H, H1′), 5.95 (s, 2H, H1′’), 7.30–7.71 (m, 9H, H4, 5, 6, 7, 3″, 4″, 5″, 6″, 7″), 12.07 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.8 (Ca,b), 28.8 (C2′), 51.3 (C1″), 54.4 (C1′), 113.1 (C4), 113.8 (C7), 127.0 (C6), 127.1 (C5), 128.3 (C3″;7″), 129.1 (C5′'), 129.3 (C4′';6′'), 131.1 (C9), 131.7 (C8), 132.9 (C2″), 144.0 (C2). Elemental analysis % calcd. (found) for C18H21ClN2:C, 71.866% (71.9); H, 7.036% (7.1); N, 9.312 (9.2).

2.3

2.3 1-(Isobutyl)-3-(benzyl)-5.6-dimethylbenzimidazolium chloride, 2b

Yield 95%, Mp: 238.9 °C, ν(CN) = 1566.9 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.04 (d, 6H, CH3(a,b), J = 8 Hz), 2.38 (s, 3H, CH3(c)), 2.42 (s, 3H, CH3(d)), 2.44 (Hep, 1H, H2′, J = 8 Hz), 4.36 (d, 2H, H1′, J = 8 Hz), 5.86 (s, 2H, H1′’), 7.30–7.49 (m, 7H, H4, 7, 3″, 4″, 5″, 6″, 7″), 11.81 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.8 (Cc,d), 20.7 (Ca,b), 28.7 (C2′), 51.0 (C1″), 54.2 (C1′), 112.8 (C4), 113.3 (C7), 128.1 (C3″;7″), 129.0 (C5′'), 129.3 (C4″;C6″), 129.6 (C8), 130.2 (C9), 133.2 (C5;6), 137.3 (C2″), 142.8 (C2). Elemental analysis % calcd. (found) for C20H25ClN2: C, 73.040 (73.1); H, 7.662% (7.7); N, 8.518% (8.6).

2.4

2.4 1-(Isobutyl)-3-(2.3.5.6-tetramethylbenzyl) benzimidazolium chloride, 2c

Yield 89%, Mp: 176.3 °C, ν(CN) = 1660.1 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02 (d, 6H, CH3 (a,b), J = 8 Hz), 2.25 (s, 12H, CH3(c,d,e,f)), 2.38 (Hep, 1H, H2′, J = 8 Hz), 4.49 (d, 2H, H1′, J = 8 Hz), 5.97 (s, 2H, H1′’), 7.07–7.69 (m, 5H, H4, 5, 6, 7, 5″), 11.44 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 16.12 (Cc,f), 19.7 (Cd,e), 20.5 (Ca,b), 28.8 (C2′), 48.0 (C1″), 54.2 (C1‘), 113.0 (C4), 113.8 (C7), 126.8 (C6), 127.0 (C5), 127.9 (C5“), 131.3 (C8), 131.8 (C9), 133.5 (C3”,7”), 134.0 (C4“,6”), 135.0 (C2”), 143.9 (C2).Elemental analysis % calcd. (found) for C22H29ClN2:C, 74.030% (74.1); H, 8.189% (8.2); N, 7.848%(7.9).

2.5

2.5 1-(Isobutyl)-3-(2.3.5.6 tetramethylbenzyl)-5.6-dimethylbenzimidazolium chloride, 2d

Yield 87%, Mp: 113.1 °C, ν(CN) = 1558 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm0.99 (d, 6H, CH3 (a,b), J = 4 Hz), 2.30 (m, 18H, CH3(c,d,e,f,g,h)), 2.38 (Hep, 1H, H2′, J = 8 Hz), 4.43 (d, 2H, H1′, J = 8 Hz), 5.86 (s, 2H, H1′’), 6.94–7.36 (m, 3H, H4, 7, 5″), 11.08 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm)16.1 (Ce,h), 18.4 (Cc,d), 19.7 (Ca,b,f,g), 28.8 (C2′), 47.6 (C1″), 54.1 (C1′), 112.7 (C4), 113.5 (C7), 128.0 (C5“), 129.9 (C8), 130.3 (C9), 133.4 (C3”), 133.0 (C7”), 134.9 (C5;6), 136.9 (C4”), 136.9 (C6”),142.5 (C2”), 142.6 (C2). Elemental analysis % calcd. (found) for C24H33ClN2: C, 74.875% (74.9); H, 8.640% (8.7); N, 7.276% (7.2).

2.6

2.6 1-(Isobutyl)-3-(2.3.4.5.6-pentamethylbenzyl) benzimidazolium chloride, 2e

Yield 92%, Mp: 198.2 °C, ν(CN) = 1546 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.05 (d, 6H, CH3 (a,b), J = 4 Hz), 2.24 (s, 6H, CH3(c,g)), 2.28 (s, 6H, CH3(d,f)), 2.28 (s, 3H, CH3(e)), 2.38 (Hep, 1H, H2′), 4.51 (d, 2H, H1′), 5.94 (s, 2H, H1′’), 7.22–7.70 (m, 4H, H4, 5, 6, 7), 11.29 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 16.9 (Cc,g), 17.1 (Cd,f), 17.3 (Ce), 19.7 (Ca,b), 28.8 (C2′), 48.5(C1″), 54.2 (C1‘), 113.0 (C4), 113.9 (C7), 125.1 (C5“), 126.8 (C5), 127.00(C6), 131.3 (C4”), 131.8 (C6”), 133.5 (C3”;7”), 133.8 (C8;9), 137.2 (C2”), 143.7 (C2). Elemental analysis % calcd. (found) for C23H31ClN2: C, 74.468% % (74.5); H, 8.423% (8.5); N, 7.552% (7.4).

2.7

2.7 1-(Isobutyl)-3-(2.3.4.5.6-pentamethylbenzyl)-5.6-dimethylbenzimidazolium chloride, 2f

Yield 93%, Mp: 219.9 °C, ν(CN) = 1550 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.98 (d, 6H, CH3(a,b), J = 8 Hz), 2.14 (Hep, 1H, H2′, J = 8 Hz), 2.25 (s, 6H, CH3(c,d)), 2.30 (t, 12H, CH3(e,f,h,i)), 2.41 (s, 3H, CH3(g)), 2.37 (Hep, 1H, H2′), 4.46 (d, 2H, H1′), 5.80 (s, 2H, H1′’), 7.05 (s, 1H, H7), 7.38 (s, 1H, H4), 10.48 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 16.9 (Cf,h), 17.1 (Ce,i), 17.3 (Cg), 19.7 (Ca,b), 20.6 (Cc,d), 28.7 (C2′), 47.9 (C1″), 54.1 (C1‘), 112.7 (C4), 113.4 (C7), 125.2 (C5′'), 129.9 (C8), 130.4 (C9), 133.8 (C3″;7″), 133.5 (C4″;6″), 136.8 (C5), 136.9 (C6), 137.1 (C2″), 142.3 (C2). Elemental analysis % calcd. (found) for C25H35ClN2: C, 75.253% (75.3); H, 8.841% (8.9); N, 7.021% (7.1).

2.8

2.8 1-(Isobutyl)-3-(4- methylbenzyl) benzimidazolium chloride 2g

Yield 87%, Mp: 176.1 °C, ν(CN) = 1550 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.05 (d, 6H, CH3(a,b)), 2.31 (s, 3H, CH3(c)), 2.43 (Hep, 1H, H2′), 4.44 (d, 2H, H1′), 5.88 (s, 2H, H1′’), 7.15–7.71 (m, 8H, H4, 5, 6, 7, 3″, 4″, 6″,7″), 12.05 (s, 1H, H2).). 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.8 (Ca,b), 21.1 (Cc), 28.9 (C2′), 51.2 (C1″), 54.3 (C1‘), 113.1 (C4), 113.9 (C7), 127.0 (C5;6), 128.3 (C3″;7″), 129.9 (C5″), 129.9 (C4″;6″), 131.0 (C8), 131.7 (C9), 139.1 (C2″), 143.9 (C2). Elemental analysis % calcd. (found) for C19H23ClN2: C, 72.480% (72.5); H, 7.363% (7.4); N, 8.897% (8.9).

2.9

2.9 1-(Isobutyl)-3-(2.4.6-trimethylbenzyl) −5.6-dimethylbenzimidazolium chloride 2h

Yield 89%, Mp: 249.7 °C, ν(CN) = 1550 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.01 (d, 6H, CH3(a,b)), 2.29 (d, 6H, CH3(c,d)), 2.32 (s, 6H, CH3(e,g)), 2.40 (s, 3H, CH3(f)), 2.44 (Hep, 1H, H2′), 4.40 (d, 2H, H1′), 5.84 (s, 2H, H1′’), 6.9–7.38 (m, 4H, H4, 7, 4″, 6′’), 11.34 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.7 (Ca,b), 20.2 (Cc,d), 20.6 (Ce), 20.8 (Cg), 21.0 (Cf), 28.7 (C2′), 47.1 (C1″), 54.1 (C1‘), 112.6 (C4), 113.5 (C7), 125.4 (C4″;6″), 130.0 (C3″; 5″;7″), 137.02 (C8;9), 137.89 (C5;6), 139.52 (C2″), 142.91 (C2). Elemental analysis % calcd. (found) for C23H31ClN2: C, 74.468% (74.5); H, 8.423% (8.5); N, 7.552% (7.6).

2.10

2.10 1-(Isobutyl)-3-(naphthyl)-5.6-dimethylbenzimidazolium chloride 2i

Yield 98%, Mp: 178.3 °C, ν(CN) = 1550 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.04 (d, 6H, CH3(a,b)), 2.33 (s, 3H, CH3(d)), 2.39 (s, 3H, CH3(c)), 2.44 (Hep, 1H, H2′), 4.38 (d, 2H, H1′), 6.04 (s, 2H, H1′’), 7.28–7.96 (m, 9H, H4, 7, 3″, 5″, 6″, 7″, 8″, 10″, 11″), 11.52 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) (ppm)19.8 (Ca,b), 20.6 (Cc,d), 28.8 (C2′), 51.2(C1″), 54.3 (C1‘), 112.8 (C4), 113.4 (C7), 125.0 (C7″), 126.7 (C3″), 126.8 (C10″), 127.6 (C5″), 127.7 (C8″), 128.1 (C6″), 129.4 (C11″), 130.4 (C8;9), 133.2 (C5;6), 137.4 (C2″), 141.9 (C2). Elemental analysis % calcd. (found) for C24H27 BrN2: C, 68.083% (68.1); H, 6.428% (6.5); N, 6.616% (6.7).

2.11

2.11 1-(Isobutyl)-3-(anthracen-9-ylmethyl)-5.6-dimethylbenzimidazolium chloride 2j

Yield 97%, Mp: 269,7 °C, ν(CN) = 1666 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.00 (d, 6H, CH3 (a,b)), 1.91 (s, 3H, CH3(d)), 2.23 (s, 3H, CH3(c)), 2.34 (Hep, 1H, H2′), 4.32 (d, 2H, H1′), 6.90 (s, 2H, H1′’), 6.65 (s, 1H, H9″), 7.23–8.58 (m, 10H, H4, 7, 4″, 5″, 6″, 7″, 11″, 12″, 13″, 14″), 11.95 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.7 (Ca,b), 20.4 (Cc), 20.4 (Cd), 28.6 (C2′), 45.2 (C1″), 54.2 (C1′), 112.3 (C4), 114.2 (C7), 122.1 (C9″), 123.1 (C5″, 6″, 12″, 13″), 125.4 (C4″, 14″), 128.0 (C7″, 11″), 129.7 (C4″, 15″), 129.8 (C8), 130.1 (C9), 130.4 (C8″), 130.9 (C10″), 131.2 (C2″), 136.65 (C5), 136.72 (C6), 143.04 (C2). Elemental analysis % calcd. (found) for C28H29ClN2: C, 78.392% (78.4); H, 6.814% (6.9); N, 6.530% (6.6).

2.12

2.12 General procedure for the preparation of silver(I)-NHC complexes

A solution of benzimidazolium salt (1.0 mmol) (2a-j), Ag2O (1.0 mmol) in dichloromethane (15 mL) was stirred for 24 h at room temperature in dark condition. The reaction mixture was filtered through celite and the solvent removed under reduced pressure. The crude product was recrystallized from dichloromethane/diethyl ether (1:3).

2.13

2.13 Chloro[1-isobutyl-3-(benzyl) benzimidazole-2-ylidene] silver(I) (3a)

Yield 75%, Mp: 188 °C, ν(CN) = 1466 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02 (d, 6H, CH3(a,b), J = 8 Hz), 2.38 (Hep, 1H, H2′, J = 8 Hz), 4.425 (d, 2H, H1′, J = 8 Hz), 5.63 (s, 2H, H1′’), 7.25–7.38 (m, 9H, H4, 5, 6, 7, 3″, 4″, 5″, 6″, 7″). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.3 (Ca,b), 29.3 (C2′), 53.4 (C1″), 56.8 (C1‘), 111.7 (C4), 112.2 (C7), 124.2 (C5), 124.2 (C6), 127.0 (C3″;7″), 127.1 (C8), 127.1(C9), 128.5(C5′'), 129.1 (C4′';6′'), 134.8 (C2″), C2: Ag-Ccarbene: not observed. Elemental analysis % calcd. (found) for C18H20AgClN2: C, 53.029%% (53.1); H, 4.945% (4.8); N, 6.871% (6.9).

2.14

2.14 Chloro[1-isobutyl-3-(benzyl)-5.6-dimethylbenzimidazole-2-ylidene] silver(I) (3b)

Yield 78%, Mp: 208.2 °C, ν(CN) = 1400 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.00 (d, 6H, CH3(a,b), J = 4 Hz), 2.31 (s, 3H, CH3(c)), 2.37 (s, 3H, CH3(d)), 2.37 (Hep, 1H, H2′, J = 8 Hz), 4.18 (d, 2H, H1′, J = 8 Hz), 5.56 (s, 2H, H1′’), 7.08–7.32 (m, 7H, H4, 7, 3″, 4″, 5″, 6″, 7″). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.3 (Cc,d), 20.4 (Ca,b), 29.2 (C2′), 53.1 (C1″), 56.7 (C1′), 111.2 (C4), 112.8 (C7), 126.8 (C3″;7″), 128.3 (5“), 129.0 (C4”; 6”), 132.2 (C8), 132.7 (C9), 133.6 (C5), 133.7 (C6), 135.1 (C2”), C2: Ag-Ccarbene: not observed. Elemental analysis % calcd. (found) for C20H24AgClN2: C, 53.029%% (53.1); H, 4.945% (4.8); N, 6.871% (6.9).

2.15

2.15 Chloro[1-isobutyl-3-(2.3.5.6-tetramethylbenzyl)benzimidazole-2-ylidene]silver 3c

Yield 85%, Mp: 227.3 °C, ν(CN) = 1450 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.94 (d, 6H, CH3(a,b), J = 8 Hz), 2.15 (s, 6H, CH3(d,e)), 2.29 (s, 6H, CH3(c,f)), 2.33 (Hep, 1H, H2′, J = 8 Hz), 4.17 (d, 2H, H1′, J = 8 Hz), 5.49 (s, 2H, H1′’), 7.14–7.49 (m, 5H, H4, 5, 6, 7, 5″). 13C NMR (CDCl3, 100 MHz) δ (ppm)16.1(Cc,f), 20.2 (Cd,e), 20.7 (Ca,b), 29.3 (C2′), 47.6 (C1″), 57.3 (C1′), 111.4 (C4), 111.5 (C7), 124.0 (C5), 124.2(C6), 129.6 (C5′'), 133.1 (C3″;7″), 133.5 (C4′';6″), 133.1 (C2″), 135.3 (C8;9), 189.3 (C2). Elemental analysis % calcd. (found) for C22H28AgClN2: C, 56.973% (56.8); H, 6.085% (6.1); N, 6.040% (6.1).

2.16

2.16 Chloro[1-isobutyl-3-(2.3.5.6-tetramethylbenzyl)-5.6-dimethylbenzimidazole-2-ylidene]silver 3d

Yield 82%, Mp: 231.4 °C, ν(CN) = 1466 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.92 (d, 6H, CH3(a,b), J = 8 Hz), 2.13 (s, 6H, CH3(f,g)), 2.29 (s, 6H, CH3(e,h)), 2.30 (Hep, 1H, H2′, J = 8 Hz), 2.4 (s, 6H, CH3(c,d)), 4.09 (d, 2H, H1′, J = 8 Hz), 5.40 (s, 2H, H1′’), 7.14 (s, 1H, H5″), 7.21 (d, 2H, H4,7, J = 4 Hz). 13C NMR (CDCl3, 100 MHz) δ (ppm)16.1 (Ce,h), 20.2 (Cc,d), 20.7 (Ca,b,f,g), 29.2 (C2′), 47.1 (C1″), 57.3 (C1′), 111.5 (C4), 111.8 (C7), 129.9 (C5′'), 133.0 (C8;9), 133.3 (C3″;4″), 133.4 (C5;6), 133.5 (C4″;6″), 135.5 (C2″), C2: Ag-Ccarbene: not observed. Elemental analysis % calcd. (found) for C24H32AgClN2: C, 58.607% (58.7); H, 6.558% (6.6); N, 5.696% (5.7).

2.17

2.17 Chloro[1-isobutyl-3-(2.3.4.5.6-pentamethylbenzyl)benzimidazole-2-ylidene]silver 3e

Yield 86%, Mp: 275.3 °C, ν(CN) = 1458 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.93 (d, 6H, CH3(a,b), J = 4 Hz), 2.19 (s, 6H, CH3(d,f)), 2.28 (s, 6H, CH3(c,g)), 2.30 (Hep, 1H, H2′, J = 8 Hz), 2.33 (s, 3H, CH3(e)), 4.15 (d, 2H, H1′, J = 8 Hz), 5.48 (s, 2H, H1′’), 7.27–7.48 (m, 4H, H4, 5, 6, 7). 13C NMR (CDCl3, 100 MHz) δ (ppm)17.1 (Cc,d,f,g), 17.3 (Ce), 20.2 (Ca,b), 29.3 (C2′), 47.8 (C1″), 57.3 (C1′), 111.4 (C4), 111.6 (C7), 123.9 (C5), 124.1 (C6), 126.5 (C5′'), 132.9 (C4″;6″), 133.2 (C8;9;3″;7″), 137.2(C2″), 189.0 (C2). Elemental analysis % calcd. (found) for C23H30 AgClN2: C, 57.814% (57.9); H, 6.328% (6.4); N, 5.863% (5.9).

2.18

2.18 Chloro[1-isobutyl-3-(2.3.5.6-tetramethylbenzyl)-5.6-dimethylbenzimidazole-2-ylidene]silver 3f

Yield 89%, Mp: 208.3 °C, ν(CN) = 1591 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.91 (d, 6H, CH3(a,b), J = 8 Hz), 2.18 (s, 6H, CH3(f,h)), 2.24 (Hep, 1H, H2′, J = 8 Hz), 2.28 (s, 6H, CH3(e,i)), 2.33 (s, 3H, CH3(g)), 2.41(s, 6H, CH3(c,d)), 4.08 (d, 2H, H1′, J = 8 Hz), 5.39 (s, 2H, H1′’), 7.20 (s, 1H, H4), 7.27 (s, 1H, H7). 13C NMR (CDCl3, 100 MHz) δ (ppm) 17.0 (Cf,h), 17.1 (Ce,i), 17.3 (Cg), 20.4 (Ca,b), 20.4 (Cc), 20.5 (Cd), 29.1 (C2′), 47.3 (C1″), 57.3 (C1′), 111.5 (C4), 111.8 (C7), 126.7 (C5′'), 132.9 (C8;9), 133.2(C3″), 133.5 (C7″), 134.2 (C5;6;4″;6″), 137.1 (C2″), 185.2 (C2). Elemental analysis % calcd. (found) for C25H34 AgClN2: C, 59.356% (59.4); H, 6.774% (6.8); N, 5.538% (5.6).

2.19

2.19 Chloro[1-isobutyl-3-(4--methylbenzyl) benzimidazole-2-ylidene]silver 3g

Yield 79%, Mp: 202.3 °C, ν(CN) = 1468 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.01 (d, 6H, CH3(a,b), J = 8 Hz), 2.31 (s, 3H, CH3(c)), 2.83 (Hep, 1H, H2′, J = 8 Hz), 4.24 (d, 2H, H1′, J = 8 Hz), 5.57 (s, 2H, H1′’), 7.11–7.48 (m, 8H, H4, 5, 6, 7, 3″, 4″, 6″,7″). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.3 (Ca,b), 21.1 (Cc), 29.3 (C2′), 53.3 (C1″), 56.8 (C1′), 112.2 (C4), 111.6 (C7), 124.1 (C5), 124.2 (C6), 127.1 (C3″;7″), 129.7 (C4″;6″), 131.8 (C5″), 133.6 (C8), 134.2 (C9), 138.4 (C2″), C2: Ag-Ccarbene: not observed. Elemental analysis % calcd. (found) for C19H22AgClN2: C, 54.114% (54.2); H, 5.258% (5.3); N, 6.643% (6.7).

2.20

2.20 Chloro[1-isobutyl-3-(2.4.6-trimethylbenzyl)-5.6-dimethylbenzimidazole-2-ylidene]silver 3h

Yield 86%, Mp: 273.4 °C, ν(CN) = 1458 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.94 (d, 6H, CH3(a,b), J = 4 Hz), 2.23 (s, 6H, CH3(c,d)), 2.28 (Hep, 1H, H2′, J = 8 Hz), 2.34 (s, 3H, CH3(e)), 2.35 (s, 3H, CH3(f)), 2.38 (s, 3H, CH3(g)), 4.11 (d, 2H, H1′, J = 8 Hz), 5.40 (s, 2H, H1′’), 6.97 (s, 2H, H 4″, 6″), 7.18 (s, 2H, H 4, 7). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.2 (C(c,d)), 20.3 (C (a,b)), 20.4 (Ce), 20.5 (Cg), 21.1 (C f), 29.2 (C2′), 47.4 (C1″), 57.1 (C1′), 111.7 (C4), 111.8 (C7), 126.8 (C4″;6″), 130.2 (C3″;5″;7″), 133.3 (C8;9), 137.4 (C5;6), 139.4 (C2″), 187.9 (C2).Elemental analysis % calcd. (found) for C23H30AgClN2: C, 57.814% (57.9); H, 6.328% (6.4); N, 5.863% (5.9).

2.21

2.21 Chloro[1-isobutyl-3-(3-(naphthyl)-5.6-dimethylbenzimidazole-2-ylidene] silver 3i

Yield 85%, Mp: 284.6 °C, ν(CN) = 1400 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.98 (d, 6H, CH3(a,b)), J = 8 Hz), 2,26 (s, 3H, CH3(d)), 2.35 (s, 3H, CH3(c)), 2.36 (Hep, 1H, H2′, J = 8 Hz), 4.19 (d, 2H, H1′), J = 8 Hz), 5.71 (s, 2H, H1′’), 7.10–7.76 (m, 9H, H4, 7, 3″, 5″, 6″, 7″, 8″, 10″, 11″). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.3 (C (a,b)), 20.3 (C (c,d)), 29.2 (C2′), 53.2 (C1″), 56.6 (C1′), 111.8 (C4), 112.2 (C7), 124.4 (C7″), 125.9(C3″), 126.3 (C10″), 126.5(C5″), 127.7 (C8″), 127.9 (C6″), 129.0 (C11″), 132.3 (C8), 132.8 (C9), 133.0 (C5), 133.1 (C6), 133.6 (C2″), 168.6 (C2). Elemental analysis % calcd. (found) for C24H26AgClN2: C, 59.337% (59.4); H, 5.395% (5.4); N, 5.766% (5.8).

2.22

2.22 Chloro[1-isobutyl-3-(anthracen-9-ylmethyl) dimethylbenzimidazole-2-ylidene]silver 3j

Yield 86%, Mp: 214.2, ν(CN) = 1468 cm−1. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.90 (d, 6H, CH3(a,b), J = 4 Hz), 2.12 (s, 3H, CH3(d)), 2.22 (Hep, 1H, H2′, J = 8 Hz), 2.31 (s, 3H, CH3(c)), 4.08 (d, 2H, H1′, J = 4 Hz), 6.38 (s, 2H, H1′’), 7.87–8.22 (m, 11H, H4, 7, 4″, 5″, 6″, 7″, 9″, 11″, 12″, 13″, 14″). 13C NMR (CDCl3, 100 MHz) δ (ppm) 20.2(C (a,b)), 20.3 (C (c)), 20.4 (C (d)), 29.1 (C2′), 46.2 (C1″), 57.0 (C1′), 111.7 (C4), 112.3 (C7), 122.9 (C9″), 125.2 (C5″; 6″; 12″; 13″), 127.5 (C4″; 7″; 11″; 14″), 129.9 (C3″, 8″, 10″, 15″), 131.1 (C8;9), 131.4 (C5;6), 132.7 (C2″), C2: Ag-Ccarbene: not observed. Elemental analysis % calcd. (found) for C28H28AgClN2: C, 62.759% (62.8); H, 5.267% (5.3); N, 5.228% (5.3).

Antibacterial activities were prepared according the reported procedures (boubakri et al., 2018)

2.23

2.23 Cytotoxicity assay

Cytotoxicity of benzimidazoles salts 2a-j and silver–NHC complexes 3a-j was assessed using the reported procedures (Song et al., 2010).

3

3 Results and discussion

3.1

3.1 Preparation of benzimidazolium salts

benzimidazoles salts (2a-j) were prepared via the two step N-alkylation process as depicted in Scheme 1. Compound 1 was obtained by N-alkylation of benzimidazole with isobutyl bromide (1-Bromo-2-methylpropane) in the presence of KOH in DMSO at 80 °C for 8 h. The benzimidazolium salts (2a-j) were prepared by reacting N-(isobutyl)-benzimidazole (1) with various aryl chloride in DMF at 80 °C for 24 h (Scheme 1). The reaction has been monitored following thin layer chromatography, and after this time the formation of salts (2a-j), has been observed for every target compound. The benzimidazolium salts (2a-j) were air- and moisture-stable both in the solid state and in solution.

Synthesis of the benzimidazoles salts (2a-j).
Scheme 1
Synthesis of the benzimidazoles salts (2a-j).

The FTIR spectroscopy, 1H- and 13C{1H} NMR spectroscopy, and elemental analysis data of the title compounds confirm the proposed structures.

NMR spectra of all the compounds were analyzed in d-CDCl3. In the 1H NMR spectra, acidic protons (NCHN) for benzimidazolium salts (2a-j) were seen at 12.07, 11.81, 11.44, 11.08, 11.29, 10.48, 12.05, 11.34, 11.52 and 11.95 ppm, respectively, as a characteristic sharp singlet. In the 13C{1H} NMR spectra of benzimidazoles salts (2a-j), the NCHN carbon were detected as typical singlets at 144.5, 142.8, 144.02, 142.66, 143.78, 142.39, 143.96, 142.91, 141.91 and 143.04 ppm, respectively. These values are consistent with related literature. (Hu et al.,2004; Doǧan et al., 2001; Ozdemir et al., 2010; Iqbal et al., 2013).

In the IR spectra, the ν(C⚌N) bands for salts (2a-j) were observed at 1650, 1566, 1660, 1558, 1546, 1550, 1550, 1550, 1550 and 1666 cm−1 respectively.

Aromatic protons of benzimidazolium salts (2a-j) were detected in the range of 6.94–8.64 ppm. –CH– protons of isopropyl group on all benzimidazolium salts where seen as septets in the range of 2.34–2.44 ppm. Methylic protons of isopropyl group on benzimidazolium salts (2a-j) were resonated between 0.98 and 1.06 as doublets however methyl protons of benzimidazolium salts (2a-j) signaled at 2.24–2.44 ppm as singlets. In the 1H NMR spectra of (2a-j) H1′ protons appeared at 4.49 ppm while H1′' protons were detected as typical singulets between at 5.90 ppm (Fig. 1).

1H NMR spectra of benzimidazole salt 2e in CDCl3.
Fig. 1
1H NMR spectra of benzimidazole salt 2e in CDCl3.

The 13C NMR spectra showed aromatic carbons of benzimidazolium salts (2a-j) in the range of 112.35–143.97 ppm. NCHN carbons on salts (2a-j) were observed at 144.5, 142.8, 144.02, 142.66, 143.78, 142.39, 143.96, 142.91, 141.91 and 143.04 ppm, respectively. Terminal carbons(a,b) of the isopropyl group of all benzimidazolium salts (2a-j) gave peaks at 19.86, 20.70, 20.57, 19.72, 19.79, 19.71, 19.86, 19.74, 19.87 and 19.73 respectively while –CH carbons of the isobutyl group were observed at 28.89, 28.77, 28.87, 28.87, 28.88, 28.79, 28.90, 28.77, 28.84, 28.69 respectively (Fig. 2).

13C NMR spectra of benzimidazole salt 2e in CDCl3.
Fig. 2
13C NMR spectra of benzimidazole salt 2e in CDCl3.

The general procedure for the preparation of silver(I)-NHC complexes (2a-j) was performed according to the procedure of Organ (O’Brien et al., 2006). Benzimidazolium salts (2a-j) were incorporated into the silver(I)-NHC complexes (3a-j) by reaction with Ag2O in dichloromethane for 24 h resulted in the silver-NHC complex as a white solid. Monitoring of the reaction by 1H NMR spectroscopy in CDCl3 showed that benzimidazolium salts were completely transformed into silver complexes with moderate yields (75–85%) under argon atmosphere. Ag(I) complexes were synthesized in the absence of light and all products were stored in the dark Scheme 2.

Synthesis of silver(I) complexes 3a-j.
Scheme 2
Synthesis of silver(I) complexes 3a-j.

The silver complexes (3a-j) have a good solubility in polar solvents and are stable in the air and toward the moisture.

In the 1H NMR spectra the acidic imino proton of benzimidazolium salts (NCHN) were not observed between δ10.48–12.07 ppm. Fig. 3 Similarly, in the 13C NMR spectra, imino carbon of benzimidazolium salts (NCHN) were not observed between δ 141–144 ppm.

1H NMR spectra of silver complex 3e in CDCl3.
Fig. 3
1H NMR spectra of silver complex 3e in CDCl3.

Therefore, in the 1H NMR spectrum Ag(I)-NHC complexes (3a-j), the disappearance of an acidic proton is evidence of formation complex. In the13C NMR spectra of salts (2a-j) the characteristic signals of carbon (NCHN) were seen as singlets at 144.5, 142.8, 144.02, 142.66, 143.78, 142.39, 143.96, 142.91, 141.91 and 143.04 ppm, respectively for benzimidazolium salts while for complex (3a-j) a signal of carbon (NCN) have shifted greatly downfield region compared to the corresponding benzimidazolium salt (2a-j) and were observed at 189.35, 189.06, 185.29, 187.95, 168.65, ppm respectively for complexes 3b, 3e, 3f, 3h and 3i however, the rest of carbon signal for complexes 3a, 3b, 3e, 3g and 3j were not observed. Fig. 4. These values, and the lack of the carben peak are in agreement with reported data for similar Ag-NHC complexes (Pytkowicz et al., 2001). At the same time, formation of the Ag(I)-NHC complexes (3a-j) was proven by IR spectra, which showed CN bond vibrations at 1466, 1400, 1450, 1466, 1458, 1591, 1468, 1458, 1400, 1468 cm−1, respectively.

13C NMR spectra of silver complex 3e in CDCl3.
Fig. 4
13C NMR spectra of silver complex 3e in CDCl3.

All the synthesized benzimidazolium salts (2a-j) and their corresponding silver(I) complexes (3a-j) were tested for antibacterial and antioxidant activities as per details given in the following text.

4

4 Biological activities

All the synthesized benzimidazolium salts (2a-j) and their corresponding silver(I) complexes (3a-j) were investigated for antibacterial against the both gram (+)/(−) bacterials. The DMSO did not exhibit any antimicrobial activity as reported earlier (Shahini et al., 2017; Patil et al., 2010a,b; Gleeson et al.,2008). The antimicrobial activities of the NHC precursors (2a-j) and their corresponding silver complexes (3a-j) are reported in Table 1.

Table 1 Zone of bacterial inhibition measured in mm of the synthesized salts and silver complexes.
Microorganisms Compounds Micrococcus luteus LB 14,110 Listeria monocytogenes ATCC 19,117 Salmonella Typhimurium ATCC 14,028 Staphylococcus aureus ATCC 6538 Pseudomonas aeruginosa
3a 20 ± 0.6 14 ± 0.5 18 ± 0.54 16 ± 0.25 16 ± 0.13
3b 22 ± 0.6 15 ± 0.6 18 ± 0.5 17 ± 0.3 17 ± 0.14
3c 35 ± 0.5 16 ± 0.2 18 ± 0.5 18 ± 0.5 22 ± 0.2
3d 30 ± 0.5 14 ± 0.5 16 ± 0.10 18 ± 0.11 16 ± 0.19
3e 25 ± 0.33 22 ± 0.5 18 ± 0.5 18 ± 0.18 20 ± 0.45
3f 36 ± 0.2 16 ± 0.3 18 ± 0.5 20 ± 0.1 20 ± 0.4
3g 28 ± 0.32 16 ± 0.5 22 ± 0.44 18 ± 0.15 22 ± 0.5
3h 30 ± 0.4 16 ± 0.2 16 ± 0.2 20 ± 0.2 18 ± 0.2
3i 38 ± 0.2 22 ± 0.2 22 ± 0.3 22 ± 0.2 20 ± 0.4
3j 34 ± 0.44 22 ± 0.5 22 ± 0.15 22 ± 0.3 20 ± 0.25
2a 20 ± 0.22 – 22 ± 0.22 18 ± 0.05 18 ± 0.22
2b 18 ± 0.2 20 ± 0.2 16 ± 0.3 20 ± 0.2 18 ± 0.2
2c 16 ± 0.2 18 ± 0.3 18 ± 0.22 16 ± 0.0 16 ± 0.5
2d 22 ± 0.2 16 ± 0.2 14 ± 0.2 20 ± 0.2 16 ± 0.2
2e 18 ± 0.2 18 ± 0.22 18 ± 0.33 18 ± 0.23 18 ± 0.22
2f 30 ± 0.4 22 ± 0.7 30 ± 0.4 25 ± 0.2 18 ± 0.22
2g 22 ± 0.3 16 ± 0.4 22 ± 0.4 18 ± 0.2 18 ± 0.2
2h 10 ± 0.4 14 ± 0.5 12 ± 0.10 14 ± 0.15 16 ± 0.10
2i 32 ± 0.32 – 16 ± 0.15 18 ± 0.1 18 ± 0.15
2j 20 ± 0.4 18 ± 0.5 18 ± 0.24 18 ± 0.5 18 ± 0.16

Minimum inhibitory concentration (MIC) determination

Compound 3i is more active than compounds 3h and 3c against the Micrococcus luteus LB 14110. The complexes have shown antibacterial activity to different extents, according on the typr of ligand. The silver complexes have shown enhanced activity compared with the benzimidazolium salts. The complexes exhibited enhanced antibacterial activity, which could be explained by the increased lipophilicity due to the synergistic effect of the complexes. Observed antibacterial activity of these complexes is comparable to that of our previous silver complexes (Achar et al., 2018a,b).

The MIC values of tested silver complexes and their starting material against Listeria monocytogenes ATCC 19117, Salmonella Typhimurium ATCC 14,028 and Micrococcus luteus are presented in Tables 2.

Table 2 Minimal bacterial inhibitory concentration measured in mg/mL of benzimidazoles salts and silver–NHC complexes.
Microorganismindicator Compounds MIC (mg/ml)
Listeria monocytogenes ATCC 19,117 2h 1,25
2j 0,625
3f 0,0048
Ampicillin 0.039
Salmonella Typhimurium ATCC 14,028 2h 1,25
2j 0,039
3f 0,0024
Ampicillin 0,625
Micrococcus luteus 2h 0,3125
2j 0,3125
3f 0,0024
Ampicillin 0,0195

Silver complex 3f showed good activity than that of ampicillin against Micrococcus luteus with a MIC of 0.0024 mg/mL. while a MIC of 0.048 mg/mL was observed in the case of Salmonella Typhimurium for the silver complex 3f. MICs of other compounds remained within the tested range.

4.1

4.1 Antioxydant activities

The scavenging activity of the synthesized of the NHC precursors (Scheme 3) and silver complexes with DPPH (1,1-diphenyl-2-picrylhydrazyl) is represented in Scheme 4.

DPPH radicals scavenging activity of benzimidazoles salts, 2a, 2d, 2g.
Scheme 3
DPPH radicals scavenging activity of benzimidazoles salts, 2a, 2d, 2g.
DPPH radicals scavenging activity of (Ag-NHC) complexes, 3d, 3g.
Scheme 4
DPPH radicals scavenging activity of (Ag-NHC) complexes, 3d, 3g.

The analysis of the results showed that the profiles of obtained antiradical activity of the tested synthetic products 3g and 3d have a very important anti-radical activity and showed higher antioxidant activity than other products. For a used concentration (0.0625 mg/ml), the product 2d has the lowest radical activity comparing to the gallic acid and BHT (butylated hydroxytoluene). On the same way the compounds 2a, 2g, and 3d for a concentration equal to 0.0625 mg/ml had a lower radical activity than gallic acid and BHT (butylated hydroxytoluene). At a concentration of 1 mg/ml, these products 2a, 2d, 2g, 3g and 3d revealed a significant activity of DPPH compared with the synthetic antioxidants.

Cytotoxic Activities

In order to evaluate their cytotoxicity, the benzimidazoles salts 2a-j and silver–NHC complexes 3a-j were screened against the two human cancer cell lines, MDA-MB-231 and MCF7. The results are presented in Table 3

Table 3 Anticancer of synthesized of benzimidazoles salts 2a-j and silver–NHC complexes 3a-j.
benzimidazoles salts 2a-j and silver–NHC complexes 3a-j Anticancer activity LC50 in µg/ml
3a MCF7 MDA-MB-231
3b 4.2 ± 3.6 2.5 ± 4.3
3c 3.1 ± 3.1 2.6 ± 5.9
3d 1.7 ± 3.1 16 ± 2.8
3e 4.3 ± 1.8 0.0 ± 00
3f 0.68 ± 3.2 1.93 ± 2.6
3g 1.3 ± 4.1 3.3 ± 2.9
3h 2.0 ± 3.2 2.8 ± 2.9
3i 0.62 ± 3.1 1.95 ± 2.5
3j 1.3 ± 4.1 3.4 ± 2.9
2a 2.0 ± 3.2 2.7 ± 2.8
2b NA NA
2c 3.1 ± 5.9 6.3 ± 3.2
2d NA NA
2e 0.6 ± 2.9 3.1 ± 5.9
2f Higher than 100 µg/ml Higher than 100 µg/ml
2g Higher than 100 µg/ml Higher than 100 µg/ml
2h Higher than 100 µg/ml Higher than 100 µg/ml
2i Higher than 100 µg/ml Higher than 100 µg/ml
2j Higher than 100 µg/ml Higher than 100 µg/ml
Tetracyclinea NT NT

Values are mean value ± standard deviation of three different replicates.

a The concentration was 30 µg, NT: not tested, NA: not active.

As shown in Table 3, the cytotoxicity of 3i and 3f were much greater in MCF7 with IC50 values 0.68 and 0.6 µg/ml, respectively as compared to their activity on MDA-MB-231 cells. The cytotoxicity of compound 3j in MCF7 and MDA-MB-231 cells was 2.3 and 3.4 µg/ml, while the IC50 values of compound on 2a were 2 and 2.7 µg/ml against MCF7 and MDA-MB-231, respectively. For the compounds 2f-j their IC50 values were more than 100 µg/ml. The compound 2d was inactive.

5

5 Conclusion

In this study six benzimidazolium salts and their silver(I)–NHC complexes have been prepared and characterized by 1H NMR, 13C NMR, IR and elemental analysis. In addition, these compounds showed significant activities compared with standard antibiotic. In addition, the silver(I)–NHC complexes showed significant antitumor activity against the cell lines MCF-7 and MDA-MB-231. In the aim to determine the antimicrobial activity specificity and spectra of action, studies are now in progress including a larger collection of bacteria of different species in order to provide possible application in different fields. Also advanced investigations focusing on new Au and Ag–NHC complexes as metallopharmaceutical compounds are in process.

Acknowledgements

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding this research group No (RG-1435-023) and İnönü University support by Research Fund (İÜ‐BAP: FOA-2018-1135)

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Further reading

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  5. Pugh, A.A., Danopoulos, 2007. Metal complexes with ‘pincer’-type legends incorporating N-heterocyclic carbine functionalities. Coord. Chem. Rev., 251, 610–641.

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