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BMC Chemistry

, 13:50 | Cite as

Design, synthesis and biological profile of heterocyclic benzimidazole analogues as prospective antimicrobial and antiproliferative agents

  • Sumit Tahlan
  • Sanjiv Kumar
  • Kalavathy Ramasamy
  • Siong Meng Lim
  • Syed Adnan Ali Shah
  • Vasudevan Mani
  • Ranjana Pathania
  • Balasubramanian NarasimhanEmail author
Open Access
Research article
Part of the following topical collections:
  1. Medicinal Chemistry

Abstract

Background

Nitrogen containing heterocycles are widely used and investigated by pharmaceutical industry, as they are important in discovery and designing of new drug molecules. Drugs with a benzimidazole nucleus possess exclusive structural features and electron-rich atmosphere, which enable them to bind to a number of biologically important targets and result in a wide range of activities. This has served as the basis of the present study whereby new scaffolds with benzimidazole moiety were designed and synthesized.

Methods

The structures of synthesized compounds were confirmed by physicochemical and spectral means. The synthesized compounds were screened for their antimicrobial and antiproliferative activities by tube dilution and Sulforhodamine B (SRB) assays, respectively.

Results and conclusion

The in vitro biological screening results revealed that compound Z24 exhibited promising antimicrobial and anticancer activities which are comparable to standards.

Keywords

Antibacterial Antifungal Anticancer 2-Mercaptobenzimidazole SAR 

Abbreviations

CRC

Colorectal Cancer

HDAC

Histone Deacetylase Inhibitor

WHO

World Health Organization

IR

Infrared

NMR

Nuclear Magnetic Resonance

MS

Mass Spectrometry

TLC

Thin Layer Chromatography

ATR

Attenuated Total Reflection

DMSO

Dimethyl Sulfoxide

SRB

Sulforhodamine B

HCT116

Human colorectal carcinoma 116

MIC

Minimum Inhibitory Concentration

5-FU

5-Fluorouracil

µM

micro mole

SAR

Structure Activity Relationship

MTCC

Microbial Type Culture Collection

SA

Staphylococcus aureus

ST

Salmonella typhi

KP

Klebsiella pneumoniae

EC

Escherichia coli

CA

Candida albicans

AN

Aspergillus niger

Introduction

The increased incidences of drug resistance caused by extensive use of antibiotics and immunosuppressive drugs have emerged as a key issue in treatment of microbial infections. There is, therefore, a need for search of efficient, less toxic and structurally new molecules for treatment of these diseases. The discovery and development of drugs with benzimidazole moiety is now an important and attractive subject of interest given their huge therapeutic values [1]. Heterocyclic compounds offer a high degree of structural diversity and have proven to be broadly and economically useful as therapeutic agents like quinoline-branched amines and dimers [2], 8-substituted quinolines [3], 2,5- and 4,5-dihydroisoxazole [4].

The structural isosters of nucleotides, benzimidazole and heterocycles, which interact with biopolymer through the fused heterocyclic nuclei in their structure, may possess potential activity of chemotherapeutics with lower toxicity. It is well established that heterocyclic compounds with nitrogen and sulphur exhibit a wide scope of biological activities. 2-Mercaptobenzimidazole, for example, has been reported for their wide range of pharmacological and clinical applications [5]. On the other hand, azomethine group which is present in various natural and non-natural compounds, is also an important scaffold critical for biological activity of Schiff bases. Owing to their broad spectrum of biological profile, Schiff bases derived from benzimidazole compounds are extensively studied [6].

Colorectal cancer (CRC) is one of the most common malignancies and a noteworthy reason for growth related mortality around the world. According to World Health Organization (WHO), CRC is the third most regular malignancy, with 1,361,000 cases worldwide. Unfortunately, about 25% of CRC cases are only identified at stage IV (with far off metastases) and nearly half of CRC patients suffered from metastasis in the midst of their lifetime. The treatment outcomes for these patients remain inauspicious whilst approximately half of the patients responded to traditional chemotherapy, most encountered resistance at some stage of treatment, and reoccurrence of the tumors regularly take after. This could be due to cancer stem cells (CSCs) which give rise to heterogeneity within and between tumors [7].

In recent years, remarkable attention has been directed towards the advancement of benzimidazole heterocyclic molecules as antihistaminic (H1-receptor antagonist, e.g. bilastine, 5-HT3 antagonist, e.g. lerisetron) [8], antimicrobial (antibiotic, e.g. ridinilazole) [9, 10], antiulcer (proton pump inhibitor (PPI), e.g. ilaprazole) [11, 12], antihypertensive (calcium channel blocker, e.g. mibefradil) [13], antiviral (non-structural protein inhibitor (NS5A), e.g. samatasvir) [14, 15], antiparasitic (specifically anthelmintic, e.g. flubendazole) [16], antipsychotic (D2 receptor antagonist, e.g. clopimozide) [17], analgesic (opioid analgesic, e.g. clonitazene) [18], phosphodiesterase inhibitor (PDE3 inhibitor e.g. adibendan) [19, 20] and anticancer (aromatase inhibitor, e.g. liarozole, histone deacetylase inhibitor (HDAC), e.g. pracinostat) [21, 22] agents (Fig. 1).
Fig. 1

Marketed medicines containing benzimidazole as core moiety

Prompted by the aforementioned facts and literature on pharmacologically active heterocyclic benzimidazole nucleus (as reviewed in Fig. 2), the present work aimed to synthesize a new series of benzimidazole compounds and evaluate their biological activities.
Fig. 2

Design of benzimidazole analogues for antimicrobial and anticancer activity based on biological profile

Results and discussion

Chemistry

The synthesis of benzimidazole derivatives (Z1Z30) by multistep procedure was shown in Scheme 1. The 1H-benzo[d]imidazol-2-yl 2-chloroethanethioate (intermediate-i) was synthesized by the reaction of chloroacetyl chloride with 2-mercaptobenzimidazole, which on further reaction with corresponding anilines in presence of ethanolic solvent yielded the title compounds (Z1Z15). The reaction of above synthesized intermediate-i with hydrazine hydrate yielded intermediate-ii. The intermediate-ii on reaction with substituted aldehydes in ethanol resulted in development of title compounds (Z16Z30) with appreciable yields. The physicochemical properties of compounds (Z1Z30) are shown in Table 1.
Scheme 1

Synthesis of heterocyclic benzimidazole derivatives

Table 1

The physicochemical properties of synthesized benzimidazole derivatives

Comp.

IUPAC name

Mol. structure

Mol. formula

Rf valuea

m. p. (oC)

% yield

Z1

1H-Benzo[d]imidazol-2-yl 2-(2,4-dinitrophenyl-amino) ethanethioate

Open image in new window

C15H11N5O5S

0.48

180–183

83.64

Z2

1H-Benzo[d]imidazol-2-yl 2-(2-nitrophenylamino)ethanethioate

Open image in new window

C15H12N4O3S

0.82

212–215

73.93

Z3

1H-Benzo[d]imidazol-2-yl 2-(3-nitrophenylamino)ethanethioate

Open image in new window

C15H12N4O3S

0.75

217–220

85.74

Z4

1H-Benzo[d]imidazol-2-yl 2-(3-bromophenylamino)ethanethioate

Open image in new window

C15H12N3OSBr

0.47

257–260

73.19

Z5

1H-Benzo[d]imidazol-2-yl 2-(4-bromophenylamino)ethanethioate

Open image in new window

C15H12N3OSBr

0.65

260–263

57.48

Z6

1H-Benzo[d]imidazol-2-yl 2-(4-chloro-2-nitrophenylamino) ethanethioate

Open image in new window

C15H11N4O3SCl

0.66

140–143

94.19

Z7

1H-Benzo[d]imidazol-2-yl 2-(2-chlorophenylamino)ethanethioate

Open image in new window

C15H12N3OSCl

0.60

277–280

60.63

Z8

1H-Benzo[d]imidazol-2-yl 2-(3-chlorophenylamino)ethanethioate

Open image in new window

C15H12N3OSCl

0.68

265–268

65.87

Z9

1H-Benzo[d]imidazol-2-yl 2-(2,6-dimethyyphenylamino) ethanethioate

Open image in new window

C17H17N3OS

0.59

274–277

65.52

Z10

1H-Benzo[d]imidazol-2-yl 2-(2-chloro-4-nitrophenylamino) ethanethioate

Open image in new window

C15H11N4O3SCl

0.74

180–183

91.45

Z11

1H-Benzo[d]imidazol-2-yl 2-(2-florophenylamino)ethanethioate

Open image in new window

C15H12N3OSF

0.73

272–275

72.43

Z12

1H-Benzo[d]imidazol-2-yl 2-(4-florophenylamino)ethanethioate

Open image in new window

C15H12N3OSF

0.55

270–273

68.60

Z13

1H-Benzo[d]imidazol-2-yl 2-(4-methylphenylamino)ethanethioate

Open image in new window

C16H15N3OS

0.61

266–269

64.13

Z14

1H-Benzo[d]imidazol-2-yl 2 (methyl (phenyl)amino)ethanethioate

Open image in new window

C17H17N3OS

0.70

245–248

53.40

Z15

H-Benzo[d]imidazol-2-yl 2-(ethy l(phenyl)amino)ethanethioate

Open image in new window

C16H15N3OS

0.75

261–264

56.95

Z16

1H-Benzo[d]imidazol-2-yl 2-(2-(2-nitrobenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H13N5O3S

0.58

258–260

59.40

Z17

1H-Benzo[d]imidazol-2-yl 2-(2-(3-nitrobenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H13N5O3S

0.54

262–265

82.89

Z18

1H-Benzo[d]imidazol-2-yl 2-(2-(4-nitrobenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H13N5O3S

0.59

250–253

65.04

Z19

1H-Benzo[d]imidazol-2-yl 2-(2-(4-hydroxy-3-methoxybenzylidene) hydrazinyl)ethanethioate

Open image in new window

C17H16N4O3S

0.53

263–266

53.93

Z20

1H-Benzo[d]imidazol-2-yl 2-(2-(3-ethoxy-4-hydoxybenzylidene) hydrazinyl)ethanethioate

Open image in new window

C18H18N4O3S

0.52

269–272

60.65

Z21

1H-Benzo[d]imidazol-2-yl 2-(2-(4-bromobenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H13N4OSBr

0.50

277–280

65.52

Z22

1H-Benzo[d]imidazol-2-yl 2-(2-(2-hydroxybenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H14N4O2S

0.57

259–262

63.60

Z23

1H-Benzo[d]imidazol-2-yl 2-(2-(3,4-dimethoxybenzylidene) hydrazinyl)ethanethioate

Open image in new window

C18H18N4O3S

0.46

264–267

72.30

Z24

1H-Benzo[d]imidazol-2-yl 2-(2-(2-bromo-3-phenylallylidene) hydrazinyl)ethanethioate

Open image in new window

C18H15N4OSBr

0.51

160–163

78.68

Z25

1H-Benzo[d]imidazol-2-yl 2-(2-(4-(dimethylamino)benzylidene) hydrazinyl)ethanethioate

Open image in new window

C17H14N4O2S

0.57

250–253

72.58

Z26

1H-Benzo[d]imidazol-2-yl 2-(2-(4-formylbenzylidene) hydrazinyl)ethanethioate

Open image in new window

C18H19N5OS

0.65

200–203

87.45

Z27

1H-Benzo[d]imidazol-2-yl 2-(2-(2,4-dichlorobenzylidene) hydrazinyl) ethanethioate

Open image in new window

C16H12N4OSCl2

0.49

255–257

81.69

Z28

1H-Benzo[d]imidazol-2-yl 2-(2-(2-chlorobenzylidene)hydrazinyl) ethanethioate

Open image in new window

C16H13N4OSCl

0.64

259–262

74.33

Z29

1H-Benzo[d]imidazol-2-yl 2-(2-(3-phenylallylidene)hydrazinyl) ethanethioate

Open image in new window

C18H16N4OS

0.56

264–267

64.68

Z30

1H-Benzo[d]imidazol-2-yl 2-(2-(2-methoxylbenzylidene) hydrazinyl)ethanethioate

Open image in new window

C17H16N4O2S

0.48

267–270

57.12

aTLC mobile phase-ethyl acetate

Spectral characterization data

The assigned molecular scaffolds of the benzimidazole derivatives were authenticated by Infrared (IR), Nuclear Magnetic Resonance (NMR) (proton, carbon), Mass spectrometry (MS) and elemental analysis. The spectroanalytical data has been presented in Table 2. The IR spectra of compounds exhibited the characteristic secondary (–C=N–) absorption bands around 1345–1254 cm−1 while the tertiary (–C=N–) bands was observed at 1386–1337 cm−1. Appearance of IR stretching vibrations at 1600 and 1450 cm−1 in the spectra of compounds showed the presence of aromatic C=C– and the peaks at 3112–3068 cm−1. The N–N peak in the spectra of synthesized derivatives was observed at 1168–1163 cm−1. The presence of ketonic stretching vibrations was observed at 1732–1698 cm−1. In the synthesized derivatives, the methylene group (–CH2–) showed the vibrations at 2935–2915 cm−1 and 2884–2865 cm−1. The compounds (Z1Z3, Z6, Z10 and Z16Z18) showed the characteristic NO2 group stretching vibrations in the range of 1512–1484 cm−1. The compounds (Z4, Z5, Z21 and Z24) exhibited the peaks of Br at 700–600 cm−1 while compounds (Z6Z8, Z10, Z27 and Z28) showed peaks in the range of 744–738 cm−1 and the fluorine group indicated its peak at 1012–1007 cm−1. The methyl group present in the compounds (Z9, Z13 and Z20) showed the bands at 2948–2870 cm−1. The N–CH3 stretching band in the compounds (Z14, Z15 and Z26) was observed at 2857–2843 cm−1. The phenolic group present in the compounds (Z19, Z20 and Z22) showed its peaks in the range of 3648–3645 cm−1. The aldehydic group was confirmed by the appearance of absorption bands at 1728 cm−1 in the compound Z25. The presence of OCH3 in compounds (Z19, Z20, Z23 and Z30) was observed at peaks in the range of 2839–2818 cm−1. The 1H-NMR spectra of the synthesized compounds have been recorded in dimethyl sulfoxide (DMSO) solvent. Multiplet signals at 6.62–8.66 δ ppm indicated the aromatic protons. The presence of singlet signal at 1.04–2.12 δ ppm indicated the presence of NH group while the singlet signal at 5.61–7.18 δ ppm confirmed the presence of NH group in imidazole ring. The appearance of singlet signals at 2.00–3.82 δ ppm indicated the presence of –CH2 in the compounds. The appearance of singlet signal at 1.21–3.63 δ ppm indicated the presence of CH3 in Z9, Z13Z15, Z20 and Z26. The singlet signal at 3.59–3.75 δ ppm confirmed the appearance of OCH3 group in the compounds (Z19, Z23 and Z30) while the singlet signal at 1.21 δ ppm indicated the presence of OC2H-5 in compound Z20. 13C-NMR spectral analyses exhibit the appearance of the carbon atoms in synthesized molecular structures is shown in experimental section. The elemental analyses of compounds were around ± 0.3% of the theoretical results.
Table 2

Spectral data of synthesized benzimidazole derivatives

Comp.

IR (ATR cm−1)

13C-NMR (DMSO-d6, δ ppm)

1H-NMR (DMSO-d6, δ ppm)

C, H, N analyses calculated (found); MS ES + (ToF): m/z—[M++1]

Z1

{3074 (C–H str.), 1461 (C=C str.) of phenyl nucleus (pn)}, 1337 (C=N str.), 1258 (C–N str.), 706 (C–S str.), 2840 (C–H str., –CH2–), 1512 (C–NO2 str.), 1698 (C=O str.)

109.33, 119.56, 122.12, 123.10, 128.46, 132.16, 134.99, 149.64, 168.06

7.03–8.66 (m, 7H, Ar–H), 7.03 (s, 1H, NH of imidazole), 3.51 (s, 2H, CH2), 2.01 (s, 1H, NH)

C, 48.26; H, 2.97; N, 18.76; (C, 48.22; H, 2.93; N, 18.72); 374

Z2

{3076 (C–H str.), 1459 (C=C str.) pn}, 1347 (C=N str.), 1254 (C–N str.), 695 (C–S str.), 2916 (C–H str., –CH2–), 1508 (C–NO2 str.), 1705 (C=O str.)

30.61, 109.41, 115.41, 119.11, 122.23, 125.31, 130.29, 132.20, 135.60, 146.12, 168.10, 206.31

6.62–7.99 (m, 8H, Ar–H), 6.62 (s, 1H, NH of imidazole), 3.49 (s, 2H, CH2), 2.10 (s, 1H, NH)

C, 54.87; H, 3.68; N, 17.06; (C, 54.83; H, 3.64; N, 17.02); 329

Z3

{3070 (C–H str.), 1457 (C=C str.) pn}, 1351 (C=N str.), 1334 (C–N str.), 696 (C–S str.), 2835 (C–H str., –CH2–), 1507 (C–NO2 str.), 1716 (C=O str.)

30.59, 107.01, 109.41, 109.75, 119.90, 122.23, 129.82, 132.20, 148.69, 150.01 168.10

6.99–7.44 (m, 8H, Ar–H), 6.99 (s, 1H, NH of imidazole), 3.49 (s, 2H, CH2), 2.10 (s, 1H, NH)

C, 54.87; H, 3.68; N, 17.06; (C, 54.91; H, 3.72; N, 17.10); 329

Z4

{3078 (C–H str.), 1461 (C=C str.) pn}, 1351 (C=N str.), 1333 (C–N str.), 698 (C–S str.), 2915 (C–H str., –CH2–), 654 (C–Br str.), 1719 (C=O str.)

109.40, 119.56, 122.22, 128.46, 132.16, 149.64, 168.06

6.82–7.11 (m, 8H, Ar–H), 6.82 (s, 1H, NH of imidazole), 3.63 (s, 2H, CH2), 1.05 (s, 1H, NH)

C, 49.73; H, 3.34; N, 11.60; (C, 49.77; H, 3.38; N, 11.64); 363

Z5

{3092 (C–H str.), 1462 (C=C str.) pn}, 1353 (C=N str.), 1335 (C–N str.), 701 (C–S str.), 2850 (C–H str., –CH2–), 656 (C–Br str.), 1714 (C=O str.)

109.40, 119.32, 122.22, 128.34, 132.18, 134.99, 149.64, 168.06

6.65–7.25 (m, 8H, Ar–H), 6.65 (s, 1H, NH of imidazole), 3.77 (s, 2H, CH2), 2.12 (s, 1H, NH)

C, 49.73; H, 3.34; N, 11.60; (C, 49.77; H, 3.38; N, 11.64); 363

Z6

{3083 (C–H str.), 1602 (C=C str.) pn}, 1356 (C=N str.), 1340 (C–N str.), 704 (C–S str.), 2850 (C–H str., –CH2–), 763 (C–Cl str.), 1503 (C–NO2 str.), 1716 (C=O str.)

109.37, 118.37, 121.02, 122.15, 123.94, 132.20, 135.41, 144.95, 168.10

7.06–7.22 (m, 8H, Ar–H), 7.06 (s, 1H, NH of imidazole), 3.51 (s, 2H, CH2), 2.12 (s, 1H, NH)

C, 49.66; H, 3.06; N, 15.44; (C, 49.70; H, 3.10; N, 15.48); 363

Z7

{3071 (C–H str.), 1454 (C=C str.) pn}, 1352 (C=N str.), 1334 (C–N str.), 691 (C–S str.), 2924 (C–H str., –CH2–), 739 (C–Cl str.), 1715 (C=O str.)

109.41, 119.65, 122.23, 128.56, 132.19, 134.99, 149.46, 168.09

7.16–7.22 (m, 8H, Ar–H), 7.16 (s, 1H, NH of imidazole), 3.61 (s, 2H, CH2), 2.12 (s, 1H, NH)

C, 56.69; H, 3.81; N, 13.22; (C, 56.65; H, 3.85; N, 13.18); 318

Z8

{3082 (C–H str.), 1459 (C=C str.) pn}, 1352 (C=N str.), 1334 (C–N str.), 695 (C–S str.), 2842 (C–H str., –CH2–), 738 (C–Cl str.), 1714 (C=O str)

109.40, 119.85, 122.21, 128.56, 132.18, 134.79, 149.46, 168.08

7.03–7.70 (m, 8H, Ar–H), 7.03 (s, 1H, NH of imidazole), 3.68 (s, 2H, CH2), 1.04 (s, 1H, NH)

C, 56.69; H, 3.81; N, 13.22; (C, 56.65; H, 3.77; N, 13.126); 318

Z9

{3091 (C–H str.), 1454 (C=C str.) pn}, 1352 (C=N str., N=CH), 1334 (C–N str.), 691 (C–S str., CH2–S), 2844 (C–H str., –CH2–), 2948 (C–H str., CH3), 1714 (C=O str., ketone)

30.59, 109.41, 119.56, 122.23, 128.41, 132.19, 134.52, 149.27, 168.10, 206.30

7.15–7.22 (m, 7H, Ar–H), 7.15 (s, 1H, NH of imidazole), 3.63 (s, 6H, (CH3)2), 2.11 (s, 1H, NH)

C, 65.57; H, 5.50; N, 13.49; (C, 65.53; H, 5.54; N, 13.45); 312

Z10

{3099 (C–H str.), 1623 (C=C str.) pn}, 1317 (C=N str.), 1305 (C–N str.), 704 (C–S str.), 2918 (C–H str., –CH2–), 744 (C–Cl str.), 1484 (C–NO2 str.), 1715 (C=O str.)

109.39, 113.46, 115.53, 122.18, 124.47, 125.51, 132.20, 135.92, 151.91, 168.10

6.91–7.99 (m, 7H, Ar–H), 6.91 (s, 1H, NH of imidazole), 3.59 (s, 2H, CH2), 2.12 (s, 1H, NH)

C, 49.66; H, 3.06; N, 15.44; (C, 49.62; H, 3.02; N, 15.40); 363

Z11

{3070 (C–H str.), 1454 (C=C str.) pn}, 1352 (C=N str.), 1335 (C–N str.), 693 (C–S str.), 2835 (C–H str., –CH2–), 1012 (C–F str.), 1716 (C=O str.)

30.60, 109.41, 115.21, 122.24, 132.19, 145.42, 150.32, 168.10;

7.14–7.20 (m, 8H, Ar–H), 7.14 (s, 1H, NH of imidazole), 3.53 (s, 2H, CH2), 2.10 (s, 1H, NH);

C, 59.79; H, 4.01; N, 13.94; (C, 59.75; H, 4.05; N, 13.90); 302

Z12

{3068 (C–H str.), 1454 (C=C str.) pn}, 1351 (C=N str.), 1332 (C–N str.), 691 (C–S str.), 2933 (C–H str., –CH2–), 1007 (C–F str.), 1714 (C=O str.)

109.40, 112.47, 122.23, 125.27, 132.19, 137.90, 146.32, 168.09

7.10–7.24 (m, 8H, Ar–H), 7.10 (s, 1H, NH of imidazole), 3.69 (s, 2H, CH2), 2.11 (s, 1H, NH)

C, 59.79; H, 4.01; N, 13.94; (C, 59.83; H, 4.04; N, 13.98); 302

Z13

{3073 (C–H str.), 1455 (C=C str.) pn}, 1351 (C=N str.), 1333 (C–N str.), 693 (C–S str.), 2844 (C–H str., –CH2–), 2870 (C–H str., CH3), 1713 (C=O str.)

30.62, 109.41, 114.34, 122.24, 125.86, 127.89, 132.20, 144.56, 149.64, 168.10

7.13–7.19 (m, 8H, Ar–H), 7.13 (s, 1H, NH of imidazole), 3.47 (s, 3H, CH3), 2.10 (s, 1H, NH)

C, 64.62; H, 5.08; N, 14.13; (C, 64.66; H, 5.04; N, 14.10); 298

Z14

{3069 (C–H str.), 1454 (C=C str.) pn}, 1352 (C=N str.), 1335 (C–N str.), 691 (C–S str.), 2914 (C–H str., –CH2–), 2850 (C–H str., N–CH3), 1714 (C=O str.)

30.96, 109.42, 114.37, 122.25, 128.79, 132.21, 145.64, 168.11

7.14–7.20 (m, 9H, Ar–H), 7.14 (s, 1H, NH of imidazole), 3.51 (q, 2H, –CH2), 2.10 (t, 3H, CH3)

C, 65.57; H, 5.50; N, 13.49; (C, 65.53; H, 5.54; N, 13.45); 312

Z15

{3079 (C–H str.), 1458 (C=C str.) pn}, 1344 (C=N str.), 1327 (C–N str.), 693 (C–S str.), 2844 (C–H str., –CH2–), 2857 (C–H str., N–CH3), 1706 (C=O str.)

30.59, 109.41, 114.33, 122.23, 127.89, 132.19, 139.27, 144.75, 168.10

7.08–7.22 (m, 9H, Ar–H), 7.08 (s, 1H, NH of imidazole), 3.61 (s, 31H, CH2), 2.11 (s, 3H, CH3)

C, 64.62; H, 5.08; N, 14.13; (C, 64.58; H, 5.12; N, 14.17); 298

Z16

{3105 (C–H str.), 1455 (C=C str.) pn}, 1701 (–CO str.), 1386 (C=N str.), 1343 (C–N str.), 1165 (N–N str., hydrazide), 694 (C–S str.), 2915 (C–H str., –CH2–), 1510 (C–NO2 str.)

109.41, 114.33, 119.17, 122.23, 126.32, 132.19, 137.42, 144.27, 168.09

7.04–7.35 (m, 8H, Ar–H), 7.04 (s, 1H, NH of imidazole), 2.11 (s, 1H, NH), 12.62 (s, 1H, N=CH)

C, 54.08; H, 3.69; N, 19.71; (C, 54.04; H, 3.65; N, 19.75); 356

Z17

{3112 (C–H str.), 1600 (C=C str.) pn}, 1701 (–CO str.), 1355 (C=N str.), 1337

(C–N str.), 1178 (N–N str., hydrazide), 702 (C–S str.), 2844 (C–H str., –CH2–), 1512 (C–NO2 str.)

109.39, 122.21, 130.92, 132.18, 139.87, 141.50, 145.71, 150.72, 168.08

7.18–8.26 (m, 8H, Ar–H), 6.84 (s, 1H, NH of imidazole), 3.55 (s, 2H, CH2), 2.12 (s, 1H, NH), 12.66 (s, 1H, N=CH)

C, 54.08; H, 3.69; N, 19.71; (C, 54.03; H, 3.73; N, 19.67); 356

Z18

{3106 (C–H str.), 1604 (C=C str.) pn}, 1703 (–CO str.), 1337 (C=N str.), 1270

(C–N str.), 1174 (N–N str., hydrazide), 697 (C–S str.), 2843 (C–H str., –CH2–), 1509 (C–NO2 str.)

61.89, 111.30, 122.91, 123.16, 130.29, 132.18, 139.78, 146.17, 146.54, 150.27, 191.68

7.23–8.38 (m, 8H, Ar–H), 5.61 (s, 1H, NH of imidazole), 3.57 (s, 2H, CH2), 2.12 (s, 1H, NH), 12.63 (s, 1H, N=CH)

C, 54.08; H, 3.69; N, 19.71; (C, 54.12; H, 3.64; N, 19.68); 356

Z19

{3081 (C–H str.), 1449 (C=C str.) pn}, 1716 (–CO str.), 1351 (C=N str.), 1331 (C–N str.), 1163 (N–N str., hydrazide), 689 (C–S str.), 2924 (C–H str., –CH2–), 3648 (O–H str.), 2839 (C–H str., –OCH3), 1256 (C–O–C str., phenyl ether)

30.60, 109.41, 111.19, 122.23, 127.89, 130.92, 132.19, 138.79, 145.92, 168.09

7.15–7.21 (m, 7H, Ar–H), 7.15 (s, 1H, NH of imidazole), 3.58 (s, 2H, CH2), 2.11 (s, 1H, NH), 12.60 (s, 1H, N=CH)

C, 57.29; H, 4.52; N, 15.72; (C, 57.25; H, 4.56; N, 15.76); 357

Z20

{3085 (C–H str.), 1454 (C=C str.) pn}, 1714 (–CO str.), 1352 (C=N str.), 1334 (C–N str.), 1166 (N–N str., hydrazide), 688 (C–S str.), 2852 (C–H str., –CH2–), 3645 (O–H str.), 2822 (C–H str., –OCH3), 1255 (C–O–C str., phenyl ether), 2901 (C–H str., CH3)

30.59, 109.41, 122.23, 125.21, 132.19, 130.18, 137.13, 144.65, 168.09

7.03–7.86 (m, 7H, Ar–H), 7.03 (s, 1H, NH of imidazole), 3.63 (s, 1H, OH), 2.11 (s, 1H, NH), 1.21 (t, 3H, CH3), 12.61 (s, 1H, N=CH)

C, 58.36; H, 4.90; N, 15.12; (C, 58.40; H, 4.94; N, 15.16); 371

Z21

{3109 (C–H str.), 1466 (C=C str.) pn}, phenyl nucleus), 1732 (–CO str.), 1356 (C=N str.), 1338 (C–N str.), 1178 (N–N str., hydrazide), 703 (C–S str.), 2842 (C–H str., –CH2–), 658 (C–Br str.)

30.59, 109.41, 122.23, 128.61, 131.05, 132.13, 132.19, 134.95, 192.01

7.17–7.22 (m, 8H, Ar–H), 7.17 (s, 1H, NH of imidazole), 3.66 (s, 2H, CH2), 2.11 (s, 1H, NH), 12.62 (s, 1H, N=CH)

C, 49.37; H, 3.37; N, 14.39; (C, 49.33; H, 3.33; N, 14.35); 390

Z22

{3091 (C–H str.), 1603 (C=C str.) pn}, 1703 (–CO str.), 1346 (C=N str.), 1294 (C–N str.), 1168 (N–N str., hydrazide), 690 (C–S str.), 2841 (C–H str., –CH2–), 3648 (O–H str.)

109.40, 122.22, 129.51, 131.03, 134.59, 146.32, 149.66, 168.08

7.18–7.24 (m, 8H, Ar–H), 7.18 (s, 1H, NH of imidazole), 3.74 (s, 1H, OH), 2.11 (s, 1H, NH), 12.64 (s, 1H, N=CH)

C, 58.88; H, 4.32; N, 17.17; (C, 58.84; H, 4.36; N, 17.13); 327

Z23

{3075 (C–H str.), 1452 (C=C str.) pn}, 1730 (–CO str.), 1380 (C=N str.), 1345 (C–N str.), 1170 (N–N str., hydrazide), 695 (C–S str.), 2876 (C–H str.,

–CH2–), 2835 (C–H str., –OCH3), 1253 (C–O–C str., phenyl ether)

109.40, 119.38, 122.22, 123.45, 128.67, 131.55, 132.18, 147.82, 168.08

7.18–7.24 (m, 7H, Ar–H), 7.18 (s, 1H, NH of imidazole), 375 (s, 6H, (OCH3)2), 2.12 (s, 1H, NH), 12.64 (s, 1H, N=CH)

C, 58.36; H, 4.90; N, 15.12; (C, 58.40; H, 4.94; N, 15.16); 371

Z24

{3087 (C–H str.), 1601 (C=C str.) pn}, 1713 (–CO str.), 1354 (C=N str.), 1337 (C–N str.), 1176 (N–N str., hydrazide), 694 (C–S str.), 2843 (C–H str., –CH2–), 684 (C–Br str.), 1623 (conjugated C=C and phenyl subst. C=C)

109.42, 122.21, 123.89, 128.66, 128.90, 130.55, 131.36, 132.23, 132.82, 150.14, 187.80

7.13–7.94 (m, 9H, Ar–H), 7.06 (s, 1H, NH of imidazole), 2.00 (s, 2H, CH2), 7.06 (s, 1H, NH), 12.55 (s, 1H, N=CH), 7.19 (s, 1H, Br–C=CH)

C, 52.06; H, 3.64; N, 13.49; (C, 52.02; H, 3.68; N, 13.45); 416

Z25

{3070 (C–H str.), 1453 (C=C str.) pn}, 1712 (–CO str.), 1352 (C=N str.), 1334 (C–N str.), 1167 (N–N str., hydrazide), 688 (C–S str.), 2846 (C–H str., –CH2–), 1728 (C–H str., CHO)

78.04, 111.42, 122.92, 129.61, 129.94, 135.88, 139.55, 145.74, 192.70

7.25–7.98 (m, 8H, Ar–H), 7.03 (s, 1H, NH of imidazole), 3.61 (s, 2H, CH2), 2.11 (s, 1H, NH), 12.60 (s, 1H, N=CH), 10.04 (s, 1H, CHO)

C, 60.34; H, 4.17; N, 16.56; (C, 60.38; H, 4.13; N, 16.52); 384

Z26

{3105 (C–H str.), 1453 (C=C str.) pn}, 1713 (–CO str.), 1352 (C=N str.), 1332 (C–N str.), 1163 (N–N str., hydrazide), 686 (C–S str.), 2927 (C–H str., –CH2–), 2843 (C–H str., N–CH3)

30.55, 39.49, 109.40, 110.89, 122.24, 124.45, 132.22, 154.02, 189.66

7.17–7.86 (m, 8H, Ar–H), 7.11 (s, 1H, NH of imidazole), 3.78 (s, 2H, CH2), 2.12 (s, 1H, NH), 12.65 (s, 1H, N=CH), 2.64 (s, 6H, (CH3)2)

C, 61.17; H, 5.42; N, 19.81; (C, 61.13; H, 5.46; N, 19.85); 354

Z27

{3092 (C–H str.), 1596 (C=C str.) pn}, 1710 (–CO str.), 1354 (C=N str.), 1336 (C–N str.), 1175 (N–N str., hydrazide), 700 (C–S str.), 2930 (C–H str., –CH2–), 739 (C–Cl str.)

61.91, 109.39, 122.20, 127.94, 130.66, 132.18, 133.65, 135.28, 137.04, 139.60, 188.40

6.74–7.72 (m, 7H, Ar–H), 6.74 (s, 1H, NH of imidazole), 3.02 (s, 2H, CH2), 2.11 (s, 1H, NH), 12.62 (s, 1H, N=CH)

C, 50.67; H, 3.19; N, 14.77; (C, 50.63; H, 3.15; N, 14.73); 380

Z28

{3111 (C–H str.), 1598 (C=C str.) pn}, 1703 (–CO str.), 1355 (C=N str.), 1337 (C–N str.), 1177 (N–N str., hydrazide), 701 (C–S str.), 2845 (C–H str., –CH2–), 740 (C–Cl str.)

30.58, 109.41, 119.56, 122.23, 124.54, 131.23, 132.18, 147.12, 168.08

7.16–7.28 (m, 8H, Ar–H), 7.16 (s, 1H, NH of imidazole), 3.65 (s, 2H, CH2), 2.11 (s, 1H, NH), 12.62 (s, 1H, N=CH)

C, 55.73; H, 3.80; N, 16.25; (C, 55.77; H, 3.84; N, 16.29); 345

Z29

{3110 (C–H str.), 1598 (C=C str.) pn}, 1712 (–CO str.), 1355 (C=N str.), 1337 (C–N str.), 1176 (N–N str., hydrazide), 700 (C–S str.), 2860 (C–H str., –CH2–), 1616 (phenyl conjugation)

109.40, 122.21, 128.72, 132.17, 134.54, 139.42, 141.72, 147.21, 168.07

7.18–7.27 (m, 9H, Ar–H), 7.18 (s, 1H, NH of imidazole), 3.82 (s, 2H, CH2), 2.12 (s, 1H, NH), 12.66 (s, 1H, N=CH)

C, 64.26; H, 4.79; N, 16.65; (C, 64.22; H, 4.75; N, 16.69); 337

Z30

{3103 (C–H str.), 1599 (C=C str.) pn}, 1713 (–CO str.), 1352 (C=N str.), 1335 (C–N str.), 1168 (N–N str., hydrazide), 691 (C–S str., CH2–S), 2841 (C–H str., –CH2–), 2818 (C–H str., –OCH3), 1255 (C–O–C str., phenyl ether)

109.41, 115.26, 122.23, 124.30, 132.19, 141.50, 145.71, 168.09, 205.61

7.15–7.25 (m, 8H, Ar–H), 7.15 (s, 1H, NH of imidazole), 3.70 (s, 2H, CH2), 2.10 (s, 1H, NH), 12.60 (s, 1H, N=CH), 3.59 (s, 1H, OH)

C, 59.98; H, 4.74; N, 16.46; (C, 59.94; H, 4.98; N, 16.42); 341

Antimicrobial and anticancer screening results

The synthesized benzimidazole compounds were screened for antimicrobial potential by tube dilution method using cefadroxil (antibacterial) and fluconazole (antifungal) as standard drugs against the represented microbial species. Furthermore, the anticancer activity of synthesized compounds against human colorectal carcinoma [HCT116 (ATCC CCL-247)] cancer cell line was assessed by using SRB assay with 5-fluorouracil (5-FU) being included as the standard anticancer drug. Biological screening results revealed that compound Z24 displayed highest antimicrobial activity against Gram positive and Gram negative microorganisms (MICsa, st = 30.10 µM, MICkp,ec = 15.05 µM and MICca, an = 3.76 µM). Besides, Z24 also elicited anticancer activity against HCT116 cell line (IC50 = 0.46 µM) which was more potent than the standard drug. The antimicrobial screening results are presented in Table 3 and Figs. 3, 4 whereas the anticancer results are presented in Table 4.
Table 3

Antimicrobial screening results of synthesized derivatives

Comp.

Minimum inhibitory concentration (MIC = µM)

Bacterial strains

Fungal strains

SA

MTCC3160

ST

MTCC3231

KP

MTCC9024

EC

MTCC443

AN

MTCC281

CA

MTCC227

Z1

33.49

66.97

16.74

33.49

4.18

16.74

Z2

76.13

38.06

38.06

76.13

38.06

19.03

Z3

38.06

76.13

19.03

38.06

38.06

19.03

Z4

69.02

69.02

34.51

69.02

17.26

34.51

Z5

69.02

34.51

34.51

69.02

17.26

34.51

Z6

68.91

68.91

34.45

68.91

34.45

4.31

Z7

78.67

78.67

19.67

39.33

19.67

39.33

Z8

78.67

39.33

39.33

78.67

19.67

4.92

Z9

80.28

80.28

40.14

80.28

20.07

40.14

Z10

34.45

68.91

17.23

34.45

34.45

68.91

Z11

82.97

41.49

41.49

20.74

41.49

5.18

Z12

41.49

82.97

20.74

20.74

5.18

20.74

Z13

42.03

84.06

42.03

42.03

5.25

21.02

Z14

80.28

40.14

40.14

20.07

40.14

20.07

Z15

84.06

42.03

42.03

21.02

42.03

5.25

Z16

35.17

70.34

35.17

70.34

35.17

17.59

Z17

70.34

35.17

35.17

70.34

17.59

35.17

Z18

70.34

70.34

17.59

70.34

17.59

35.17

Z19

35.07

70.15

35.07

70.15

17.54

35.07

Z20

33.75

67.49

16.87

33.75

33.75

67.49

Z21

32.11

64.22

32.11

32.11

4.01

16.05

Z22

76.59

38.30

76.59

38.30

38.30

19.15

Z23

33.75

67.49

16.87

67.49

16.87

67.49

Z24

30.10

30.10

15.05

15.05

3.76

3.76

Z25

65.21

65.21

32.60

32.60

16.30

32.60

Z26

35.37

70.74

17.69

35.37

17.69

4.42

Z27

65.91

65.91

16.48

65.91

16.48

32.96

Z28

36.25

72.51

18.13

72.51

7.25

18.13

Z29

37.16

74.32

18.58

74.32

18.58

37.16

Z30

36.72

73.44

73.44

18.36

36.72

18.36

DMSO

NA

NA

NA

NA

NA

NA

Broth control

NG

NG

NG

NG

NG

NG

Std.

34.40a

34.40a

17.20a

17.20a

10.20b

10.20b

SA, Staphylococcus aureus; ST, Salmonella typhi; KP, Klebsiella pneumoniae; EC, Escherichia coli; CA, Candida albicans; AN, Aspergillus niger; DMSO, Dimethyl sulfoxide; NA, No activity; NG, No growth

Std drugs: aCefadroxil; bFluconazole

Fig. 3

Antibacterial screening results against bacterial species

Fig. 4

Antifungal screening results against fungal species

Table 4

Anticancer screening results of synthesized derivatives

Anticancer screening

Comp.

IC50 (μM)

Comp.

IC50 (μM)

Z1

214.30

Z16

> 281.37

Z2

> 304.51

Z17

140.69

Z3

> 304.51

Z18

121.83

Z4

220.87

Z19

> 280.58

Z5

220.87

Z20

> 269.98

Z6

179.16

Z21

> 256.87

Z7

> 314.66

Z22

> 306.37

Z8

314.66

Z23

> 269.98

Z9

> 321.13

Z24

0.46

Z10

152.70

Z25

78.25

Z11

> 331.90

Z26

198.08

Z12

> 331.90

Z27

67.49

Z13

336.25

Z28

> 290.02

Z14

> 321.13

Z29

252.68

Z15

> 336.25

Z30

> 293.77

5-Fluorouracil

8.84

5-Fluorouracil

8.84

Structure activity relationship (SAR)

The substitution of halogenated α, β-unsaturated aldehyde i.e. 2-bromo-3-phenylacrylaldehyde (compound Z24) displayed an important role in improving the antiproliferative and antimicrobial activities as compared to (compound Z29) its non-halogenated α, β unsaturated aldehyde. Structure activity relationship study is shown in Fig. 5.
Fig. 5

Structural requirements for the antimicrobial and anticancer activities of synthesized benzimidazole derivatives

Methods/experimental

The starting material were purchased from different sources and used without further purification for the synthesis and analytical purpose. The reaction steps were confirmed by TLC (thin layer chromatography). Melting point was determined using labtech melting point equipment. An infrared spectrum was recorded [Attenuated total reflection (ATR), range of 4000–600 cm−1] on Bruker 12060280 spectrometer. Proton and carbon-NMR (δ, ppm) spectral analyses were determined by Bruker Avance III at 600 NMR and 150 MHz, respectively spectrometer in deuterated solvent. Waters Micromass Q-ToF Micro instrument was used for MS spectra. Elemental analyses were carried out by C, H and N analyzer (Perkin-Elmer 2400) around ± 0.3% of the theoretical results. The tested microorganism i.e. Gram positive, Gram negative and fungal species were procured from the Institute of Microbial Technology and Gene bank, Chandigarh for the in vitro antimicrobial activity.

Procedure for synthesis of substituted benzimidazole derivative (Z1Z30)

Step a: Synthesis of intermediate-i

A mixture of 2-mercaptobenzimidazole (0.01 mol) and chloroacetylchloride (0.01 mol) in ethanol (30 mL) in presence of anhydrous K2CO3 (0.01 mol) was refluxed for 6 h. The precipitated solid was filtered, evaporated to dryness under reduced pressure to get intermediate-i [5].

Step b: Synthesis of intermediate-ii

The solution of intermediate-i (0.01 mol) and hydrazine hydrate (0.02 mol) in ethanol (20 mL) was refluxed for 5 h. The solution was then poured in ice cold water and resulting solid was filtered, dried and recrystallized from ethanol [23].

Step c: Synthesis of title compounds Z1Z15

An equimolar mixture of intermediate-i and substituted aniline in ethanol was refluxed for 4–5 h. After completion of reaction, it was poured into ice cold water and the precipitated title compound was filtered, dried and recrystallized from ethanol [24].

Step d: Synthesis of title compounds Z16Z30

An equimolar mixture of intermediate-ii and substituted aromatic aldehydes with 2–3 drops of glacial acetic acid in ethanol (20 mL) was refluxed for 6 h. The resultant precipitate was filtered and recrystallized from ethanol to yield the required compound [23].

Biological evaluation

Antimicrobial evaluation (MIC)

The antimicrobial evaluation of the synthesized derivatives was carried out by tube dilution method [25] towards selected Gram positive, Gram negative and fungal microorganisms shown in Table 3. The screening results were compared with standard drugs i.e. cefadroxil and fluconazole.

The stock solutions (100 µg/mL)

The tested compounds and standard drugs were prepared in dimethylsulfoxide and further diluted up to six concentrations [26].

Broth media

Sabouraud dextrose broth used for antifungal activity and double strength nutrient broth used for antibacterial activity.

Incubation periods

The compounds were incubated at 25 ± 1 °C for 7 days (fungi—A. niger), at 37 ± 1 °C for 24 h (bacteria) and at 37 ± 1 °C for 48 h (fungi—C. albicans), respectively.

Anticancer evaluation (IC50)

The antiproliferative activity was determined by SRB assay. Briefly, HCT116 was seeded onto the 96 well plate at 2500 cells/well. The cells were allowed to attach overnight before being exposed to the respective compounds (0.01–100 µg/mL) for 72 h. The highest concentration of each compound tested (100 µg/mL) contained only 0.1% DMSO (non-cytotoxic). SRB assay [27] was then performed whereby the cells were fixed using trichloroacetic acid for 30 min at 4 °C and stained with 0.4% (w/v) SRB mixed with 1% acetic acid for 15 min. After five washes with 1% acetic acid solution, the protein-bound dye was extracted with 10 mM tris base solution. Optical density was read at 570 nm and IC50 (i.e. concentration required to inhibit 50% of the cells) of each compound was determined. Anticancer results were presented as mean IC50 of at least triplicates.

Conclusion

In this study, the synthesized benzimidazole scaffolds were authenticated by their consistent spectral data. The antimicrobial potential of synthesized compounds was assessed against different fungal and bacterial species, along with their anticancer activity against HCT116 cell line. The activity results indicated that the presence of α-bromo group in benzylidene portion (compound 24) played an important role in improving the antimicrobial as well as antiproliferative activities and may be used as a lead for the discovery of new antimicrobial and anticancer agents.

Notes

Authors’ contributions

Authors BN, ST and SK—have designed, synthesized and carried out the antimicrobial activity and KR, SML, SAAS and VM—have carried out the spectral analysis and anticancer evaluation of synthesized compounds. All authors read and approved the final manuscript.

Acknowledgements

The authors are thankful to Head, Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, for providing necessary facilities to carry out this research work

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Authors and Affiliations

  1. 1.Faculty of Pharmaceutical SciencesMaharshi Dayanand UniversityRohtakIndia
  2. 2.Faculty of PharmacyUniversiti Teknologi MARA (UiTM)Bandar Puncak AlamMalaysia
  3. 3.Collaborative Drug Discovery Research (CDDR) Group, Pharmaceutical Life Sciences Community of ResearchUniversiti Teknologi MARA (UiTM)Shah AlamMalaysia
  4. 4.Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns)Universiti Teknologi MARA (UiTM)Bandar Puncak AlamMalaysia
  5. 5.Department of Pharmacology and Toxicology, College of PharmacyQassim UniversityBuraidahKingdom of Saudi Arabia
  6. 6.Department of BiotechnologyIndian Institute of TechnologyRoorkeeIndia

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