4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: Synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation

European Journal of Medicinal Chemistry 45 (2010) 5985e5997

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European Journal of Medicinal Chemistry

journal homepage: h ttp://www.elsevier.com/locate/ejmech

Original article

4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic

acids: Synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation

Snehlata Yadav ^a, Pradeep Kumar ^a, Erik De Clercq ^b, Jan Balzarini ^b, Christophe Pannecouque ^b,

,

Sharwan Kumar Dewan ^c, Balasubramanian Narasimhan ^a

*

^aFaculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India

^bLaboratory of Virology & Chemotherapie, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium

^cDepartment of Chemistry, Maharshi Dayanand University, Rohtak 124001, India

a r t i c l e i n f o

a b s t r a c t

Article history:

A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20)

was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that

compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-

9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR

investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial

activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the

topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological

Received 13 August 2010

Received in revised form

24 September 2010

Accepted 28 September 2010

Available online 7 October 2010

Keywords:

Benzimidazoles

QSAR

Antimicrobial

Antiviral

parameter, valence second order molecular connectivity index (^{2 v}) in describing the antimicrobial

c

activity of synthesized compounds (1-20).

1. Introduction

cellular components and bioactive compounds which makes the

benzimidazole molecule endowed with a variety of biological prop-

erties [3]. The study of recent literature reveals that benzimidazole is

reported to have number of biological activities viz. antiviral [4],

antifungal [5], antihelmintic [6], antiprotozoal [7], psychotropic [8],

anti-HIV [9], antitumor [10], antioxidant [11] and anticoagulant [12]

activities.

The increasing incidence of infection caused by the rapid

development of microbial resistance to most of the known antibi-

otics is a serious health problem. There are a number of factors

responsible for mutations in the microbial genomes. As multidrug-

resistant microbial strains proliferate, the necessity for effective

therapy has stimulated research on the design and synthesis of

novel antimicrobial molecules [1].

In spite of nearly three decades of intensive research toward the

treatment and eradication of HIV/AIDS, the disease remains a global

health problem. The advent of highly active antiretroviral therapy

(HAART) in the mid 1990s, which employed various combinations

of reverse transcriptase and protease inhibitors, led to marked

improvements of clinical outcomes. While the diversity of drugs

now available to the clinician has substantially improved HIV

treatment, still signiﬁcant challenges remain. Of particular concern

are long-term treatment side effects and the emergence of drug-

resistant viral strains [2].

Indeed, a number of important drugs used in different thera-

peutic areas contain the benzimidazole ring, as proton pump

inhibitors (omeprazole), antihypertensives (candesartan, telmi-

sartan), antihistaminics (astemizole), antihelmintics (albendazole,

mebendazole), as well as several other kinds of still investigational

therapeutic agents, including antitumorals and antivirals [1].

QSAR refers to a discipline in computational chemistry that

addresses the modeling of biological activities or chemical reac-

tivity based on the quantitative description for the chemical

structure of molecules. QSAR relies on the basic assumption that

molecules with similar physicochemical properties or structures

will have similar activities [13]. Quantitative structureeactivity

relationship (QSAR) is one of the most important areas in chemo-

metrics, and is a valuable tool that is used extensively in drug

design and medicinal chemistry. Once a reliable QSAR model is

established, we can predict the activities of molecules, and know

which structural features play an important role in biological

processes [14].

The heterocyclic molecule, benzimidazole, is isosteric with indole

and purine nuclei, which are present in a number of fundamental

* Corresponding author. Tel.: þ91 1262 272535; fax: þ91 1262 274133.

E-mail address: naru2000us@yahoo.com (B. Narasimhan).

doi:10.1016/j.ejmech.2010.09.065

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S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Bearing these results in mind and in continuation of our

reactants or reagents leading to a less efﬁcient reaction. The physi-

cochemical characteristics of the synthesized compounds are pre-

sented in Table 1.

research efforts in searching novel antiviral agents [15,16], we

hereby present the synthesis, antimicrobial and antiviral activity

and QSAR modeling of 4-[1-(substituted aryl/alkyl carbonyl)-ben-

zoimidazol-2-yl]-benzenesulfonic acids.

The structures of compounds 1-20 were assigned by IR and ¹H

NMR spectroscopic data, which are consistent with the proposed

molecular structures. The primary amino group in compound 1 is

depicted by the presence of NH asymmetric stretch at

3481.81 cm^ꢀ1. The IR bending vibration corresponding to OCH₃of

compound 8 appeared at 1425.61 cm^ꢀ1. The presence of hetero-

cyclic pyridine moiety in compound 15 is demonstrated by the

presence of CH out of plane bending at 829.04 cm^ꢀ1. The presence

of an additional SeN stretch at 808.61 cm^ꢀ1apart from the SO₃

asymmetric stretch in the region of 1260e1150 cm^ꢀ1indicated that

compound 20 contains a link between SO₂and N₁of benzimid-

azole. The appearance of C]O stretch in the range of

1630e1600 cm^ꢀ1indicated the formation of tertiary amides (1-20)

by the reaction of acid chlorides with the 4-(1H-benzoimidazol-2-

yl)-benzenesulfonic acid. Formation of tertiary amide is further

evidenced by the absence of IR bands at 1725e1700 cm^ꢀ1and

1700e1680 cm^ꢀ1corresponding to the alkyl and aryl acids,

respectively. The appearance of SO₃asymmetric stretch in the

region of 1260e1150 cm^ꢀ1demonstrated the presence of SO₃H

group of benzenesulfonic acid attached to the 2nd position of

benzimidazole.

2. Chemistry

The synthesis of compounds 1-20 followed the general pathway

elicited in Scheme 1. The key intermediate, 4-(1H-benzoimidazol-

2-yl)-benzenesulfonic acid was prepared by the condensation

of benzimidazole with aryldiazonium chloride of 4-amino-benzene-

sulfonic acid, which in turnprepared by the diazotization of 4-amino-

benzenesulfonic acid [17]. However, based on our experience, the

application of the cupric chloride for the condensation of aryldiazo-

nium chloridewithbenzimidazoleassuggestedby Dahiya and Pathak

[18] resulted in resinous (sticky) products. Therefore, the coupling

was carried out by using sodium acetate along with stirring at cold

conditions for the initial 3 h followed by 48 h stirring at room

temperature which resulted in a solid product. For the synthesis of

4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benze-

nesulfonic acids, the key intermediates 4-(1H-benzoimidazol-2-yl)-

benzenesulfonic acid has been reacted with corresponding aryl/alkyl

acid chlorides which were formed by the reaction of corresponding

aryl/alkyl acids with thionyl chloride. It is important to note here that

the yield of most of the synthesized benzimidazoles were below 50%.

The low yieldof synthetic compounds may be attributed to anyone or

more of the following reasons [17]: a). The reaction may be reversible

and position of equilibrium is unfavorable to the product; b). The

incursion of side reactions leading to the formation of by-products; c).

The premature work-up of the reaction before its completion; d). The

volatilization of products during reaction or work-up; e). The loss of

product due to incomplete extraction, inefﬁcient crystallization or

other work-up procedures; f). The presence of contaminants in the

The appearance of singlet around 2.5

d ppm corresponds to the

proton of SO₃H in the NMR of all the compounds indicated the pres-

ence of para sulfonyl phenyl nucleus to the 2nd position of synthe-

sized benzimidazoles (11-20). Further the multiplet corresponds to

6.9e8.6

and aryl nucleus. The appearance of

presenceof thepyridineringsystemincompound 15. Theappearance

doublet at 3.66e3.72 ppm (CH₂of CH]CH₂) and 3.79e3.85 ppm

d

ppm conﬁrmed the presence of protons of benzimidazole

d

at 8.46e9.66 conﬁrmed the

d

(CH of CH]CH₂) indicated the formation of compound 14 by the

reactionof4-(1H-benzoimidazol-2-yl)-benzenesulfonicacidandacid

H

N

^-lC⁺N₂

H₂N

N

NaNO₂/HCl

SO₃H

0-10⁰C

48 h

SO₃H

N

H

SO₃H

Cl

X

OH

R1

SOCl₂

X

RCOOH

R2

R3

RCOCl

R2

R3

R5

24 h

R5

R4

N

SO₃H

N

X

R1

O

R2

R

R5

12-15, 17-19

R3

R4

1-11, 16, 20

Scheme 1. Scheme for the synthesis of 4-[1-(substituted aryl/alkyl)-benzoimidazol-2-yl]-benzenesulfonic acids.

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

5987

Table 1

Physicochemical characteristics of synthesized benzimidazole derivatives.

N

SO₃H

N

SO₃H

R1

X

R2

R3

O

R

R5

12-15, 17-19

R4

1-11, 16, 20

Comp.

R₁

R₂

R₃

R₄

R₅

X

Mol. Formula

C₂₀H₁₅N₃O₄S

₂₀H₁₄N₂O₄S

Mol. Wt.

m.p.

Rf value (CHCl₃)

Yield %

1

2

3

4

5

6

7

8

NH₂

H

Cl

H

OH

H

CH₃

H

OH

H

NH₂

H

Cl

H

C]O

SO₂

393.42

378.40

393.42

412.85

394.40

410.40

408.43

423.40

392.43

394.40

428.48

116e-118

93e95

212e-214

128e-130

65e-67

98e-100

163e-165

90e92

92e-94

70e72

95e97

78e-80

0.33

0.49

0.43

0.48

0.44

0.41

0.38

0.36

0.34

0.35

0.45

0.77

0.40

70.9

43.9

99.0

37.5

63.5

101.6

70.6

60.9

46.3

37.0

28.1

60.0

35.8

C

C₂₀H₁₅N₃O₄S

C₂₀H₁₃ClN₂O₄S

C₂₀H₁₄N₂O₅S

C₂₀H₁₄N₂O₆S

C₂₁H₁₆N₂O₅S

C₂₀H₁₃N₃O₆S

C₂₁H₁₆N₂O₄S

C₂₀H₁₄N₂O₅S

C₂₀H₁₆N₂O₅S₂

H

OH

OCH₃

NO₂

H

CH₃

H

9

10

11

16

20

OH

H

CH₃

156e-158

R

12

13

14

eCH]CHeCH₃

eCH]CH₂

eC(CH₃) ¼ CH₂

C₁₇H₁₄N₂O₄S

C₁₆H₁₂N₂O₄S

C₁₇H₁₄N₂O₄S

342.37

328.34

342.37

112e-114

100e102

102e-104

0.82

0.56

0.43

30.2

32.8

33.5

15

C₁₉H₁₃N₃O₄S

379.39

110e-112

0.96

44.0

N

17

18

19

eCH₂e(CH₂)₂eCH₃

eCH₂e(CH₂)₆eCH]CHe(CH₂)₇eCH₃

eCH_2e(CH₂)₁₃eCH₃

C₁₈H₁₈N₂O₄S

C₃₁H₄₂N₂O₄S

C₂₉H₄₀N₂O₄S

358.41

538.74

512.70

107e-109

109e111

115e117

0.42*

0.75

0.83*

33.8

31.7

61.3

*TLC mobile phase e Benzene.

chloride of methacrylic acid. Further the coupling constant value of

18 Hz in compound 14 indicated that the nature of the double bond in

the synthesized compound 14 is of trans nature. Compound 8 showed

patterns of antimicrobial activity of the synthesized benzimidazoles

are in the following order: Antibacterial activity > antifungal activity.

The compound 9 is the most effective compound against

S. aureus with pMICsa value of 2.43 (Table 2), respectively. For

activity against B. subtilis the compounds 7 and 9 yielded better

activity (Table 2) in comparison to other compounds synthesized.

The antimicrobial spectrum of synthesized benzimidazoles against

E. coli demonstrated that compounds 4, 5, 7 and 9 were the most

active ones with pMICec values of 2.42, 2.42, 2.42 and 2.43 (Table 2)

respectively. From the above discussion it is evident that compound

a singlet at

conﬁrmed the attachment of the para methoxy benzoyl group to the

N₁position of benzimidazole. The absence of a singlet at 11 ppm in

d 3.78 ppm corresponding to a proton of the OCH₃. This

d

the NMR spectra of compounds 1-20 indicated the absence of the free

COOH group. This conﬁrms that the compounds 1-20 are tertiary

amides and not the physical mixture of aryl/alkyl acids and 4-(1H-

benzoimidazol-2-yl)-benzenesulfonic acid. Therefore, this assures

the reactionofaryl/alkylacidchlorides withthesecondarynitrogenof

the benzimidazole nucleus.

9

emerged as the most active antibacterial benzimidazole.

Compounds 9 and 18 emerged as the most effective antifungal

agents against C. albicans whereas compound 18 was most active

against A. niger (Table 2). From the above discussion it is evident

that compound 18 emerged as the most effective antifungal

benzimidazole.

3. Results and discussion

3.1. Antimicrobial activity

The minimum bactericidal concentration/minimum fungicidal

concentration (MBC/MFC) (Table 3) determination results revealed

that the synthesized compounds were fungistatic against both

fungi and bacteriostatic against S. aureus, B. subtilis but bacter-

iocidal against E. coli. In general, the MBC and MFC of synthesized

benzimidazole derivatives were 3-fold higher than their MIC

values, which indicated that they were bacteriostatic and fungi-

static in action except for E. coli (a drug is considered to be bac-

teriosatic/fungistatic when its MBC and MFC values are 3-fold

higher than its MIC values) [20]. In the case of S. aureus compounds

The synthesized compounds were evaluated for their in vitro

antimicrobial activities against two Gram-positive bacteria e Staph-

ylococcus aureus, Bacillus subtilis; the Gram-negative bacterium e

Escherichia coli and the fungal strains e Aspergillus niger and Candida

albicans by tube dilution method [19] using ciproﬂoxacin and ﬂuco-

nazole as control drugs for antibacterial and antifungal activity,

respectively. The results of the antimicrobial studies are presented in

Table 2. In general the compounds showed an improved antibacterial

activity when compared to their antifungal activity. The deduced

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S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Table 2

Antimicrobial activity of synthesized benzimidazole derivatives.

Comp.

For ot-QSAR

pMICsa

For mt-QSAR

pMICan

pMICbs

pMICec

pMICca

pMICab

pMICaf

pMICam

1

2

3

4

5

6

7

8

1.80

2.08

2.10

2.09

2.12

2.10

2.12

2.43

2.10

1.85

1.72

1.74

2.13

2.10

1.76

2.24

2.23

1.84

0.19

2.61*

2.03

2.12

1.80

1.82

2.13

2.15

2.42

2.12

2.43

2.10

1.95

1.85

2.02

1.74

2.13

2.10

1.76

2.24

2.23

1.84

0.20

2.61*

2.40

2.12

2.10

2.42

2.40

2.42

2.12

2.43

2.10

1.85

2.32

2.04

2.39

2.26

1.76

1.85

1.61

1.54

0.28

2.61*

1.70

1.78

1.20

1.52

1.50

1.52

1.51

2.13

1.50

1.44

1.42

1.44

1.75

1.50

1.46

1.94

1.61

1.54

0.20

2.64**

1.50

1.48

1.50

1.22

1.20

1.22

1.21

1.53

1.20

0.89

0.84

1.12

1.14

1.48

1.50

1.16

1.63

1.61

1.23

0.22

2.64**

2.08

2.11

2.00

2.11

2.22

2.32

2.12

2.43

2.10

2.05

1.85

2.02

1.84

2.22

2.15

1.76

2.11

2.02

1.74

0.18

2.61

1.60

1.63

1.35

1.37

1.35

1.37

1.36

1.83

1.35

1.20

1.14

1.27

1.29

1.62

1.50

1.31

1.79

1.61

1.39

0.19

2.64

1.89

1.92

1.74

1.81

1.88

1.87

1.94

1.82

2.19

1.80

1.71

1.57

1.72

1.62

1.98

1.89

1.58

1.98

1.86

1.60

0.16

2.62

9

10

11

12

13

14

15

16

17

18

19

20

SD^a

Std.

*Ciproﬂoxacin, **Fluconazole.

a

Standard deviation.

10 and 17 and for Bacillus subtitlis compounds 11 and 17 were found

to be active bacteriocidal agents.

values and used as dependent variables in a QSAR study. The

different molecular descriptors (independent variables) like log of

octanol-water partition coefﬁcient (log P), molar refractivity (MR),

Kier’s molecular connectivity (^{0 0}c^{v 1 1}c^{v 2}c ²c^v) and shape (k_1,

c, , c, , ,

3.2. QSAR studies

ka₁) topological indices, Randic topological index (R), Balaban

topological index (J), Wiener topological index (W), Total energy

(Te), energies of highest occupied molecular orbital (HOMO) and

3.2.1. Development of one-target QSAR model

In order to understand the experimental antimicrobial data on

a theoretical basis, we established a quantitative structure activity

relationship (QSAR) between the in vitro antimicrobial activity of

synthesized benzimidazole derivatives and descriptors coding for

lipophilic, electronic, steric and topological properties of the mole-

cules under consideration using the linear free energy relationship

model (LFER) described by Hansch and Fujita [21]. Biological activity

data determined as MIC values were ﬁrst transformed into pMIC

lowest unoccupied molecular orbital (LUMO), dipole moment (m),

electronic energy (Ele.E), nuclear energy (Nu.E) and molecular

surface area (SA) calculated for of 4-[1-(substituted aryl/alkyl

carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids are used as

independent variables and are presented in Table 4 [22e27].

In the present study, a data set of 20 benzimidazole derivatives

was subjected to linear free energy regression analysis for model

generation. The reference drugs were not included in model devel-

opment as they belong to different structural series. Preliminary

Table 3

MBC/MFC of synthesized benzimidazole derivatives.

Table 4

Comp.

MBC (

mg/ml)

MFC (mg/ml)

Values of selected parameters used in regression analysis.

S. aureus

B. subtilis

E. coli

C. albicans

A. niger

Comp. log P MR

²c^v

R

J

Te

NE

LUMO

1

2

3

4

5

6

7

8

50

12.5

25

>50

25

>50

50

>50

6.25

50

12.5

>50

25

6.25

50

12.5

0.019

1.56

25

50

>50

50

12.5

>50

25

>50

0.040

1

2

3

4

5

6

7

8

3.07 104.11

3.87 99.29

7.69 13.36 1.36 ꢀ4861.42 32108.70 ꢀ1.28

7.47 12.95 1.34 ꢀ4640.27 29585.80 ꢀ1.37

7.72 13.34 1.34 ꢀ4861.39 30708.30 ꢀ1.13

8.02 13.36 1.36 ꢀ5000.25 32054.10 ꢀ1.34

8.08 13.34 1.34 ꢀ5000.34 31558.70 ꢀ1.43

7.65 13.34 1.34 ꢀ4955.73 31701.40 ꢀ1.43

7.80 13.75 1.37 ꢀ5281.53 34388.40 ꢀ1.41

7.83 13.88 1.33 ꢀ5116.18 32616.70 ꢀ1.18

7.90 14.25 1.33 ꢀ5470.94 36375.50 ꢀ1.85

7.92 13.36 1.36 ꢀ4796.08 32177.00 ꢀ1.34

7.97 13.34 1.34 ꢀ4796.16 30732.20 ꢀ1.18

6.63 11.41 1.54 ꢀ4256.52 24803.10 ꢀ1.40

6.34 10.91 1.53 ꢀ4100.52 22838.50 ꢀ1.45

6.88 11.29 1.56 ꢀ4256.30 25159.20 ꢀ1.41

7.34 12.95 1.34 ꢀ4705.22 29639.90 ꢀ1.43

7.62 13.36 1.36 ꢀ4960.77 32297.30 ꢀ1.32

7.29 11.91 1.54 ꢀ4440.90 27410.30 ꢀ1.40

1.56

3.12

1.56

3.12

1.56

3.12

25

12.5

1.56

12.5

1.56

12.5

6.25

3.12

12.5

0.019

3.07 104.11

4.43 103.90

3.48 101.10

3.09 102.92

3.74 106.54

3.16 106.32

4.36 105.19

25

12.5

>50

50

6.25

12.5

6.25

12.5

25

6.25

12.5

6.25

0.019

9

10

11

12

13

14

15

16

17

18

19

20

Std.

50

9

10

11

12

13

14

15

16

17

18

19

20

>50

50

12.5

50

>50

50

3.02

2.65

3.00

2.53

90.36

84.44

88.48

97.76

3.48 101.10

3.46

8.56

93.10

154.26 11.52 18.41 1.24 ꢀ6438.19 48954.00 ꢀ1.39

8.05 143.70 11.18 17.41 1.29 ꢀ6155.08 46304.10 ꢀ1.39

0.040

3.96 108.96

9.97 13.68 1.39 ꢀ5182.61 34218.00 ꢀ1.41

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

5989

analysis was carried out in terms of correlation analysis. A correla-

tion matrix constructed for antibacterial activity against S. aureus is

presented in Table 5. The correlations of different molecular

descriptors with antimicrobial activity are presented in Table 6. In

general, high colinearity (r > 0.8) was observed between different

parameters. The high interrelationship was observed between Te

and Nu.E (r ¼ 0.990) and low interrelationship was observed

observed and predicted antimicrobial activities is presented in

Table 7. It can be seen from the results that the observed and pre-

dicted antimicrobial activities lie close to each other as evidenced

by their low residual values. The plot of predicted pMICsa against

observed pMIC_sa(Fig. 1) also favors the model expressed by Eq. (3).

Further, the plot of observed pMIC_savs residual pMIC_sa(Fig. 2)

indicated that there was no systemic error in model development

as the propagation of residuals was observed on both positive and

negative sides [28].

between ²

c

^vand LUMO (r ¼ 0.001).

Correlation matrix (Table 5) indicated the importance of the

topological parameter, Balaban index (J) in describing antibacterial

activity of synthesized benzimidazole derivatives against S. aureus

[Eq. (1)].

The MLR Eqs. (4)e(7) were developed to predict the antimi-

crobial activity of benzimidazole derivatives against B. subtilis, E.

coli, C. albicans and A. niger.

ot-QSAR model for antibacterial activity against S. aureus

ot-QSAR model for antibacterial activity against B. subtilis

pMIC_sa¼ ꢀ1:749 J þ 4:455

(1)

pMIC_bs¼ ꢀ1:490 J ꢀ 0:726 LUMO þ 3:107

(4)

(5)

n ¼ 20 r ¼ 0.824 q²¼ 0.628 s ¼ 0.110 F ¼ 38.10

n ¼ 20 r ¼ 0.798 q²¼ 0.544 s ¼ 0.128 F ¼ 14.95

Here and thereafter, n e number of data points, r e correlation

coefﬁcient, q²e cross validated r²obtained by leave one out

method, s e standard error of the estimate and F e Fischer statistics.

As the coefﬁcient of J in Eq. (1) is negative, therefore the anti-

bacterial activity against S. aureus will increase with a decrease in

value of J. This is clearly evident from Table 4 that compounds 9, 18

and 19 having low J value of 1.33, 1.24 and 1.29 have higher pMICsa

of 2.43, 2.24 and 2.23, respectively than the other compounds.

Similarly, compound 14 having maximum J values 1.56 (Table 4),

has minimum antibacterial activity against S. aureus.

ot-QSAR model for antibacterial activity against E. coli

pMIC_ec¼ ꢀ0:230 ²c^vꢀ 2:747 J ꢀ 0:496 LUMO þ 7:092

n ¼ 20 r ¼ 0.860 q²¼ 0.560 s ¼ 0.157 F ¼ 15.22

ot-QSAR model for antifungal activity against C. albicans

pMIC_ca¼ ꢀ1:185 J ꢀ 0:990 LUMO þ 1:847

(6)

n ¼ 20 r ¼ 0.836 q²¼ 0.603 s ¼ 0.117 F ¼ 19.84

QSAR model for antifungal activity against A. niger

The addition of electronic parameter, the energy of lowest

unoccupied molecular orbital (LUMO) to Balaban index [Eq. (1)]

improved the correlation (r ¼ 0.883, Eq. (2)).

pMIC_an¼ ꢀ0:087 log P þ 0:00004 NE þ 0:285

n ¼ 20 r ¼ 0.710 q²¼ 0.350 s ¼ 0.166 F ¼ 8.65

(7)

ot-QSAR model for antibacterial activity against S. aureus

As in case of S. aureus, the MLR equations derived for B. subtilis

and E. coli also indicated the importance of the topological

parameter, Balaban index (J) followed by the electronic parameter,

LUMO and topological parameter, valence second order molecular

pMIC_sa¼ ꢀ1:811 J ꢀ 0:421 LUMO þ 3:962

(2)

n ¼ 20 r ¼ 0.883 q²¼ 0.592 s ¼ 0.093 F ¼ 30.25

Further the inclusion of the topological parameter, valence

connectivity index (^{2 v}) in describing antibacterial activity against

c

second order molecular connectivity index (²

c

^v) improved the

B. subtilis and E. coli and antifungal activity against C. albicans. But in

case of antifungal activity of benzimidazole derivatives against A.

niger the MLR equation indicated importance of the lipophilic

parameter, log of octanolewater partition coefﬁcient log P and the

electronic parameter, nuclear energy (Nu. E) in description of the

activity.

As in case of Eq. (3), the predictive ability of Eqs. 4e7 against

respective microorganisms is supported by the low residual activity

values (Table 7). Further the high q²values observed also supports

the suitability of the QSAR models (q²> 0.5) described by Eqs. 5 and

6. In case of the MLR models derived for A. niger, the q²value is less

than 0.5, which shows that the developed models are invalid one.

But one should not forget the recommendations of Golbraikh and

Tropsha [29] who have reported that the only way to estimate the

true predictive power of a QSAR model is to test their ability to

correlation coefﬁcient value closer to 0.9 [Eq. (3)].

ot-QSAR model for antibacterial activity against S. aureus

pMIC_sa¼ ꢀ0:269 ²c^vꢀ 2:073 J ꢀ 0:436 LUMO þ 4:519

n ¼ 20 r ¼ 0.895 q²¼ 0.536 s ¼ 0.091 F ¼ 21.57

(3)

The above results indicated that the antibacterial activity of

synthesized benzimidazole derivatives are determined mainly by

the topological parameter, Balaban index (J) followed by the elec-

tronic parameter, LUMO and topological parameter, valence second

order molecular connectivity index (^{2 v}).

c

The QSAR model expressed by Eq. (3) was cross validated by its

appreciable q²values (q²¼ 0.536) obtained by leave one out (LOO)

method. The value of q²greater than 0.5 is the basic requirement

for qualifying a QSAR model to be valid one. The comparison of

Table 5

Correlation matrix of synthesized benzimidazole derivatives against S. aureus.

pMICsa

1.000

log P

MR

²c^v

J

Te

Nu. E

0.657

0.862

0.972

LUMO

HOMO

m

pMICsa

log p

MR

0.420

1.000

0.562

0.935

1.000

0.438

0.897

0.950

1.000

0.824

ꢀ0.699

ꢀ0.815

ꢀ0.945

ꢀ0.907

0.790

ꢀ0.242

0.063

0.028

ꢀ0.001

ꢀ0.091

0.131

ꢀ0.234

ꢀ0.145

ꢀ0.129

ꢀ0.173

ꢀ0.019

0.193

0.118

ꢀ0.549

ꢀ0.723

ꢀ0.642

1.000

ꢀ0.196

ꢀ0.038

0.085

ꢀ0.200

ꢀ0.050

ꢀ0.012

0.222

²c^v

0.930

J

Te

Nu. E

LUMO

HOMO

m

ꢀ0.773

ꢀ0.990

1.000

ꢀ0.099

ꢀ0.176

1.000

0.390

1.000

ꢀ0.057

1.000

5990

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Table 6

Correlation of antimicrobial activity of benzimidazole derivatives with studied molecular descriptors.

pMICsa

pMICbs

pMICec

pMICca

pMICan

pMICab

pMICaf

pMICam

log P

MR

⁰c^v

¹c^v

²c^v

k₁

0.420

0.562

0.530

0.474

0.438

0.576

0.497

0.527

0.458

0.261

0.416

0.387

0.346

0.294

0.472

0.413

0.427

0.377

ꢀ0.484

ꢀ0.391

ꢀ0.438

ꢀ0.499

ꢀ0.529

ꢀ0.375

ꢀ0.414

ꢀ0.418

ꢀ0.443

ꢀ0.277

ꢀ0.144

ꢀ0.385

0.221

0.306

0.429

0.414

0.398

0.363

0.467

0.435

0.438

0.410

0.389

0.574

0.546

0.544

0.504

0.591

0.563

0.568

0.542

ꢀ0.014

0.148

0.099

0.402

0.580

0.555

0.545

0.503

0.610

0.576

0.581

0.550

0.182

0.376

0.332

0.281

0.227

0.414

0.350

0.361

0.308

0.031

ꢀ0.018

0.182

k₂

0.110

0.124

0.067

0.291

ka₁

ka₂

R

J

W

0.669

0.531

0.493

0.634

0.650

0.506

ꢀ0.824

ꢀ0.610

ꢀ0.457

ꢀ0.632

ꢀ0.606

ꢀ0.630

ꢀ0.707

0.525

0.439

0.458

0.577

0.146

0.597

0.383

Te

ꢀ0.699

ꢀ0.661

0.657

ꢀ0.242

ꢀ0.234

0.118

ꢀ0.585

ꢀ0.551

0.547

ꢀ0.458

ꢀ0.179

ꢀ0.150

ꢀ0.517

0.516

ꢀ0.656

ꢀ0.379

ꢀ0.122

ꢀ0.621

ꢀ0.636

0.637

ꢀ0.165

ꢀ0.127

ꢀ0.135

ꢀ0.352

ꢀ0.295

0.289

ꢀ0.354

ꢀ0.054

ꢀ0.088

ꢀ0.655

ꢀ0.664

0.664

ꢀ0.454

ꢀ0.284

ꢀ0.143

ꢀ0.549

ꢀ0.515

0.511

ꢀ0.453

ꢀ0.173

ꢀ0.127

El.E

Nu. E

LUMO

HOMO

m

0.279

ꢀ0.284

ꢀ0.172

0.172

ꢀ0.137

predict accurately the biological activities of compounds. As the

observed and predicted values are close to each other (Table 7), the

QSAR model for A. niger [Eq. (7)] is a valid one.

(Table 2) observed in the antimicrobial activity data justiﬁes its use

in QSAR studies.

It is important to note that all the equations were derived using

the entire data set as there were no outliers in the data set.

Generally for QSAR studies, the biological activities of compounds

should span 2e3 orders of magnitude. But in the present study the

range of antimicrobial activities of the synthesized compounds is

within one order of magnitude. But it is important to note that the

predictability of the QSAR models developed in the present study is

highly evidenced by the low residual values. This is in accordance

with results suggested by Bajaj et al. [30], who stated that the

reliability of the QSAR model lies in its predictive ability even

though the activity data are in the narrow range. Further, recent

literature reveals that the QSAR have been applied to describe the

relationship between narrow range of biological activity and

physicochemical properties of the molecules [31e33]. When bio-

logical activity data lies in the narrow range, the presence of

minimum standard deviation of the biological activity justiﬁes its

use in QSAR studies [34,35]. The minimum standard deviation

3.2.2. Development of multi-target QSAR model

According to the above ot-QSAR models one should use ﬁve

different equations to predict the activity of a new compound

against the ﬁve microbial species. The ot-QSAR models, which are

almost in all the literature, become unpractical or complicated to

use when we have to predict each compound results for more than

one-target. In these cases we have to develop one ot-QSAR for each

target. However, very recently the interest has been increased in

development of multi-target QSAR (mt-QSAR) models. In opposi-

tion to ot-QSAR, the mt-QSAR model is a single equation that

considers the nature of molecular descriptors which are common

and essential for describing the antimicrobial activity [36e40].

In the present study we have attempted to develop three

different types of mt-QSAR models viz. mt-QSAR model for

describing antibacterial activity of synthesized compounds against

S. aureus, B. subtilis and E. coli, mt-QSAR model for describing

antifungal activity of synthesized compounds against C. albicans

Table 7

Comparison of observed and predicted antibacterial and antifungal activity obtained by ot-QSAR model.

Comp.

pMICsa (Eq. (3))

pMICbs (Eq. (4))

pMICec (Eq. (5))

pMICca (Eq. (6))

pMICan (Eq. (7))

Obs.

Pre.

Res.

Obs.

Pre.

Res.

0.02

0.01

ꢀ0.13

ꢀ0.23

ꢀ0.02

0.01

Obs.

Pre.

Res.

0.18

ꢀ0.26

ꢀ0.10

0.26

0.15

0.05

0.18

ꢀ0.10

ꢀ0.11

ꢀ0.09

ꢀ0.05

ꢀ0.18

0.17

Obs.

Pre.

Res.

0.20

Obs.

Pre.

Res.

0.13

0.29

0.19

ꢀ0.03

ꢀ0.01

ꢀ0.11

ꢀ0.24

ꢀ0.12

ꢀ0.01

ꢀ0.06

ꢀ0.31

ꢀ0.22

0.11

0.06

0.17

0.16

0.02

0.03

0.08

ꢀ0.15

1

2

3

4

5

6

7

8

1.80

2.08

2.10

2.09

2.12

2.10

2.12

2.43

2.10

1.85

1.72

1.74

2.13

2.10

1.76

2.24

2.23

1.84

2.04

2.14

2.03

2.06

2.15

2.09

2.06

2.35

2.06

2.03

1.76

1.81

1.71

2.17

2.06

1.74

2.24

2.16

1.98

ꢀ0.24

ꢀ0.06

0.07

2.03

2.12

1.80

1.82

2.13

2.15

2.42

2.12

2.43

2.10

1.95

1.85

2.02

1.74

2.13

2.10

1.76

2.24

2.23

1.84

2.01

2.11

1.93

2.05

2.15

2.14

2.10

1.98

2.47

2.05

1.96

1.83

1.88

1.80

2.15

2.03

1.83

2.27

2.20

2.06

2.40

2.12

2.10

2.42

2.40

2.42

2.12

2.43

2.10

1.85

2.32

2.04

2.39

2.26

1.76

1.85

1.61

1.54

2.22

2.38

2.20

2.16

2.27

2.35

2.24

2.22

2.54

2.19

2.15

2.03

2.15

1.92

2.44

2.25

1.88

1.72

1.68

1.70

1.78

1.20

1.52

1.50

1.52

1.51

2.13

1.50

1.44

1.42

1.44

1.75

1.50

1.46

1.94

1.61

1.54

1.50

1.62

1.38

1.55

1.67

1.62

1.44

2.10

1.56

1.43

1.41

1.47

1.39

1.68

1.54

1.41

1.76

1.70

1.59

1.50

1.48

1.50

1.22

1.20

1.22

1.21

1.53

1.20

0.89

0.84

1.12

1.14

1.48

1.50

1.16

1.63

1.61

1.23

1.37

1.19

1.31

1.25

1.23

1.31

1.46

1.33

1.54

1.26

1.20

1.06

1.01

1.08

1.31

1.34

1.14

1.60

1.53

1.38

0.16

ꢀ0.18

ꢀ0.03

ꢀ0.15

ꢀ0.17

ꢀ0.10

0.07

0.03

ꢀ0.03

ꢀ0.05

0.03

0.06

0.08

0.04

0.07

0.09

0.32

0.14

9

ꢀ0.04

0.03

10

11

12

13

14

15

16

17

18

19

20

0.05

ꢀ0.06

ꢀ0.01

0.02

0.14

ꢀ0.06

ꢀ0.02

0.07

ꢀ0.07

ꢀ0.03

0.03

0.07

0.03

ꢀ0.09

ꢀ0.05

0.03

0.12

0.05

ꢀ0.04

0.04

0.02

0.00

0.07

ꢀ0.05

0.07

0.01

ꢀ0.04

ꢀ0.12

0.13

0.05

0.18

ꢀ0.07

ꢀ0.09

ꢀ0.14

ꢀ0.22

ꢀ0.14

ꢀ0.05

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

5991

2.4

2.3

2.2

2.1

2.0

1.9

improved the correlation to 0.732 [Eq. (9)] and 0.805 [Eq. (10)]

respectively.

mt-QSAR model for antibacterial activity

pMIC_ab¼ ꢀ1:271 J ꢀ 0:505 LUMO þ 3:134

(9)

n ¼ 20 r ¼ 0.732 q²¼ 0.280 s ¼ 0.127 F ¼ 9.82

mt-QSAR model for antibacterial activity

²c^v

pMIC_ab¼ ꢀ0:091

ꢀ 2:077 J þ 5:677

(10)

n ¼ 20 r ¼ 0.805 q²¼ 0.541 s ¼ 0.110 F ¼ 15.74

Based on the above-improved correlations, we decided to study

the addition of electronic parameter, LUMO and topological

parameter, valence second order molecular connectivity index (²c^v

)

1.8

1.7

to the topological parameter, Balaban index (J). This addition

resulted in appreciable improvement in the statistical parameters

as depicted in [Eq. (11)].

1.7

1.8

1.9

2.0

2.1

2.2

2.3

2.4

2.5

mt-QSAR model for antibacterial activity

Observed pMICsa

pMIC_ab¼ ꢀ0:097 ²c^vꢀ 2:219 J ꢀ 0:559 LUMO þ 5:151

Fig. 1. Plot of predicted pMIC_saagainst the experimental pMIC_safor the MLR model

developed by Eq. (3).

(11)

n ¼ 20 r ¼ 0.925 q²¼ 0.768 s ¼ 0.073 F ¼ 31.61

The mt-QSAR MLR model for antifungal activity revealed the

importance of electronic parameter, LUMO and the topological

parameter, Balaban index (J) in describing antifungal activity [Eq.

(12)].

and A. niger as well a common mt-QSAR model for describing the

antimicrobial activity of synthesized benzimidazole derivatives

against all the above mentioned microorganisms.

In order to develop mt-QSAR models, we have calculated the

average antibacterial activity [pMIC_b¼ (pMIC_saþ pMICbs þ pMICec)/

3], antifungal activity [pMIC_f¼ (pMIC_caþ pMIC_an)/2] and antimicro-

mt-QSAR model for antifungal activity

pMIC_af¼ ꢀ1:417 J ꢀ 0:669 LUMO þ 2:472

n ¼ 20 r ¼ 0.812 q²¼ 0.567 s ¼ 0.115 F ¼ 16.47

(12)

bial activity values [pMIC_am¼ (pMIC_saþ pMICbs þ pMIC_ec

þ

pMIC_caþ pMIC_an)/5] of benzimidazole derivatives which are pre-

sented in Table 2. These average activity values were also correlated

with the molecular descriptors of synthesized compounds (Table 6).

The LR model derived for the antibacterial activity of benzimidazole

derivatives indicated the importance of topological parameter, Bala-

ban index (J) [Eq. (8)].

The mt-QSAR MLR model for antimicrobial activity revealed the

importance of the topological parameter, Balaban index (J) followed

by the electronic parameter, LUMO and topological parameter,

valence second order molecular connectivity index (^{2 v}) [Eq. (13)].

c

mt-QSAR model for antimicrobial activity

mt-QSAR model for antibacterial activity

pMIC_am¼ ꢀ0:052 ²c^vꢀ 1:831 J ꢀ 0:597 LUMO þ 3:942

pMIC_ab¼ ꢀ1:197 J þ 3:726

(8)

(13)

n ¼ 20 r ¼ 0.605 q²¼ 0.245 s ¼ 0.144 F ¼ 10.44

n ¼ 20 r ¼ 0.940 q²¼ 0.809 s ¼ 0.057 F ¼ 41.10

The addition of electronic parameter, LUMO and topological

The predictability of Eqs. (11)e(13) was veriﬁed by calculating

the antibacterial, antifungal and antimicrobial activities for

substituted benzimidazoles respectively and the low residual

activity values indicated the high predictability of above mentioned

equations (Table 8). Further the plot of observed pMICam and

predicted pMICam (Fig. 3) also in favor of the mt-QSAR target

model for antimicrobial activity. The propagation of activity values

on both sides of zero, in the plot of observed pMICam against

residual pMICam, indicated that there was no systemic error in the

development of mt-QSAR model (Fig. 4). The other statistically

signiﬁcant ot-QSAR and mt-QSAR models derived are presented in

Table 9.

parameter, valence second order molecular connectivity index (²c^v

)

.3

.2

.1

The Balaban index J is a variant of connectivity index and

represents extended connectivity. It is a good descriptor for the

shape of molecules and is one of the widely used topological indices

for QSAR and QSPR studies. The Balaban index of a connected

(molecular) graph G is deﬁned as [41]:

-.0

-.1

-.2

-.3

X

J ¼ ðm=

m

þ 1Þ

ðD_uD_vÞ^ꢀ1=2

uv

e

EðGÞ

1.6

1.8

2.0

2.2

2.4

2.6

where, m is the number of edges,

the sum of distances between vertex u and all other vertices of G,

m is the cyclomatic number, D_uis

Observed pMICsa

and the summation goes over all edges from the edge set E (G). The

Fig. 2. Plot of residual pMIC_saagainst the experimental pMIC_saby Eq. (3).

5992

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Table 8

.2

Comparison of observed and predicted antibacterial, antifungal and antimicrobial

activity obtained by mt-QSAR model.

Comp. pMICab (Eq. (11))

Obs. Pre. Res.

pMICaf (Eq. (12))

Obs. Pre. Res.

pMICam (Eq. (13))

.1

Obs. Pre.

Res.

0.08

0.00

1

2

3

4

5

6

7

8

2.08 2.09 ꢀ0.01 1.60 1.40

2.11 2.22 ꢀ0.11 1.63 1.49

2.00 2.06 ꢀ0.06 1.35 1.33

0.20 1.89 1.81

0.14 1.92 1.92

0.02 1.74 1.76 ꢀ0.02

2.11 2.09

2.22 2.19

2.22 2.22

2.32 2.15

2.12 2.09

0.02 1.37 1.43 ꢀ0.06 1.81 1.83 ꢀ0.02

0.03 1.37 1.53 ꢀ0.16 1.88 1.92 ꢀ0.04

0.00 1.35 1.52 ꢀ0.17 1.87 1.94 ꢀ0.07

0.0

0.17 1.37 1.48 ꢀ0.11 1.94 1.88

0.03 1.36 1.37 ꢀ0.01 1.82 1.80

0.06

0.02

-.1

-.2

9

2.43 2.46 ꢀ0.03 1.83 1.82

0.01 2.19 2.20 ꢀ0.01

10

11

12

13

14

15

16

17

18

19

20

2.10 2.10

2.05 2.05

0.00 1.35 1.43 ꢀ0.08 1.80 1.83 ꢀ0.03

0.00 1.20 1.36 ꢀ0.16 1.71 1.77 ꢀ0.06

1.85 1.87 ꢀ0.02 1.14 1.23 ꢀ0.09 1.57 1.61 ꢀ0.04

2.02 1.95

1.84 1.80

0.07 1.27 1.27

0.04 1.29 1.20

0.00 1.72 1.68

0.09 1.62 1.56

0.09 1.98 1.97

0.08 1.89 1.84

0.09 1.58 1.58

0.15 1.98 1.90

0.03 1.86 1.84

0.04

0.06

0.01

0.05

0.00

0.08

0.02

1.5

1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.22 2.27 ꢀ0.05 1.62 1.53

Observed pMICam

2.15 2.12 0.03 1.50 1.42

1.76 1.81 ꢀ0.05 1.31 1.22

Fig. 4. Plot of predicted pMIC_amvalues against the experimental pMIC_amvalues for the

MLR model developed by Eq. (13).

2.11 2.05

2.02 1.98

0.06 1.79 1.64

0.04 1.61 1.58

1.74 1.88 ꢀ0.14 1.39 1.44 ꢀ0.05 1.60 1.72 ꢀ0.12

Furthermore, the topological parameter, Balaban index (J) fol-

lowed by the electronic parameter, LUMO and topological

parameter, valence second order molecular connectivity index

electronic parameter LUMO, which denotes the energy of lowest

unoccupied molecular orbital directly relates to the electron afﬁnity

and characterizes the sensibility of the molecule towards an attack

by necleophile. The contribution of LUMO in describing antimi-

crobial activity may be attributed to the interaction of benzimid-

azole derivatives with nucleophilic amino acid residue like cysteine

of microorganisms [42]. The topological descriptor, i.e. the valence

second order molecular connectivity index encodes information

related to the degree of stargraph likeness and takes a large value

for more linear molecule [43]. The trend in Eq. (13) indicated that

(

²c^v) is describing the antimicrobial activity of 4-[1-(substituted

aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids

(1-20).

It is important to mention here that the development of multi-

QSAR target models exhibited the following advantages over one-

target QSAR models: (a). There is an improvement in statistical

parameters when compared to one-target models (improvement in

r, q2, etc. cf. Eq. (13) with Eqs. (1)e(7)). (b). No change in the trend

of molecular descriptors has been observed, i.e. all the three

parameters, i.e. J, LUMO and ²c^vshowed the same negative corre-

lation with antimicrobial activity as observed in the case of one-

target models. (c). There was a signiﬁcant decrease in residual

values when compared to the residual values observed in one-

target QSAR models, i.e. mt-QSAR model has better predictability

than the ot-QSAR model.

higher the values of J, LUMO and ^{2 v}lower will be the antimicrobial

c

activity of benzimidazole derivatives.

The residual activity values in the case of mt-QSAR model for

antimicrobial activity are less when compared to the residuals of

one-target models (Table 7) as well the multi-target models

for antibacterial and antifungal activities (Table 8). This mt-QSAR

equation (Eq. (13)) can be used to predict the activity of

substituted benzimidazoles against different microbial species.

2.3

2.2

2.1

2.0

1.9

1.8

1.7

Table 9

Regression analysis and quality of correlation for modeling antibacterial and anti-

fungal activity of synthesized Benzimidazole derivatives.

S.

No.

QSAR model

n

r

q²

s

F

B. subtilis

1

E. coli

2

3

pMIC_bs¼ ꢀ1.383J þ 3.959

20 0.610 0.269 0.164 10.66

20 0.528 0.108 0.247 6.97

pMIC_ec¼ ꢀ0.112 ²c^vþ 3.034

pMIC_ec¼ ꢀ0.224 ²c^vþ 2.622J

þ 7.559

20 0.823 0.558 0.170 17.90

C. albicans

4

A. niger

5

Antifungal activity

6

Antimicrobial activity

pMIC_ca¼ ꢀ0.923 LUMO þ 0.302

20 0.656 0.237 0.157 13.60

20 0.636 0.314 0.177 12.28

20 0.629 0.278 0.149 11.81

pMIC_an¼ 0.00002 NE þ 0.556

1.6

1.5

pMIC_af¼ ꢀ1.319J þ 3.257

7

8

pMIC_am¼ ꢀ1.244J þ 3.535

20 0.707 0.419 0.113 18.03

20 0.877 0.705 0.079 28.60

1.5

1.6

1.7

1.8

1.9

2.0

2.1

2.2

pMIC_am¼ ꢀ1.370 Je0.568 LUMO

þ 2.869

Observed pMICam

9

pMIC_am¼ ꢀ0.045 ²c^ve 1.680 LUMO 20 0.767 0.456 0.106 12.15

þ 4.503

Fig. 3. Plot of predicted pMIC_amagainst the experimental pMIC_amvalues for the MLR

model developed by Eq. (13).

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

5993

Table 10

3.3. Antiviral activity

Anti-Feline Corona Virus (FIPV) and anti-Feline Herpes Virus activity and cytotox-

icity of synthesized benzimidazole derivatives in CRFK cell cultures.

A broad antiviral screening of the 4-[1-(substituted aryl/alkyl

carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids (1-20) was

performed against a variety of DNA and RNA viruses (Tables 10e14).

None of the compounds were inhibitory to the virus-induced

cytopathicity at subtoxic concentrations.

a

b

Comp.

CC₅₀

(

m

g/mL)

EC₅₀(mg/mL)

Feline Herpes

Virus (FIPV)

Feline

Corona

Virus

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

11

>100

82

>100

14

>4

>100

>20

>100

32.6

>4

>100

>20

>100

2.0

3.4. Structure activity relationship

From the results of antimicrobial and antiviral activities, the

following structure activity relationship can be drawn:

1. The results of antibacterial activity indicated that compound 9,

4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzene-

sulfonic acid was effective against all the three bacterial species

under test. It may be due to the presence of the electron

withdrawing nitro group. The role of electron withdrawing

group in increasing the antimicrobial activity is similar to the

results of Sharma et al. [44].

2. The results of antifungal activity indicated that compound 18,

4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzene-

sulfonic acid was effective against both tested fungal strains.

3. The comparison of most effective antibacterial and antifungal

compound gave information that the aromatic acid substitu-

tion at N₁of benzimidazole is required for antibacterial activity

and aliphatic acid substitution at N₁of benzimidazole is

required for antifungal activity. This indicated that different

structural requirements are essential for binding of drug to

bacterial or fungal targets respectively [45].

17

18

19

20

HHA

UDA

Ganciclovir (

1.5

>100

0.4

1.7

m

M)

>100

CRFK cells: CrandelleRees Feline Kidney cells.

50% Cytotoxic concentration, as determined by measuring the cell viability with

the colorimetric formazan-based MTS assay.

50% Effective concentration, or compound concentration resulting in 50% inhi-

bition of the virus-induced cytopathic effect, as determined by measuring the cell

viability with the colorimetric formazan-based MTS assay.

a

b

4. None of the compounds were endowed with antiviral activity

at subtoxic concentrations.

Table 11

Cytotoxicity and antiviral activity of synthesized benzimidazole derivatives in HEL cell cultures.

b

Comp.

Minimum

EC₅₀

(m

g/mL)

cytotoxic

Herpes

simplex

virus-1 (KOS)

Herpes

simplex

virus-2 (G)

Vaccinia

virus

Vesicular

stomatitis

virus

Herpes

concentration^a

simplex

(mg/mL)

virus-1 TK^ꢀ

KOS ACV^r

1

2

3

4

5

6

7

>100

100

>100

>20

>100

>20

>100

>20

>100

>20

>100

>20

8

9

10

11

12

13

>100

100

>100

>20

>100

>20

>100

>20

>100

>20

>100

>20

14

15

16

17

18

19

20

>100

>250

>100

0.08

>100

250

>100

112

>100

>250

>100

>250

2

Brivudin (

m

M)

Ribavirin (

Cidofovir (

Ganciclovir

1

0.4

0.03

2

0.2

0.03

10

>250

>100

>250

58

(mM)

a

Required to cause a microscopically detectable alteration of normal cell morphology.

Required to reduce virus-induced cytopathogenicity by 50%.

b

5994

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Table 12

Cytotoxicity and antiviral activity of synthesized benzimidazole derivatives in HeLa cell cultures.

c

Comp.

Cytotoxicity (

m

g/ml)

EC₅₀

(

mg/ml)

a

CC₅₀

Minimum

Vesicular stomatitis virus

Coxsackie virus B4

Respiratory syncytial virus

cytotoxic

visual CPE

score

MTS

visual CPE

score

MTS

>20

visual CPE

score

MTS

concentration^b

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

>100

>250

ꢁ20

>100

>250

>20

>100

>250

10

>20

>100

20

>20

>100

4

>20

>100

>250

>100

17

18

19

20

DS-5000

(S)-DHPA (

Ribavirin (

80.5

>250

14

3.6

>250

2.8

m

M)

>250

50

>250

6

m

M)

3.6

a

50% Cytotoxic concentration, as determined by measuring the cell viability with the colorimetric formazan-based MTS assay.

Minimum compound concentration that causes a microscopically detectable alteration of normal cell morphology.

50% Effective concentration, or concentration resulting in 50% inhibition of virus-induced cytopathic effect, as determined by visual scoring of the CPE, or by measuring the

b

c

cell viability with the colorimetric formazan-based MTS assay.

Table 13

Cytotoxicity and antiinﬂuenza activity of synthesized benzimidazole derivatives in MDCK cell cultures.

c

Comp.

Cytotoxicity (

m

g/ml)

MCC^b

EC₅₀

(

m

g/ml)

a

CC₅₀

Inﬂuenza A H1N1 subtype

Inﬂuenza A H3N2 subtype

Inﬂuenza B

visual CPE

score

MTS

visual CPE

score

MTS

visual CPE

score

MTS

>4

>100

>4

1

2

3

4.1

>100

46.8

ꢁ4

>100

20

>4

>100

>4

>100

>4

>100

>4

>100

>4

>100

>4

4

5

6

7

>100

54.0

>100

100

>100

>20

>4

>100

>20

>100

>20

>4

>100

>20

>100

>20

>100

>20

20

>4

8

9

10

11

12

13

14

15

16

17

18

19

>100

14.1

>100

>200

>100

>0.8

>100

>20

>100

12

>100

>0.8

>100

>20

>100

9

>100

>0.8

>100

>20

>100

7

>100

ꢁ0.8

>0.8

>100

100

>100

>20

>100

28

>100

>20

>100

>20

>100

>200

20

Oseltamivir carboxylate (

Ribavirin (

Amantadine (

Rimantadine (

m

M)

6.9

8.4

0.2

0.02

m

M)

m

9

18

4

12

44

12

9

0.3

0.03

4.3

>200

M)

>200

a

50% Cytotoxic concentration, as determined by measuring the cell viability with the colorimetric formazan-based MTS assay.

Minimum cytotoxic concentration, i.e. Minimum compound concentration that causes a microscopically detectable alteration of normal cell morphology.

50% Effective concentration, or compound concentration resulting in 50% inhibition of the virus-induced cytopathic effect, as determined by visual scoring of the CPE, or by

b

c

measuring the cell viability with the colorimetric formazan-based MTS assay.

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

5995

Table 14

Cytotoxicity and antiviral activity of synthesized benzimidazole derivatives in in Vero cell cultures.

b

Comp.

Minimum

EC₅₀

(m

g/ml)

cytotoxic

Para-inﬂuenza-3

virus

Reovirus-1

Sindbis

virus

Coxsackie

virus B4

Punta

Toro

virus

concentration^a

(

mg/ml)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

20

>4

>100

>250

>4

>100

>250

>4

>100

100

>4

>100

58

>4

>100

100

>100

>250

17

18

19

20

DS-5000

(S)-DHPA

>250

(

m

M)

Ribavirin

M)

>250

95

112

>250

250

112

(

m

a

Required to cause a microscopically detectable alteration of normal cell morphology.

Required to reduce virus-induced cytopathogenicity by 50%.

b

4. Conclusion

maintaining temperature at 5e10 ^ꢂC. The above solution was stir-

red initially for 3 h at cold condition followed by continuation of

stirring at room temperature for 48 h. The product, 4-(1H-benzoi-

midazol-2-yl)-benzenesulfonic acid obtained was ﬁltered, dried

and recrystallized using alcohol.

A solution of 4-(1H-benzoimidazol-2-yl)-benzenesulfonic acid

(0.002 mol) in diethyl ether (50 ml) was added with a solution of

acid chloride of anthranilic acid (0.002 mol) in diethyl ether

(50 ml). The above mixture was stirred for 24 h at room tempera-

ture. The resultant product, 4-[1-(2-amino-benzoyl-1H-benzoimi-

dazol-2-yl]-benzenesulfonic acid was isolated by evaporation of

ether and puriﬁed by recrystallisation with methanol.

A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-

2-yl]-benzenesulfonic acids (1-e20), was synthesized by the reac-

tion of 4-(1H-benzoimidazol-2-yl)-benzenesulfonic acid with cor-

responding aryl/alkyl acid chlorides. The synthesized compounds

were characterized by physicochemical and spectral means and the

IR and NMR spectral data are found in agreement with the assigned

molecular structures. Further, the synthesized compounds were

evaluated for their in vitro antimicrobial activities against the

bacterial strains S. aureus, B. subtilis; E. coli and fungal strains e

A. niger and C. albicans by tube dilution method. The antimicrobial

screening results indicated that compounds 4-[1-(4-Nitrobenzoyl)-

1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-

9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were the

most active ones. The antiviral evaluations revealed no speciﬁc

antiviral activity for the test compounds. The QSAR study carried

out to ﬁnd the relationship between physicochemical parameters

and antimicrobial activity of benzimidazole derivatives indicated

the importance of the topological parameter, Balaban index

(J) followed by the electronic parameter, LUMO and the topo-

logical parameter, valence second order molecular connectivity

The compounds 2-20 are synthesized by the similar procedure

followed for compound 1 using corresponding aryl/alkyl acid

chlorides with 4-(1H-benzoimidazol-2-yl)-benzenesulfonic acid.

Compound 1: Mp (^ꢂC) 116e118; Yield-70.9%; ¹H NMR (DMSO)

d

ppm: 6.54e8.56 (m, 12H, AreH of ArNH_2,ArSO₃H and benz-

imidazole), 2.50 (s, 1H, OH of SO₃H); IR (KBr pellets, cm^ꢀ1): 1618.29

(C]O str., tertiary amide), 755.51 (OCN bending), 1442.0 (C]C str.,

skeletal vibration of phenyl nucleus),1233.60 (SO₃asymmetric str.),

3481.81 (NH asymmetric str., primary amine).

Compound 6: Mp (^ꢂC) 98e100; Yield-101.6%; ¹H NMR (DMSO)

index

(

²c^v

)

in describing the antimicrobial activity of 4-[1-

d ppm: 7.0e8.11 (m, 12H, AreH of ArOH ArSO₃H and benzimid-

(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene-

sulfonic acids (1-20).

azole), 2.50 (s, 1H, OH of SO₃H); IR (KBr pellets, cm^ꢀ1): 1610.90 (C]

O str., tertiary amide), 750.67 (OCN bending), 1452.01 (C]C str.,

skeletal vibration of phenyl nucleus), 1106.82 (SO₃asymmetric str.),

1715.01 (CH str., aromatic), 991.75 (CeC out of plane bending; 1,3-

disubstituted benzene).

4.1. Synthesis of 4-[1-(2-amino-benzoyl-1H-benzoimidazol-2-yl]-

benzenesulfonic acid (1)

Compound 8: Mp (^ꢂC) 90e92; Yield-60.9%; ¹H NMR (DMSO)

4-Amino-benzenesulfonic acid (0.13 mol) in hydrochloric acid/

water mixture (1:1) was diazotized using solution of sodium nitrite

at 0e10 ^ꢂC. To the diazotized mixture, benzimidazole (0.004 mol)

was added with vigorous shaking. A solution of sodium acetate

(40 g in 100 ml) was added drop wise to the above mixture by

d ppm: 6.95e8.10 (m, 12H, AreH of ArOCH_3,ArSO₃H and benz-

imidazole), 3.78 (s, 3H, OH, OCH₃); IR (KBr pellets, cm^ꢀ1): 1601.31

(C]O str., tertiary amide), 751.4 (OCN bending), 1454.21 (C]C str.,

skeletal vibration of phenyl nucleus), 1258.08 (SO₃asymmetric str.),

1687.12 (CH str., aromatic), 1425.61(CH₃bending of OCH₃).

5996

S. Yadav et al. / European Journal of Medicinal Chemistry 45 (2010) 5985e5997

Compound 14: Mp (^ꢂC) 102e104; Yield-33.5%; ¹H NMR (DMSO)

ppm: 6.90e7.84 (m, 8H, AreH of ArSO₃H and benzimidazole),

of the performance is obtained from cross validated q²) method

which is deﬁned as

d

3.66e3.72 (d, 2H, CH₂of C]CH₂; J_trans¼ 18 Hz); IR (KBr pellets,

cm^ꢀ1): 1613.57 (C]O str., tertiary amide), 755.49 (OCN bending),

1450.12 (C]C str., skeletal vibration of phenyl nucleus), 1233.56

(SO₃asymmetric stretch), 1004.74 (CeH out of plane bending of C

(CH₃) ¼ CH₂), 1384.75 (CH in plane bending of C(CH₃) ¼ CH₂),

1531.84 (C]C str.), 1262.16 (CH in plane bending of phenyl ring).

Compound 15: Mp (^ꢂC) 110e112; Yield-44.0%; ¹H NMR (DMSO)

X

q²¼ 1 ꢀ

Y_predictedꢀ Y_a²_ctual

=

Y_actualꢀ Y_m²_ean

where, Y_predicted, Y_actualand Y_meanare predicted, actual and mean

2

values of target property (pMIC) respectively. S (Y_predictedꢀ Y_actual

)

is predictive residual error sum of squares [51].

4.4. Evaluation of antiviral activity

4.4.1. Antiviral assays

d

ppm: 7.27e8.12 (m, 8H, AreH of ArSO₃H and benzimidazole), 2.50

(s, 1H, OH of SO₃H), 8.46e9.66 (m, 4H, H of pyridine ring); IR (KBr,

pellets, cm^ꢀ1): 1617.65 (C]O str., tertiary amide), 751.40 (OCN

bending), 1450.12 (C]C str., skeletal vibration of phenyl nucleus),

1233.56 (SO₃asymmetric stretch), 1531.84 (C]C str.), 1266.25 (CH

in plane bending of phenyl ring), 1392.92 (CeN str. of tertiary

amide), 829.04 (CeH out of plane bending of 3-substituted

pyridine).

The antiviral screening of the 4-[1-(substituted aryl/alkyl

carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids (1-20) was

performed against Feline Corona virus (FIPV), Feline Herpes virus in

CRFK cell cultures; Herpes simplex virus-1 (KOS) [HSV-1 KOS],

Herpes simplex virus-2 (G) [HSV-2G], Vaccinia virus [VV], Vesicular

stomatitis virus [VSV], Herpes simplex virus-1 TK^ꢀKOS ACV^r[HSV-

1 TK^ꢀKOS ACV^r] in HEL cell cultures; Vesicular stomatitis virus

(VSV), Coxsackie virus B4, Respiratory syncytial virus in HeLa cell

cultures; Para-inﬂuenza-3 virus, Reovirus-1, Sindbis virus, Cox-

sackie virus B4, Punta Toro virus in Vero cell cultures; Inﬂuenza A

virus H1N1 subtype, Inﬂuenza A virus H3N2 subtype and inﬂuenza

B virus in MDCK cell cultures, human immunodeﬁciency virus type

1 (HIV-1)(III_B) and HIV-2(ROD) in MT-4 cell cultures and the results

were expressed as the 50% effective concentration (EC₅₀) or drug

concentration required to inhibit virus-induced cytopathicity by

50%. Read-out was through microscopical inspection or the MTS

viability staining method. Cells, grown in 96-well plates, were

infected with 100 CCID₅₀of virus, one CCID₅₀being the 50% cell

culture infective dose in the presence of serial dilutions of the

compounds. The cultures were further incubated at 37 ^ꢂC for

several (2e4) days, until complete cytopathicity was observed in

the infected and untreated virus control.

Compound 20: Mp (^ꢂC) 156e158; Yield-35.8%; ¹H NMR (DMSO)

d

ppm: 7.12e7.88 (m, 12H, AreH of ArCH_3,ArSO₃H and benzimid-

azole), 2.50 (s, 3H, CH₃of ArCH₃); IR (KBr pellets, cm^ꢀ1): 1621.74

(C]O str., tertiary amide), 1450.12 (C]C str., skeletal vibration of

phenyl nucleus),1192.7 (SO₃asymmetric stretch), 808.61 (SeN str.),

1033.34 (SO₂symmetric str.), 747.32 (OCN bending).

4.2. Evaluation of antimicrobial activity

4.2.1. Determination of minimum inhibitory concentration

The antimicrobial activity was performed against Gram-positive

bacteria: S. aureus, Bacillus sublitis, Gram-negative bacterium: E. coli

and fungal strains: C. albicans and A. niger by tube dilution method.

Dilutions of test and standard compounds [ciproﬂoxacin (antibac-

terial) and ﬂuconazole (antifungal)] were prepared in double

strength nutrient broth e I.P. (bacteria) and Sabouraud dextrose

broth I.P. (fungi) [46]. The samples were incubated at 37 ^ꢂC for 24 h

(bacteria), at 25 ^ꢂC for 7 d (A. niger) and at 37 ^ꢂC for 48 h (C. albi-

cans), respectively, and the results were recorded in terms of MIC

(the lowest concentration of test substance which inhibited the

growth of microorganisms).

4.4.2. Cytotoxic assays

The cytotoxicity of the compounds was evaluated in parallel

with their antiviral activity in uninfected cell cultures, and is

expressed as the minimum cytotoxic concentration (MCC) that

causes a microscopically detectable alteration of normal cell

morphology (HEL, HeLa, CRFK, MDCK and Vero cells).

4.2.2. Determination of minimum bactericidal/fungicidal

concentration (MBC/MFC)

The minimum bactericidal concentration (MBC) and fungicidal

concentration (MFC) were determined by subculturing 100 mL of

Acknowledgements

culture from each tube that remained clear in the MIC determina-

tion into fresh medium. MBC and MFC values represent the lowest

concentration of compound that produces a 99.9% end point

reduction [47].

We would like to thank Mrs. Leentje Persoons, Frieda De Meyer,

Kristien Erven and Kris Uyttersprot, Rega Institute for Medical

Research, Belgium for their excellent technical assistance in the

evaluation of antiviral activity. The antiviral evaluations were

supported by the K.U. Leuven (GOA no. 10/014).

4.3. QSAR studies

References

The structures of substituted benzimidazole derivatives are ﬁrst

pre-optimized with the Molecular Mechanics Force Field (MMþ)

procedure included in Hyperchem 6.03 [48] and the resulting

geometries are further reﬁned by means of the semiempirical

method PM3 (parametric Method-3). We chose a gradient norm

limit of 0.01 kcal/A^ꢂfor the geometry optimization. The lowest

energy structure was used for each molecule to calculate physico-

chemical properties using TSAR 3.3 software for Windows [49].

Further, the regression analysis was performed using the SPSS

software package [50].

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Article Doi

4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: Synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation

DOI: 10.1016/j.ejmech.2010.09.065

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