Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and

Tris Heterocycles

*

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India

*

E-mail: vkpuram2001@yahoo.com

Received October 20, 2016

DOI 10.1002/jhet.2878

Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).

The bis and tris heterocycles-benzoxazolyl/benzothiazolyl/benzimidazolyl quinazolines linked by sulfur

and/or nitrogen were prepared from 2,4-dichloroquinazoline and benzazolyl-2-thiol/benzazolyl-2-amine

and studied their antibacterial activity. The nitro-substituted sulfur-linked bisbenzothiazolylquinazoline

(12f), bisbenzimidazolylquinazoline (13f), and nitro-substituted sulfur and nitrogen-linked

bisbenzothiazolylquinazoline (15f) were found to be potential antibacterial agents against Staphylococcus

aureus.

J. Heterocyclic Chem., 00, 00 (2017).

INTRODUCTION

RESULTS AND DISCUSSION

The heterocycles with two or more heteroatoms have

intensively studied as they represent the most important

structural units in a variety of bioactive molecules.

Among these, benzimidazole, benzoxazole, and

benzothiazole derivatives are frequently encountered in

many therapeutic agents. Substituted benzoxazoles are

associated with diverse pharmacological activities such as

antibacterial, antifungal [1], analgesic [2], anti-

inﬂammatory [3], and antioxidant [4]. Benzothiazoles

have also been studied extensively for their antimicrobial

[5], antitumor [6,7], and antiviral [8] activities.

Benzimidazoles have been reported to possess potential

antitumor and anticancer activities [9–11] along with

antibacterial, antifungal [12], antiviral, and antioxidant

[13]. In addition, as an important pharmacophore,

quinazoline has a variety of biological activities such as

anticancer [14,15], antibacterial [16], and anti-

inﬂammatory [13,17], Although the medicinal chemistry

fraternity has put up a brave front to cover a wide range

of structurally and functionally derivatized heterocyclic

compounds, the libraries of bis and tris heterocycles have

not been extensively studied. Fascinated by multifarious

bioactivity of these heterocycles and our continued efforts

in this direction [18–20], we planned to synthesize

compact molecules encompassing benzazole and

quinazoline entities conjugated by a heteroatom with a

scope to develop compounds possessing noteworthy

pharmacological properties.

The synthetic scheme involves the synthesis and

antibacterial activity of multifaceted heterocycles linked

by heteroatoms. The reactive intermediate 2,4-

dichloroquinazoline (1) was obtained by the reaction

of substituted anthranilic acid with urea followed by

chlorination with POCl₃in the presence of a base

[21]. The compounds benzo[d]oxazole-2-thiol (2),

benzo[d]thiazole-2-thiol (3), and 1H-benzo[d]imidazole-

2-thiol (4) were prepared by the reaction of 2-

aminophenol/2-aminothiophenol/o-phenylenediamine with

CS₂in the presence of KOH in ethanol [22]. The

compounds benzo[d]oxazol-2-amine (5), benzo[d]

thiazol-2-amine (6), and 1H-benzo[d]imidazol-2-amine

(7) were obtained by the reaction of respective o-

disubstituted benzenes with cyanogen bromide in

ethanol [23–25]. The reaction of one equivalent of 1

with two equivalents of

2

in the presence of

methanesulfonic acid gave 4-(benzo[d]oxazol-2-ylthio)-

2-chloroquinazoline (8) instead of the expected 2,4-

bis(benzo[d]oxazol-2-ylthio)quinazoline (11). Similarly,

4-(benzo[d]thiazol-2-ylthio)-2-chloroquinazoline (9) and

4-(1H-benzo[d]imidazol-2-ylthio)-2-chloroquinazoline (10)

were obtained by treating one equivalent of 1 with

two equivalents of 3 and 4, respectively. The reaction

was found to be regiospeciﬁc. In the presence of two

equivalents

of

benzazole-2-thiol,

only

mono

thioheteroarylation takes place leading to 8–10 along

with unreacted benzazole-2-thiol, which was removed

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Vol 000

by column chromatography. The ¹H NMR spectra

Mechanism.

of 8a, 9a, and 10a displayed multiplets in the

regions δ 6.95–8.25, 6.97–8.28, and 6.70–8.23 for

aromatic protons. The compound 10a showed

a

broad singlet at 12.07 ppm because of NH, which

disappeared on deutiration. The ¹³C NMR spectra of

8a, 9a, and 10a exhibited signals at δ 167.3, 168.3,

165.4 (C-4), 155.6, 157.6, 154.2 (C-2), 156.2, 171.7,

150.4 ppm (C-2⁰) in addition to the signals of

aromatic carbons. However, bisthioheteroarylation

takes place when the reaction was performed with

one equivalent of 1 and twofold excess of 2 in

the presence of methanesulfonic acid in ethanol,

which resulted in 2,4-bis(benzo[d]oxazol-2-ylthio)

quinazoline (11). Adopting similar methodology, 2,4-

bis(benzo[d]thiazol-2-ylthio)quinazoline (12) and 2,4-

bis(1H-benzo[d]imidazol-2-ylthio)quinazoline (13) were

prepared by the reaction of 1 with 3 and 4, respectively.

Under the aforementioned conditions, thioheteroarylation

takes place at positions 2 and 4 of quinazoline. The ‘N’ of

quinazoline activates the cites via quarternization as

shown in the mechanism. The¹H NMR spectra of 11a,

12a, and 13a exhibited multiplets in the regions δ

7.04–8.27, 6.88–8.29, and 6.72–8.24 because of

Antibacterial Studies.

The compounds 8–16 were

tested for antibacterial activity at three different

concentrations: 50, 75, and 100 μg/well. The results of

antibacterial activity presented in Table 1 and Figure 1

indicated that Gram-positive bacteria were more

susceptible toward the tested compounds than Gram-

negative ones. Among bis and tris heterocycles, the latter

compounds 11–16 displayed greater activity than 8–10.

Among tris heterocycles, those linked by two sulfur atoms

(11–13) showed higher activity than the corresponding

sulfur and amino-linked heterocycles (14–16). Further, it

was observed that bisbenzothiazolylquinazolines (12, 15)

and bisbenzimidazolylquinazolines (13, 16) exhibited

greater activity than bisbenzoxazolylquinazolines (11, 14).

The presence of electron-withdrawing chloro, bromo, and

nitro substituents on the aromatic ring increases the

activity. It was noticed that with increasing electro

negativity the activity also increased. In fact, the

compounds having nitro substituent 12f, 13f, and 15f

exhibited excellent activity against Staphylococcus aureus

greater than the standard drug, Chloramphenicol at all

tested concentrations. However, the compounds 12c, 13c,

15c, and 16f showed good activity against S. aureus. On

the other hand, the presence of electron-donating

substituents decreases the activity. In fact the methyl and

methoxy substituted compounds displayed less activity

than unsubstituted compounds, which may be due to +I

and +M effects. The structure-antibacterial activity of the

tested compounds revealed that the presence of

electronegative chloro, bromo, and nitro groups enhance

the biological potency, bioavailability, metabolic stability,

and lipophilicity. In fact, the increase in absorption and

transportation of molecules within the biological system

depends upon the lipophilicity.

aromatic protons. Moreover, 13a showed

a broad

singlet at 11.90 ppm because of NH, which disappeared

on deutiration. The ¹³C NMR spectra of 11a, 12a, and

13a exhibited signals at δ 156.6, 157.3, 154.2 (C-4),

162.1, 164.3, 160.1 (C-2) and 155.2, 160.7, 150.2 ppm

(C-2⁰) besides the signals of aromatic carbons. The

compounds 8, 9, and 10 were also utilized to prepare

tris heterocycles linked by two different heteroatoms by

nucleophilic displacement of chlorine at position 2 with

appropriate heteroaryl amines. The compound 8 was

treated with 5 in the presence of concentrated HCl in

dry ethanol to obtain sulfanyl and amino-linked tris

heterocycles-N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-

2-ylthio)quinazolin-2-amine (14). Likewise, N-(benzo[d]

thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)quinazolin-2-amine

(15) and N-(1H-benzo[d]imidazol-2-yl)-4-(1H-benzo[d]

imidazol-2-ylthio)quinazolin-2-amine (16) were prepared

by the reaction of 9 with 6 and 10 with 7 (Scheme 1).

The ¹H NMR spectra of 14a, 15a, and 16a displayed

a broad singlet at δ 9.05, 9.02, 8.95 ppm because of

NH in addition to the signals of aromatic protons. The

compound 16a showed another broad singlet at 12.08

because of NH of benzimidazole. The signals of highly

acidic protons disappeared on deutiration. The ¹³C

NMR spectra of 14a, 15a, and 16a exhibited signals at

δ 158.6, 159.3, 156.4 (C-4), 174.2, 175.4, 173.2 (C-2),

160.2, 167.7, 155.3 ppm (C-2⁰) apart from the signals

of aromatic carbons. All the new compounds were

further characterized by IR, mass, and elemental

analysis.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

Scheme 1. Synthesis of sulfur and/or nitrogen linked bis and tris heterocycles.

Table 1

The in vitro antibacterial activity of compounds 8–16.

Diameter of zone of inhibition (mm)

Gram-positive

Staphylococcus aureus Bacillus substilis

Gram-negative

Pseudomonas aeruginosa Klebsiella pneumoniae

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

Compound

8a

8b

8c

8d

8e

8f

9a

9b

9c

9d

9e

9f

10a

10b

10c

10d

10e

10f

11a

11b

11c

11d

11e

11f

12a

12b

12c

12d

12e

—

9

—

10

—

12

—

10

—

11

12

20

22

—

8

10

—

12

—

12

13

—

15

—

10

11

—

13

—

8

—

10

—

9

—

8

10

—

15

—

12

16

—

11

12

—

18

10

15

19

—

8

—

9

—

11

—

8

—

10

12

13

16

2

1

—

9

10

—

12

—

2

1

2

1

8

—

1

2

1

2

1

2

—

9

—

13

—

11

14

—

10

2

9

—

1

2

9

—

2

—

1

2

—

9

10

12

—

17

14

21

22

—

10

—

10

11

14

—

16

14

22

23

8

9

—

9

2

1

2

1

2

1

2

1

2

9

2

1

11

1

2

1

2

1

10

18

21

—

14

23

25

1

2

1

11

12

15

—

13

14

17

8

9

11

—

2

1

2

1

2

1

—

10

25

20

30

31

11

14

2

1

3

2

1

12

27

23

31

33

12

17

1

2

3

2

1

12

21

17

25

26

1

2

1

2

10

19

16

24

25

9

1

2

1

2

23

1

2

1

2

1

2

1

2

19

2

1

2

1

2

14

2

1

2

1

3

1

2

1

18

27

29

8

15

23

24

—

11

12

18

20

—

9

2

—

14

12

1

—

2

10

13

(Continued)

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Vol 000

Table 1

(Continued)

Diameter of zone of inhibition (mm)

Gram-positive

Staphylococcus aureus Bacillus substilis

Gram-negative

Pseudomonas aeruginosa Klebsiella pneumoniae

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

50

(μg/

well)

75

(μg/

well)

100

(μg/

well)

Compound

12f

13a

13b

13c

13d

13e

13f

14a

14b

14c

14d

14e

14f

15a

15b

15c

15d

15e

15f

16a

16b

16c

16d

16e

35

17

26

28

—

10

33

9

13

15

—

1

2

1

38

2

1

2

3

1

2

41

2

1

2

28

1

2

1

31

2

1

2

34

2

1

3

1

18

—

13

—

1

20

—

10

15

—

1

23

3

26

2

1

27

3

2

1

2

30

2

1

2

1

18

28

32

9

11

36

10

14

16

20

30

34

11

13

40

12

17

18

12

18

20

—

27

—

10

12

—

13

10

16

18

14

21

22

15

23

25

9

14

18

—

1

2

10

15

19

—

24

—

9

10

—

11

12

15

12

18

21

14

20

24

8

10

29

10

12

14

1

2

1

—

2

1

9

29

9

11

13

—

16

1

2

12

32

11

14

15

—

18

1

2

—

19

8

26

8

10

12

—

15

2

1

2

1

17

1

22

2

—

12

—

16

—

8

—

10

14

—

18

—

9

11

—

14

27

—

1

2

—

19

—

10

20

17

29

32

11

37

16

26

28

9

2

1

3

1

2

1

2

1

2

9

17

14

17

21

2

1

2

17

1

2

1

2

3

1

2

3

2

1

2

1

2

1

2

1

2

9

1

2

1

2

14

25

27

—

16

26

30

9

10

34

13

24

25

12

17

22

15

19

24

10

13

16

—

20

—

12

13

—

12

14

18

1

2

1

—

8

22

8

12

15

—

17

32

2

1

2

1

10

24

10

14

16

1

2

1

12

28

12

15

18

2

1

2

1

8

20

9

10

12

—

17

38

2

1

9

22

12

15

—

19

40

1

2

1

11

24

13

14

8

9

21

42

2

3

32

1

2

1

2

1

11

21

23

—

2

1

9

—

12

25

—

8

27

33

1

2

1

10

29

35

9

20

34

1

3

11

23

38

1

2

1

—

18

30

16f

24

30

1

3

1

3

1

2

3

1

2

Chloramphenicol

Em dash (—) means no activity; “ ” indicates standard deviation.

Figure 1. The in vitro antibacterial activity of compounds 8–16.

The minimum inhibitory concentration (MIC) and

minimum bactericidal concentration (MBC) values of the

compounds tested are listed in Table 2. MIC is the lowest

concentration of an antimicrobial that will inhibit the

visible growth of a microorganism. (But it is not sure that

the microorganisms are completely killed.) The MBC is

the lowest concentration of antibiotic required to kill a

particular bacterium. The MBC involves an additional set

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

Table 2

MIC and MBC of compounds 12c, 12f, 13c, 13f, 15c, 15f, and 16f.

Minimum inhibitory concentration MIC (MBC) μg/well

Compound

Staphylococcus aureus

Bacillus subtilis

Pseudomonas aeruginosa

Klebsiella pneumoniae

12c

12f

13c

13f

15c

15f

16f

12.5 (50)

6.25 (12.5)

12.5 (50)

6.25 (12.5)

12.5 (50)

6.25 (12.5)

25 (100)

6.25

100 (>200)

12.5 (50)

100 (>200)

12.5 (50)

100 (>2000)

50 (200)

100 (>200)

6.25

—

50 (200)

—

50 (200)

—

100 (>200)

—

100 (>200)

—

200 (>200)

—

100 (>200)

—

Chloramphenicol

Ketoconazole

6.25

—

12.5

—

Em dash (—) means no activity.

of steps performed once the MIC is determined. The

antimicrobials are usually regarded as bactericidal if

the MBC is not greater than four times the MIC [26].

The compounds 12f, 13f, and 15f exhibited low MIC

values in case of S. aureus. In fact, in these compounds,

the MBC value is 2xMIC against S. aureus.

2,4-dichloroquinazoline(1) [20], benzo[d]oxazole-2-thiol

(2) [25], benzo[d]thiazole-2-thiol (3) [25] and 1H-

benzo[d]imidazole-2-thiol(4) [25], benzoxazol-2-amine

(5) [26], benzothiazol-2-amine (6) [27], and 1H-

benzimidazol-2-amine (7) [28] were prepared by adopting

the literature precedents.

General

2-chloroquinazoline

procedure. 4-(Benzo[d]oxazol-2-ylthio)-

(8a–f)/4-(benzo[d]thiazol-2-ylthio)-2-

CONCLUSIONS

chloroquinazoline (9a–f)/4-(1H-benzo[d]imidazol-2-ylthio)

-2-chloroquinazoline (10a–f).

A

mixture of 2,4-

The

bis

and

tris

heterocycles-benzoxazolyl/

dichloroquinazoline (1) (1 mmol), benzoxazole-2-thiol

(2)/benzothiazole-2-thiol (3)/1H-benzimidazole-2-thiol (4)

(2 mmol), dry ethanol (10 mL), and a catalytic amount of

methanesulfonic acid (0.3 mL) was reﬂuxed for 3–5 h.

The contents of the ﬂask were cooled and diluted with

water (20 mL). The separated solid was ﬁltered, washed

with water, and dried. It was puriﬁed by column

chromatography (silica gel, 60–120 mesh) using hexane-

ethyl acetate (3:1) as eluent.

4-(Benzo[d]oxazol-2-ylthio)-2-chloroquinazoline (8a). Yield

68%; mp 146–148°C; IR (KBr): 1564 (C═N), 1598, 1487,

benzothiazolyl/benzimidazolyl quinazolines linked by

sulfur and/or nitrogen were prepared from 2,4-

dichloroquinazoline and benzazolyl-2-thiol/ bezazolyl-2-

amine adopting simple and versatile synthetic

methodologies and tested for their antibacterial

activity. The nitro-substituted sulfur linked bisbenzo-

thiazolylquinazoline (12f), bisbenzimidazolylquinazoline

(13f), and sulfur and nitrogen-linked bisbenzo-

thiazolylquinazoline (15f) are the potential antibacterial

agents against S. aureus.

1466 (Ar, C═C) cm^ꢀ1; ¹H-NMR (400 MHz, DMSO-d₆): δ

6.95–8.25 (m, 8H, Ar─H) ppm; ¹³C-NMR (100 MHz,

DMSO-d₆): δ 167.3 (C-4), 156.2 (C-2⁰), 155.6 (C-2),

153.4, 150.6, 138.7, 132.4, 131.2, 128.6, 127.1, 126.2,

125.6, 124.5, 111.3, 109.3 (aromatic carbons) ppm; MS:

(m/z): 313.76 [M⁺]. Anal. Calcd for C₁₅H₈ClN₃OS: C,

57.42; H, 2.57; N, 13.39; found: C, 57.49; H, 2.59; N,

EXPERIMENTAL

Melting points were determined in open capillaries on a

Mel-Temp apparatus and are uncorrected. The purity of the

compounds was checked by TLC (silica gel H, BDH, ethyl

acetate/hexane, 1:3). The IR spectra were recorded on a

Thermo Nicolet IR 200 FTIR spectrometer as KBr

pellets, and the wave numbers were given in cm^ꢀ1. The

¹H and ¹³C NMR spectra were recorded in DMSO-d₆on

13.54%.

4-(Benzo[d]oxazol-2-ylthio)-6-bromo-2-chloroquinazoline

(8b). Yield 65%; mp 162–164°C; IR (KBr): 1568 (C═N)

1

1601, 1447, 1450 (Ar, C═C) cm^ꢀ1; H-NMR (400 MHz,

a

Bruker-400 spectrometer operating at 400 and

DMSO-d₆): δ 7.02–8.28 (m, 7H, Ar─H)ppm ; ¹³C-NMR

(100 MHz, DMSO-d₆): δ 168.3 (C-4), 157.5 (C-2⁰),

156.2 (C-2), 150.2, 149.3, 136.5, 131.6, 128.4, 127.4,

124.3, 123.6, 122.6, 120.3, 110.4, 109.5 (aromatic

carbons) ppm; MS: (m/z): 392.66 [M⁺]. Anal. Calcd for

C₁₅H₇BrClN₃OS: C, 45.88; H, 1.80; N, 10.70; found: C,

45.99; H, 1.83; N, 10.87%.

100 MHz, respectively. All chemical shifts are reported

in δ (ppm) using TMS as an internal standard. The

mass spectra were recorded on Jeol JMS-D 300 and

Finnigan Mat 1201 B at 70 eV with an emission current

of 100 μA. The microanalyses were performed on a

Perkin-Elmer 240C elemental analyzer. The compounds

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Vol 000

4-(Benzo[d]oxazol-2-ylthio)-2,6-dichloroquinazoline (8c). Yield

68%; mp 153–155°C; IR (KBr): 1576 (C═N), 1610, 1470,

1441 (Ar, C═C) cm^ꢀ1; ¹H-NMR (400 MHz, DMSO-d₆): δ

7.12–8.34 (m, 7H, Ar─H) ppm; ¹³C-NMR (100 MHz,

DMSO-d₆): δ 169.3 (C-4), 158.7 (C-2⁰), 157.2 (C-2),

151.3, 150.5, 134.3, 132.4, 131.2, 130.6, 128.2, 127.4,

126.3, 124.2, 111.3, 110.9 (aromatic carbons) ppm; MS:

(m/z): 348.21 [M⁺]. Anal. Calcd for C₁₅H₇Cl₂N₃OS: C,

51.74; H, 2.03; N, 12.07; found: C, 51.83; H, 2.02; N,

12.19%.

(100 MHz, DMSO-d₆): δ 172.3 (C-2⁰),169.2 (C-4), 158.4

(C-2), 152.4, 150.3, 137.5, 132.5, 129.2, 128.4, 126.4,

123.3, 122.4, 121.4, 120.4, 118.4 (aromatic carbons) ppm;

MS: (m/z): 408.72 [M⁺]. Anal. Calcd for C₁₅H₇BrClN₃S₂:

C, 44.08; H, 1.75; N, 10.28; found: C, 44.15; H, 1.74; N,

10.40%.

4-(Benzo[d]thiazol-2-ylthio)-2,6-dichloroquinazoline (9c). Yield

75%; mp 172–174°C; IR (KBr): 1584 (C═N), 1576, 1445,

1436 (Ar, C═C) cm^ꢀ1; ¹H NMR (400 MHz, DMSO-d₆): δ

7.08–8.35 (m, 7H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 173.5(C-2⁰), 170.4(C-4), 159.5 (C-2),

154.3, 150.3, 137.2, 135.3, 132.2, 131.4, 130.2, 128.2,

126.1, 124.7, 123.4, 122.1 (aromatic carbons) ppm; MS:

(m/z): 364.27 [M⁺]. Anal. Calcd for C₁₅H₇Cl₂N₃S₂: C,

49.46; H, 1.94; N, 11.54; found: C, 49.38; H, 1.98; N,

11.45%.

4-(Benzo[d]oxazol-2-ylthio)-2-chloro-6-methylquinazoline (8d).

Yield 63%; mp 134–136°C; IR (KBr): 1558 (C═N), 1610,

;

1467, 1438 (Ar, C═C) cm^ꢀ^{1 1}H-NMR (400 MHz,

DMSO-d₆): δ 7.02–8.13 (m, 7H, Ar─H), 2.42 (s, 3H,

Ar─CH₃) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ 166.1

(C-4), 155.4 (C-2⁰), 154.3 (C-2), 25.1 (CH₃), 148.4, 147.3,

137.6, 132.4, 131.5, 130.1, 129.3, 127.2, 123.8, 123.2,

111.5, 108.4 (aromatic carbons) ppm; MS: (m/z): 327.79

[M⁺]. Anal. Calcd for C₁₆H₁₀ClN₃OS: C, 58.63; H, 3.07;

N, 12.82; found: C, 58.75; H, 3.11; N, 13.00%.

4-(Benzo[d]thiazol-2-ylthio)-2-chloro-6-methylquinazoline (9d).

Yield 71%; mp 156–158°C; IR (KBr): 1564 (C═N), 1602,

1490, 1466 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 6.88–8.20 (m, 7H, Ar─H), 2.36 (s, 3H,

Ar─CH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 170.4

(C-2⁰), 167.1 (C-4), 156.2 (C-2), 25.3 (CH₃), 152.4, 148.4,

138.3, 136.4, 131.1, 130.6, 130.3, 128.4, 124.5, 123.4,121.3,

120.1 (aromatic carbons) ppm; MS: (m/z): 343.85 [M⁺].

Anal. Calcd for C₁₆H₁₀ClN₃S₂: C, 55.89; H, 2.93; N, 12.22;

found: C, 56.00; H, 2.96; N, 12.38%.

4-(Benzo[d]oxazol-2-ylthio)-2-chloro-6-methoxyquinazoline (8e).

Yield 69%; mp 130–131°C; IR (KBr): 1554 (C═N), 1589,

1480, 1423 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 6.98–8.22 (m, 7H, Ar─H), 3.78 (s, 3H,

Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 165.6

(C-4), 154.6 (C-2⁰), 153.2 (C-2), 54.6 (OCH₃), 158.6,

147.6, 144.7, 129.6, 127.2, 126.3, 125.2, 123.2, 121.4,

109.3, 108.3, 107.4 (aromatic carbons) ppm; MS: (m/z):

343.79 [M⁺]. Anal. Calcd for C₁₆H₁₀ClN₃O₂S: C, 55.90; H,

2.93; N, 12.22; found: C, 56.00; H, 2.94; N, 12.15%.

4-(Benzo[d]thiazol-2-ylthio)-2-chloro-6-methoxyquinazoline

(9e).

Yield 76%; mp 165–166°C; IR (KBr): 1558

(C═N), 1604, 1467, 1456 (Ar, C═C) cm^ꢀ1; H NMR

(400 MHz, DMSO-d₆): δ 6.85–8.22 (m, 7H, Ar─H), 3.82

(s, 3H, Ar─OCH₃) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 168.1 (C-2⁰), 166.4 (C-4), 155.4 (C-2),

55.2 (OCH₃), 159.6, 150.1, 145.2, 130.4, 128.4, 127.3,

126.2, 124.6, 119.6, 118.4, 116.8, 108.3 (aromatic

carbons) ppm; MS: (m/z): 359.85 [M⁺]. Anal. Calcd for

C₁₆H₁₀ClN₃OS₂: C, 53.40; H, 2.80; N, 11.68; found: C,

53.46; H, 2.79; N, 11.58%.

1

4-(Benzo[d]oxazol-2-ylthio)-2-chloro-6-nitroquinazoline (8f).

Yield 70%; mp 157–158°C; IR (KBr): 1582 (C═N), 1602,

;

1493,1445 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

DMSO-d₆): δ 7.16–8.42 (m, 7H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 169.3 (C-2), 167.4 (C-4), 158.6

(C-2⁰), 151.7, 150.3, 146.3, 133.4, 129.7, 128.1, 127.3,

124.1, 123.4, 121.2, 113.1, 112.1 (aromatic carbons)

ppm; MS: (m/z): 358.76 [M⁺]. Anal. Calcd for

C₁₅H₇ClN₄O₃S: C, 50.22; H, 1.97; N, 15.62; found: C,

50.34; H, 1.96; N, 15.80%.

4-(Benzo[d]thiazol-2-ylthio)-2-chloro-6-nitroquinazoline

(9f).

Yield 78%; mp 169–171°C; IR (KBr): 1592 (C═N), 1578,

1498, 1471 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 7.12–8.31 (m, 7H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 174.0 (C-2⁰), 160.8 (C-2), 160.6

(C-4), 154.5, 152.5, 147.2, 133.6, 130.4, 129.5, 127.6,

124.3, 123.9, 122.8, 121.2, 119.5 (aromatic carbons) ppm;

MS: (m/z): 374.82 [M⁺]. Anal. Calcd for C₁₅H₇ClN₄O₂S₂:

C, 48.07; H, 1.88; N, 14.95; found: C, 48.15; H, 1.90; N,

15.13%.

4-(Benzo[d]thiazol-2-ylthio)-2-chloroquinazoline (9a). Yield

72%; mp 160–162°C; IR (KBr): 1572 (C═N), 1603, 1499,

1466 (Ar, C═C) cm^ꢀ1; ¹H NMR (400 MHz, DMSO-d₆): δ

6.97–8.28 (m, 8H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 171.7 (C-2⁰), 168.3 (C-4), 157.6 (C-2),

154.8, 153.4, 139.5, 137.3, 132.4, 128.7, 127.4, 126.6,

125.4, 124.2, 123.1, 122.6 (aromatic carbons) ppm; MS:

(m/z): 329.83 [M⁺]. Anal. Calcd for C₁₅H₈ClN₃S₂: C,

54.62; H, 2.44; N, 12.74; found: C, 54.70; H, 2.46; N,

4-(1H-Benzo[d]imidazol-2-ylthio)-2-chloroquinazoline (10a).

Yield 73%; mp 149–150°C; IR (KBr): 3273 (NH),1563

1

(C═N), 1607, 1493, 1466 (Ar, C═C) cm^ꢀ1; H NMR

12.58%.

4-(Benzo[d]thiazol-2-ylthio)-6-bromo-2-chloroquinazoline (9b).

(400 MHz, DMSO-d₆): δ 12.07 (bs, 1H, Imidazole-NH),

6.70–8.23 (m, 8H, Ar-H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 165.4 (C-4),154.2 (C-2), 150.4 (C-2⁰),

151.5, 137.2, 131.2, 130.7, 126.3, 125.6, 125.4, 121.6,

Yield 73%; mp 178–180°C; IR (KBr): 1578 (C═N), 1593,

1478, 1460 (Ar, C═C) cm^{ꢀ1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 7.01–8.25 (m, 7H, Ar─H) ppm; ¹³C NMR

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

109.5 (aromatic carbons) ppm; MS: (m/z): 312.78 [M⁺].

Anal. Calcd for C₁₅H₉ClN₄S: C, 57.60; H, 2.90; N,

17.91; found: C, 57.67; H, 2.89; N, 18.04%.

4-(1H-Benzo[d]imidazol-2-ylthio)-6-bromo-2-chloroquinazolin

General

procedure. 2,4-Bis(benzo[d]oxazol-2-ylthio)

quinazoline (11a–f)/2,4-bis(benzo[d]thiazol-2-ylthio)quinazoline

(12a–f)/2,4-bis(1H-benzo[d]imidazol-2-ylthio)quinazoline (13a–f).

To a solution of 2,4-dichloroquinazoline (1) (1.0 mmol),

benzoxazole-2-thiol

(2)/benzothiazole-2-thiol

(3)/1H-

(10b). Yield 66%; mp 176–178°C; IR (KBr): 3279 (NH),

1569 (C═N), 1589, 1467, 1437 (Ar, C═C) cm^ꢀ^{1 1}H

;

benzimidazole-2-thiol (4) (4 mmol) in dry ethanol (15 mL),

a catalytic amount of methanesulfonic acid (0.6 mL) was

added and reﬂuxed for 3–5 h. The contents of the ﬂask

were cooled and diluted with water (25 mL). The separated

solid was ﬁltered, washed with water, dried, and

recrystallized from 2-propanol.

NMR (400 MHz, DMSO-d₆): δ 12.15 (bs, 1H, Imidazole-

NH),6.75–8.29 (m, 7H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 166.2 (C-4), 155.7 (C-2), 152.7

(C-2⁰), 148.9, 135.4, 132.6, 127.6, 126.8, 122.4, 120.2,

119.3, 109.5 (aromatic carbons) ppm; MS: (m/z): 391.67

[M⁺]. Anal. Calcd for C₁₅H₈BrClN₄S: C, 46.00; H, 2.06;

2,4-Bis(benzo[d]oxazol-2-ylthio)quinazoline (11a).

Yield

64%; mp 156–158°C; IR (KBr): 1567 (C═N), 1567,

¹H NMR (400 MHz,

N, 20.40; found: C, 46.09; H, 2.09; N, 20.28%.

4-(1H-Benzo[d]imidazol-2-ylthio)-2,6-dichloroquinazoline

1474, 1456 (Ar, C═C) cm^ꢀ1

;

DMSO-d₆): δ 7.04–8.27 (m, 12H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 162.1 (C-2), 156.6 (C-4),

155.2 (C-2⁰), 152.6, 148.4, 137.3, 131.1, 130.2, 127.6,

126.1, 125.6, 124.5, 123.2, 110.1, 108.4 (aromatic

carbons) ppm; MS: (m/z): 428.49 [M⁺]. Anal. Calcd for

C₂₂H₁₂N₄O₂S₂: C, 61.67; H, 2.82; N, 13.08; found: C,

(10c). Yield 76%; mp 157–159°C; IR (KBr): 3286 (NH),

1576 (C═N), 1578, 1478, 1456 (Ar, C═C) cm^ꢀ^{1 1}H

;

NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H, Imidazole-

NH),6.79–8.32 (m, 7H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 167.4 (C-4), 156.6 (C-2), 154.3

(C-2⁰), 148.6, 132.6, 130.6, 129.7, 128.6, 127.6, 126.4,

122.8, 110.8 (aromatic carbons) ppm; MS: (m/z): 347.22

[M⁺]. Anal. Calcd for C₁₅H₈Cl₂N₄S: C, 51.89; H, 2.32;

61.78; H, 2.84; N, 13.21%.

2,4-Bis(benzo[d]oxazol-2-ylthio)-6-bromoquinazoline (11b).

Yield 65%; mp 185–187°C; IR (KBr): 1572 (C═N),

N, 16.14; found: C, 52.00; H, 2.34; N, 16.29%.

4-(1H-Benzo[d]imidazol-2-ylthio)-2-chloro-6-methylquinazoline

1

1565, 1467, 1451 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

DMSO-d₆): δ 7.06–8.31 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 163.8 (C-2), 157.2 (C-4),

156.4 (C-2⁰), 151.2, 150.1, 136.3, 132.4, 131.3, 127.4,

125.2, 124.3, 122.5, 121.2, 111.2, 110.9 (aromatic

carbons) ppm; MS: (m/z): 507.38 [M⁺]. Anal. Calcd for

(10d). Yield 74%; mp 136–138°C; IR (KBr): 3270 (NH),

1558 (C═N), 1589, 1497, 1460 (Ar, C═C) cm^ꢀ^{1 1}H

;

NMR (400 MHz, DMSO-d₆): δ 12.02 (bs, 1H, Imidazole-

NH), 6.74–8.13 (m, 7H, Ar─H), 2.44 (s, 3H, Ar─CH₃)

ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 23.6 (CH₃),

149.2 (C-2⁰), 153.4 (C-2), 164.5 (C-4), 147.6, 134.2,

131.5, 130.4, 129.5, 128.4, 126.3, 119.8, 109.4 (aromatic

carbons) ppm; MS: (m/z): 326.80 [M⁺]. Anal. Calcd for

C₁₆H₁₁ClN₄S: C, 58.80; H, 3.39; N, 17.14; found: C,

C₂₂H₁₁BrN₄O₂S₂: C, 52.08; H, 2.19; N, 11.04; found: C,

52.19; H, 2.22; N, 10.93%.

2,4-Bis(benzo[d]oxazol-2-ylthio)-6-chloroquinazoline (11c).

Yield 66%; mp 168–170°C; IR (KBr): 1580 (C═N),

1

58.72; H, 3.42; N, 17.26%.

4-(1H-Benzo[d]imidazol-2-ylthio)-2-chloro-6-methoxyquinazoline

1571, 1472, 1443 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

DMSO-d₆): δ 7.08–8.36 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 164.4 (C-2), 158.4 (C-4),

157.7 (C-2⁰), 149.1, 148.2, 133.2, 132.1, 130.6, 129.5,

128.6, 126.4, 125.1, 123.8, 110.9, 109.1 (aromatic

carbons) ppm; MS: (m/z): 462.93 [M⁺]. Anal. Calcd for

C₂₂H₁₁ClN₄O₂S₂: C, 57.08; H, 2.40; N, 12.10; found: C,

(10e). Yield 71%; mp 141–143°C; IR (KBr): 3264 (NH),

1552 (C═N), 1587, 1489, 1470 (Ar, C═C) cm^ꢀ^{1 1}H

;

NMR (400 MHz, DMSO-d₆): δ 11.97 (bs, 1H, Imidazole-

NH), 6.67–8.18 (m, 7H, Ar─H), 3.73 (s, 3H, Ar─OCH₃)

ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 163.1 (C-4),

152.5 (C-2), 147.1 (C-2⁰), 52.4 (OCH₃), 157.5, 143.4,

130.1, 126.7, 125.4, 124.5, 120.1, 108.1, 106.2 (aromatic

carbons) ppm; MS: (m/z): 342.80 [M⁺]. Anal. Calcd for

C₁₆H₁₁ClN₄OS: C, 56.06; H, 3.23; N, 16.34; found: C,

57.16; H, 2.38; N, 12.23%.

2,4-Bis(benzo[d]oxazol-2-ylthio)-6-methylquinazoline (11d).

Yield 63%; mp 140–142°C; IR (KBr): 1562 (C═N),

1

1579, 1480, 1445 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

56.12; H, 3.20; N, 16.22%.

4-(1H-Benzo[d]imidazol-2-ylthio)-2-chloro-6-nitroquinazoline

DMSO-d₆): δ 7.02–8.23 (m, 11H, Ar─H),2.63 (s, 3H,

Ar─CH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

161.6 (C-2), 155.3 (C-4), 154.2 (C-2⁰), 24.5 (CH₃),

147.8, 146.4, 136.7, 132.3, 130.6, 129.3, 128.1, 126.7,

124.1, 122.8, 110.9, 107.8 (aromatic carbons) ppm; MS:

(m/z): 442.51 [M⁺]. Anal. Calcd for C₂₃H₁₄N₄O₂S₂: C,

62.43; H, 3.19; N, 12.66; found: C, 62.50; H, 3.21; N,

(10f). Yield 77%; mp 163–165°C; IR (KBr): 3292 (NH),

1583 (C═N), 1607, 1493, 1466 (Ar, C═C) cm^ꢀ^{1 1}H

;

NMR (400 MHz, DMSO-d₆): δ 12.28 (bs, 1H, Imidazole-

NH), 6.85–8.36 (m, 7H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 168.4 (C-4), 158.5 (C-2), 155.6

(C-2⁰), 150.2, 145.6, 133.4, 128.6, 127.2, 123.2, 122.6,

120.2, 110.3 (aromatic carbons) ppm; MS: (m/z): 357.77

[M⁺]. Anal. Calcd for C₁₅H₈ClN₅O₂S: C, 50.36; H, 2.25;

N, 19.57; found: C, 50.43; H, 2.27; N, 19.70%.

12.80%.

4-(1H-Benzo[d]imidazol-2-ylthio)-2-chloro-6-methoxyquinazoline

(11e). Yield 62%; mp 162–164°C; IR (KBr): 1558 (C═N),

1

1553, 1445, 1430 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Vol 000

DMSO-d₆): δ 6.97–8.18 (m, 11H, Ar─H), 3.81 (s, 3H,

Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 159.2

(C-2), 153.3 (C-4), 152.6 (C-2⁰), 55.3 (OCH₃), 158.2, 148.6,

146.2, 132.1, 130.3, 127.4, 126.1, 124.1, 122.3, 109.3, 108.7,

106.3 (aromatic carbons) ppm; MS:(m/z): 458.51[M⁺]. Anal.

Calcd for C₂₃H₁₄N₄O₃S₂: C, 60.25; H, 3.08; N, 12.22;

found: C, 60.33; H, 3.10; N, 12.36%.

58.20; H, 2.97; N, 11.80; found: C, 58.31; H, 2.95; N,

11.92%.

2,4-Bis(benzo[d]thiazol-2-ylthio)-6-methoxyquinazoline

(12e).

Yield 64%; mp 176–178°C; IR (KBr): 1562 (C═N), 1570,

1471, 1452 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 6.86–8.16 (m, 11H, Ar─H),3.85 (s, 3H,

Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 161.5

(C-2), 156.2 (C-2⁰), 154.6 (C-4), 56.3 (OCH₃), 159.8,

151.2, 147.3, 133.2, 131.2, 128.4, 127.6, 125.3, 120.3,

119.3, 118.1, 108.2 (aromatic carbons) ppm; MS: (m/z):

490.64 [M⁺]. Anal. Calcd for C₂₃H₁₄N₄OS₄: C, 56.30; H,

2,4-Bis(benzo[d]oxazol-2-ylthio)-6-nitroquinazoline (11f). Yield

69%; mp 178–180°C; IR (KBr): 1586 (C═N), 1562, 1456,

1

1434 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆): δ

7.13–8.41 (m, 11H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 164.3 (C-2), 160.2 (C-4), 158.5 (C-2⁰), 153.2

152.1, 146.7, 134.2, 131.2, 128.2, 126.2, 125.4, 124.8, 123.2,

113.2, 112.3 (aromatic carbons) ppm; MS: (m/z): 473.48

[M⁺]. Anal. Calcd for C₂₂H₁₁N₅O₄S₂: C, 55.81; H, 2.34; N,

14.79; found: C, 55.91; H, 2.43; N, 14.65%.

2.88; N, 11.42; found: C, 56.40; H, 2.92; N, 11.53%.

2,4-Bis(benzo[d]thiazol-2-ylthio)-6-nitroquinazoline (12f). Yield

72%; mp 188–190°C; IR (KBr): 1596 (C═N), 1589, 1470,

1436 (Ar, C═C) cm^ꢀ1; ¹H NMR (400 MHz, DMSO-d₆): δ

7.03–8.43 (m, 11H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 166.2 (C-2), 165.3 (C-2⁰), 160.3 (C-4),

155.2, 153.2, 148.3, 134.1, 132.4, 129.3, 128.1, 125.4,

124.6, 123.2, 122.8, 120.5 (aromatic carbons) ppm; MS:

(m/z): 505.62 [M^+·]. Anal. Calcd for C₂₂H₁₁N₅O₂S₄: C,

52.26; H, 2.19; N, 13.85; found: C, 52.33; H, 2.18; N,

2,4-Bis(benzo[d]thiazol-2-ylthio)quinazoline (12a). Yield

1

65%; mp 174–176°C; IR (KBr): 1576 (C═N) cm^ꢀ1; H

NMR (400 MHz, DMSO-d₆): δ 6.88–8.29 (m, 12H,

Ar─H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3

(C-2), 160.7 (C-2⁰), 157.3 (C-4), 153.4, 152.3, 138.6,

136.2, 131.5, 127.6, 126.5, 125.3, 124.5, 123.4, 122.1,

121.3 (aromatic carbons) ppm; MS: (m/z): 460.62 [M⁺].

Anal. Calcd for C₂₂H₁₂N₄S₄: C, 57.37; H, 2.63; N, 12.16;

found: C, 57.30; H, 2.64; N, 12.28%.

14.00%.

2,4-Bis(1H-benzo[d] imidazol-2-ylthio)quinazoline (13a). Yield

70%; mp 162–164°C; IR (KBr): 3305 (NH), 1567

1

(C═N), 1598, 1469, 1443 (Ar, C═C) cm^ꢀ1; H NMR

(400 MHz, DMSO-d₆): δ 11.90 (bs, 2H, Imidazole-NH),

6.72–8.24 (m, 12H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 160.1 (C-2), 154.2 (C-4), 150.2 (C-2⁰),

150.7 136.5, 132.6, 129.3, 125.3, 124.5, 123.4, 122.6,

110.3 (aromatic carbons) ppm; MS: (m/z): 426.52 [M⁺].

Anal. Calcd for C₂₂H₁₄N₆S₂: C, 61.95; H, 3.31; N, 19.70;

2,4-Bis(benzo[d]thiazol-2-ylthio)-6-bromoquinazoline (12b).

Yield 61%; mp 192–194°C; IR (KBr): 1582 (C═N),

1

1574, 1464, 1446 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

DMSO-d₆): δ 6.91–8.34 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 165.9 (C-2), 161.1 (C-

2⁰), 158.5 (C-4), 152.4, 152.1 137.6, 133.6, 132.7, 128.7,

127.21, 123.1, 122.3, 121.6, 120.8, 119.2 (aromatic

carbons) ppm; MS: (m/z): 539.51 [M⁺]. Anal. Calcd for

C₂₂H₁₁BrN₄S₄: C, 48.98; H, 2.06; N, 10.38; found: C,

49.07; H, 2.09; N, 10.55%.

found: C, 62.04; H, 3.32; N, 19.82%.

2,4-Bis(1H-benzo[d]imidazol-2-ylthio)-6-bromoquinazoline

(13b). Yield 67%; mp 181–183°C; IR (KBr): 3313(NH),

1573 (C═N), 1540, 1464, 1436 (Ar, C═C) cm^ꢀ^{1 1}H

;

NMR (400 MHz, DMSO-d₆): 11.96 (bs, 2H, Imidazole-

NH), 6.78–8.29 (m, 11H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 161.6 (C-2), 155.7 (C-4), 151.6

(C-2⁰), 150.1, 135.6, 133.2, 131.2, 126.7, 123.4, 121.2,

120.3, 110.3 (aromatic carbons) ppm; MS: (m/z): 505.41

[M⁺]. Anal. Calcd for C₂₂H₁₃BrN₆S₂: C, 52.28; H, 2.59;

2,4-Bis(benzo[d]thiazol-2-ylthio)-6-chloroquinazoline (12c).

Yield 68%; mp 183–185°C; IR (KBr): 1586 (C═N),

1

1561, 1472, 1430 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

DMSO-d₆): δ 6.96–8.36 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 166.2 (C-2), 163.2 (C-

2⁰), 159.8 (C-4), 153.1, 149.6, 136.8, 134.2, 131.4, 130.6,

129.6, 127.4, 125.2, 124.1, 122.8, 120.1 (aromatic

carbons) ppm; MS: (m/z): 495.06 [M⁺]. Anal. Calcd for

C₂₂H₁₁ClN₄S₄: C, 53.37; H, 2.24; N, 11.32; found: C,

53.45; H, 2.27; N, 11.4%.

N, 16.63; found: C, 52.30; H, 2.63; N, 16.81%.

2,4-Bis(1H-benzo[d]imidazol-2-ylthio)-6-chloroquinazoline

(13c).

Yield 75%; mp 171–173°C; IR (KBr): 3321

(NH), 1578 (C═N), 1567, 1474, 1456 (Ar, C═C)

cm^ꢀ^{1 1}H NMR (400 MHz, DMSO-d₆): δ 12.04 (bs,

;

2,4-Bis(benzo[d]thiazol-2-ylthio)-6-methylquinazoline (12d).

Yield 62%; mp 165–167°C; IR (KBr): 1568 (C═N),

2H, Imidazole-NH),6.81–8.34 (m, 11H, Ar─H) ppm;

¹³C NMR (100 MHz, DMSO-d₆): 162.1 (C-2), 156.6

(C-4), 153.1 (C-2⁰), 147.5, 133.5, 132.1, 129.4, 128.3,

127.6, 125.3, 123.5, 111.6 (aromatic carbons) ppm;

MS: (m/z): 460.96 [M⁺]. Anal. Calcd for

C₂₂H₁₃ClN₆S₂: C, 57.32, H, 2.84; N, 18.23; found: C,

57.39; H, 2.83; N, 18.34%.

1

1567, 1474, 1456 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz,

DMSO-d₆): δ 6.90–8.21 (m, 11H, Ar─H),2.65 (s, 3H,

Ar─CH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

163.1 (C-2), 159.2 (C-2⁰), 156.3 (C-4), 26.5 (CH₃),

151.9, 147.6, 137.6, 135.8, 131.5, 130.4, 129.5, 127.5,

123.4, 122.3, 121.8, 120.6 (aromatic carbons) ppm; MS:

(m/z): 474.64 [M⁺]. Anal. Calcd for C₂₃H₁₄N₄S₄: C,

2,4-Bis(1H-benzo[d]imidazol-2-ylthio)-6-methylquinazoline

(13d).

Yield 69%; mp 144–145°C; IR (KBr): 3302

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

(NH), 1562 (C═N), 1570, 1470, 1430 (Ar, C═C) cm^ꢀ1

;

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)-6-

bromoquinazolin-2-amine (14b). Yield 64%; mp 174–176°

¹H NMR (400 MHz, DMSO-d₆): δ 11.88 (bs, 2H,

Imidazole-NH),6.76–8.15 (m, 11H, Ar─H), 2.42 (s, 3H,

Ar─CH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

159.5 (C-2), 153.5 (C-4), 149.2 (C-2⁰), 25.6 (CH₃),

145.6 135.4, 130.2, 129.3, 128.2, 127.3, 125.6, 120.3,

108.1 (aromatic carbons) ppm; MS: (m/z): 440.54 [M⁺].

Anal. Calcd for C₂₃H₁₆N₆S₂: C, 62.71; H, 3.66; N,

C; IR (KBr): 3288 (NH), 1563(C═N), 1607, 1484, 1466

(Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz, DMSO-d₆): δ

;

9.08 ( bs, 1H, NH), 7.12–8.33 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 175.8 (C-2), 161.2

(C-2⁰), 159.7 (C-4), 156.2 (C-2″), 149.6, 147.6, 146.3,

144.6, 135.4, 129.5, 128.6, 127.2, 126.2, 123.6, 122.3,

121.1, 119.2, 118.3, 117.6, 111.3, 108.6, 107.6 (aromatic

carbons) ppm; MS: (m/z): 490.33 [M⁺]. Anal. Calcd for

C₂₂H₁₂BrN₅O₂S: C, 53.89; H, 2.47; N, 14.28; found: C,

19.08; found: C, 62.81; H, 3.70; N, 19.25%.

2,4-Bis(1H-benzo[d]imidazol-2-ylthio)-6-methoxyquinazoline

(13e). Yield 74%; mp 150–152°C; IR (KBr): 3297 (NH),

1554 (C═N), 1580, 1470, 1456 (Ar, C═C) cm^ꢀ^{1 1}H

;

54.01; H, 2.49; N, 14.44%.

NMR (400 MHz, DMSO-d₆): δ 11.82 (bs, 2H, Imidazole-

NH), 6.71–8.09 (m, 11H, Ar─H), 3.75 (s, 3H,

Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

157.2 (C-2), 151.2 (C-4), 147.2 (C-2⁰), 53.5 (OCH₃),

157.3, 145.4, 132.4, 131.3, 126.2, 125.2, 121.3, 109.3,

105.6 (aromatic carbons) ppm; MS: (m/z): 456.54 [M⁺].

Anal. Calcd for C₂₃H₁₆N₆OS₂: C, 60.51; H, 3.53; N,

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)-6-

chloroquinazolin-2-amine (14c). Yield 69%; mp 166–168°

C; IR (KBr): 3294 (NH), 1572 (C═N), 1601, 1484, 1476

(Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz, DMSO-d₆): δ

;

9.12 ( bs, 1H, NH),7.16–8.37 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 177.2 (C-2), 163.8

(C-2⁰), 160.2 (C-4), 157.5 (C-2″), 150.2, 148.5, 146.2,

144.3, 133.4, 132.4, 129.2, 128.4, 127.2, 126.4, 125.2,

124.2, 123.1, 121.3, 116.2, 112.6, 111.4, 110.5 (aromatic

carbons) ppm; MS: (m/z): 445.88 [M⁺]. Anal. Calcd for

C₂₂H₁₂ClN₅O₂S: C, 59.26; H, 2.71; N, 15.71; found: C,

18.41; found: C, 60.58; H, 3.55; N, 18.54%.

2,4-Bis(1H-benzo[d]imidazol-2-ylthio)-6-nitroquinazoline (13f).

Yield 77%; mp 166–168°C; IR (KBr): 3226 (NH), 1587

(C═N), 1560, 1457, 1446 (Ar, C═C) cm^ꢀ^{1 1}H NMR

;

(400 MHz, DMSO-d₆): δ 12.12 (bs, 2H, Imidazole-NH),

6.81–8.34 (m, 11H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 163.4 (C-2), 156.2 (C-4), 153.3 (C-2⁰), 151.2

145.3, 134.2, 130.2, 127.3, 124.6, 123.4, 122.4, 111.5

(aromatic carbons) ppm; MS: (m/z): 471.51 [M⁺]. Anal.

Calcd for C₂₂H₁₃N₇O₂S₂: C, 56.04; H, 2.78; N, 20.79;

found: C, 55.90; H, 2.79; N, 20.92%.

59.39; H, 2.76; N, 15.89%.

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)-6-

methylquinazolin-2-amine (14d). Yield 65%; mp 158–160°C;

IR (KBr): 3278 (NH), 1554 (C═N), 1587, 1484, 1426 (Ar,

1

C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆): δ 9.01 (bs,

1H, NH),7.07–8.22 (m, 11H, Ar─H), 2.38 (s, 3H, Ar─CH₃)

ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 173.2 (C-2),

159.4 (C-2⁰), 157.5 (C-4), 154.1 (C-2″), 23.5 (CH₃), 148.6,

146.1, 144.3, 142.1, 134.5, 131.6, 130.4, 129.5, 125.4,

124.5, 123.6, 122.3, 121.4, 117.2, 114.6, 110.6, 109.4, 108.9

(aromatic carbons) ppm; MS: (m/z): 425.46 [M⁺]. Anal.

Calcd for C₂₃H₁₅N₅O₂S: C, 64.93; H, 3.55; N, 16.46; found:

C, 65.01; H, 3.58; N, 16.63%.

General procedure. N-(benzo[d]oxazol-2-yl)-4-(benzo[d]

oxazol-2-ylthio)quinazolin-2-amine (14a–f)/N-(benzo[d]thiazol-

2-yl)-4-(benzo[d]thiazol-2-ylthio)quinazolin-2-amine (15a–f)/4-

(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-yl)

quinazolin-2-amine (16a–f).

A

solution of 2-(2-

chloroquinazolin-4-ylthio)benzo[d]oxazole (8)/2-(2-

chloroquinazolin-4-ylthio)benzo[d]thiazole (9)/4-(1H-benzo[d]

imidazol-2-ylthio)-2-chloroquinazoline (10) (1 mmol) and

benzo[d]oxazol-2-amine (5)/benzo[d]thiazol-2-amine (6)/

1H-benzo[d]imidazol-2-amine (7) (2 mmol) in dry

ethanol (10 mL) was taken and to this a drop of

concentrated HCl was added and stirred at room

temperature for 8–10 h. The solid separated was ﬁltered,

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)-6-

methoxyquinazolin-2-amine (14e).

Yield 68%; mp 163–

165°C; IR (KBr): 3272 (NH), 1550 (C═N), 1597, 1484,

1

1476 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

δ 8.96 (bs, 1H, NH), 7.02–8.18 (m, 11H, Ar─H), 3.71 (s,

3H, Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆):

δ 171.3 (C-2), 171.3 (C-2), 157.5 (C-2⁰), 156.3 (C-4),

55.4 (OCH₃), 152.3 (C-2″), 153.4, 147.2, 146.3, 145.7,

142.5, 128.6, 127.3, 125.2, 124.6, 122.3, 121.3, 120.6,

119.3, 115.3, 109.5, 106.5, 105.2, 102.3 (aromatic

carbons) ppm; MS: (m/z): 441.46 [M^+·]. Anal. Calcd for

C₂₃H₁₅N₅O₃S: C, 62.58; H, 3.42; N, 15.86; found: C,

dried, and recrystallized from 2-propanol.

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)quinazolin-2-

amine (14a). Yield 66%; mp 160–162°C; IR (KBr): 3283

1

(NH), 1560 (C═N), 1556, 1474, 1456 (Ar, C═C) cm^ꢀ1; H

NMR (400 MHz, DMSO-d₆): δ 9.05 (bs, 1H, NH),7.07–8.28

(m, 12H, Ar─H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

174.2 (C-2), 160.2 (C-2⁰), 158.6 (C-4), 155.5 (C-2″), 151.4,

149.5, 145.6, 143.3, 133.5, 131.2, 128.4, 126.3, 125.7, 124.8,

123.7, 123.6, 122.5, 121.2, 115.1, 111.4, 110.1, 109.6

(aromatic carbons) ppm; MS: (m/z): 411.44 [M⁺]. Anal.

Calcd for C₂₂H₁₃N₅O₂S: C, 64.22; H, 3.18; N, 17.02; found:

C, 64.31; H, 3.21; N, 17.16%.

62.71; H, 3.47; N, 16.07%.

N-(benzo[d]oxazol-2-yl)-4-(benzo[d]oxazol-2-ylthio)-6-

nitroquinazolin-2-amine (14f). Yield 71%; mp 170–172°

C; IR (KBr): 3297 (NH), 1578 (C═N), 1604, 1467, 1445

(Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz, DMSO-d₆): δ

;

9.17 (bs, 1H, NH), 7.20–8.43 (m, 11H, Ar─H) ppm; ¹³C

NMR (100 MHz, DMSO-d₆): δ 178.3 (C-2), 163.9

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

L. Mallikarjuna Reddy, G. Lavanya, G. Lakshmi Teja, A. Padmaja, and V. Padmavathi

Vol 000

(C-2⁰), 162.5 (C-4), 158.5 (C-2″), 152.3, 150.6, 148.3,

146.1, 145.6, 131.5, 129.3, 128.6, 127.6, 126.3, 125.3,

124.3, 123.6, 119.2, 118.4, 112.5, 110.5, 109.3 (aromatic

carbons) ppm; MS: (m/z): 456.43 [M⁺]. Anal. Calcd for

C₂₂H₁₂N₆O₄S: C, 57.89; H, 2.65; N, 18.41; found: C,

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)-6-

methoxyquinazolin-2-amine (15e).

Yield 78%; mp 180–

182°C; IR (KBr): 3252 (NH), 1555 (C═N), 1597, 1487,

1

1435 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

δ 8.95 (bs, 1H, NH), 6.85–8.24 (m, 11H, Ar─H), 3.76 (s,

3H, Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆):

δ 172.3 (C-2), 164.6 (C-2⁰), 158.6 (C-2″), 157.5 (C-4),

56.3 (OCH₃), 154.5, 153.1, 150.4, 148.6, 130.2, 129.6,

128.5, 126.3, 124.9, 123.5, 121.4, 120.6, 119.3, 118.3,

117.1, 116.5, 115.2, 103.5 (aromatic carbons) ppm; MS:

(m/z): 473.59 [M⁺]. Anal. Calcd for C₂₃H₁₅N₅OS₃: C,

58.33; H, 3.19; N, 14.79; found: C, 58.27; H, 3.21; N,

58.00; H, 2.68; N, 18.59%.

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)quinazolin-

2-amine (15a).

Yield 77%; mp 171–173°C; IR (KBr):

3261 (NH), 1568 (C═N), 1596, 1484, 1443 (Ar, C═C)

1

cm^ꢀ1; H NMR (400 MHz, DMSO-d₆): δ 9.02 (bs, 1H,

NH),6.78–8.22 (m, 12H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): 175.4 (C-2), 167.7 (C-2⁰), 161.5

(C-2″), 159.3 (C-4), 153.4, 152.8, 151.3, 136.7, 134.6,

130.2, 129.2, 127.6, 126.4, 125.6, 124.9, 124.8, 123.4,

122.6, 121.3, 120.5, 119.3, 118.5 (aromatic carbons)

ppm; MS: (m/z): 443.57 [M⁺]. Anal. Calcd for

C₂₂H₁₃N₅S₃: C, 59.57; H, 2.95; N, 15.79; found: C,

14.87%.

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)-6-

nitroquinazolin-2-amine (15f). Yield 72%; mp 188–189°C;

IR (KBr): 3279 (NH), 1589 (C═N), 1592, 1478, 1463 (Ar,

C═C) cm^ꢀ1; ¹H NMR (400 MHz, DMSO-d₆): δ 9.17 (bs,

1H, NH), 6.92–8.37 (m, 11H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 180.2 (C-2), 170.2 (C-2⁰), 165.3

(C-2″), 163.5 (C-4), 156.8, 154.2, 153.6, 147.1, 133.6,

132.5, 129.5, 128.2, 127.4, 126.3, 125.6, 124.6, 123.6,

122.3, 121.5, 120.5, 119.2, 118.9 (aromatic carbons) ppm;

MS: (m/z): 488.56 [M⁺]. Anal. Calcd for C₂₂H₁₂N₆O₂S₃:

C, 54.08; H, 2.48; N, 17.20; found: C, 54.17; H, 2.46; N,

59.71; H, 2.91; N, 15.99%.

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)-6-

bromoquinazolin-2-amine (15b). Yield 76%; mp 190–192°C;

IR (KBr): 3268 (NH), 1575 (C═N), 1587, 1487, 1456 (Ar,

1

C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆): δ 9.07 (bs,

1H, NH), 6.85–8.27 (m, 11H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 176.2 (C-2), 168.4 (C-2⁰), 162.4

(C-2″), 160.1 (C-4), 155.3, 151.5, 150.4, 137.2, 132.6,

130.2, 128.6, 127.3, 126.4, 125.4, 123.6, 122.4, 121.5,

120.1, 119.8, 119.3, 118.4, 116.8 (aromatic carbons) ppm;

MS: (m/z): 522.46 [M⁺]. Anal. Calcd for C₂₂H₁₂BrN₅S₃: C,

50.57; H, 2.32; N, 13.40; found: C, 50.66; H, 2.34; N,

17.35%.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

yl)quinazolin-2-amine (16a). Yield 67%; mp 152–154°C;

IR (KBr): 3291 (NH), 1560 (C═N), 1605, 1484, 1472

(Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz, DMSO-d₆): δ

;

12.08 (bs, 2H, Imidazole-NH), 8.95 (bs, 1H, NH), 6.75–

8.29 (m, 12H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 173.2 (C-2), 156.4 (C-4), 155.3 (C-2⁰),

150.1 (C-2″), 150.5, 137.6, 133.4, 132.1, 127.5, 125.6,

122.3, 121.7, 120.3, 119.5, 111.2, 109.1 (aromatic

carbons) ppm; MS: (m/z): 409.47 [M⁺]. Anal. Calcd for

C₂₂H₁₅N₇S: C, 64.53; H, 3.69; N, 23.95; found: C,

13.57%.

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)-6-

chloroquinazolin-2-amine (15c). Yield 79%; mp 184–186°C;

IR (KBr): 3272 (NH), 1581 (C═N), 1587, 1484, 1435 (Ar,

C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆): δ 9.13 ( bs,

1

1H, NH), 6.89–8.35 (m, 11H, Ar─H) ppm; ¹³C NMR

(100 MHz, DMSO-d₆): δ 177.2 (C-2), 169.2 (C-2⁰), 163.1

(C-2″), 161.3 (C-4), 154.5, 153.2, 149.5, 137.6, 134.2,

131.5, 130.2, 129.6, 127.4, 126.7, 125.3, 124.5, 123.8,

123.4, 122.4, 121.6, 120.4, 119.5 (aromatic carbons) ppm;

MS: (m/z): 478.01 [M⁺]. Anal. Calcd for C₂₂H₁₂ClN₅S₃: C,

55.28; H, 2.53; N, 14.65; found: C, 55.24; H, 2.54; N,

64.68; H, 3.74; N, 24.16%.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

yl)-6-bromoquinazolin-2-amine (16b). Yield 72%; mp 185–

187°C; IR (KBr): 3296 (NH), 1565 (C═N), 1607, 1574,

1

1566 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

14.78%.

δ 12.12 (bs, 2H, Imidazole-NH), 9.00 (bs, 1H, NH),

6.78–8.32 (m, 11H, Ar─H)ppm ; ¹³C NMR (100 MHz,

DMSO-d₆): δ 174.3 (C-2), 157.5 (C-4), 156.3 (C-2⁰),

151.5 (C-2″), 147.2, 140.2, 133.6, 130.6, 128.4, 126.1,

122.4, 120.5, 118.3, 117.3, 115.3, 107.4 (aromatic

carbons) ppm; MS: (m/z): 488.36 [M⁺]. Anal. Calcd for

C₂₂H₁₄BrN₇S: C, 54.11; H, 2.89; N, 20.08; found: C,

N-(benzo[d]thiazol-2-yl)-4-(benzo[d]thiazol-2-ylthio)-6-

methylquinazolin-2-amine (15d).

Yield 72%; mp 175–

177°C; IR (KBr): 3257 (NH), 1560 (C═N), 1594, 1467,

1456 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

1

δ 9.06 (bs, 1H, NH),6.93–8.20 (m, 11H, Ar─H), 2.36

(s, 3H, Ar─CH₃) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 174.5 (C-2), 166.1 (C-2⁰), 160.6 (C-2″),

158.6 (C-4), 26.4 (CH₃), 151.4 150.6, 147.5, 136.5,

135.4, 132.4, 130.5, 129.3, 126.2, 125.4, 124.3, 123.2,

122.1, 121.5, 120.4, 119.3, 118.6, 117.2 (aromatic

carbons) ppm; MS: (m/z): 457.59 [M⁺]. Anal. Calcd for

C₂₃H₁₅N₅S₃: C, 60.37; H, 3.30; N, 15.30; found: C,

60.49; H, 3.33; N, 15.49%.

54.23; H, 2.93; N, 20.10%.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

yl)-6-methylquinazolin-2-amine (16c). Yield 75%; mp 163–

165°C; IR (KBr): 3305 (NH), 1571 (C═N), 1597, 1488,

1

1476 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

δ 12.18 (bs, 2H, Imidazole-NH), 9.04 (bs, 1H, NH),

6.83–8.36 (m, 11H, Ar─H) ppm; ¹³C NMR (100 MHz,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2017

Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

DMSO-d₆): δ 175.2 (C-2), 159.5 (C-4), 158.6 (C-2⁰), 153.3

(C-2″), 147.8, 138.6, 133.2, 132.4, 128.1, 127.5, 124.2,

123.4, 121.3, 120.6, 112.4, 110.2 (aromatic carbons)

ppm; MS: (m/z): 443.91 [M⁺]. Anal. Calcd for

C₂₂H₁₄ClN₇S: C, 59.52; H, 3.18; N, 22.09; found: C,

59.62; H, 3.16; N, 22.27%.

The compounds were dissolved in DMSO of 5 mg/mL,

and from this, 10, 15, and 20 μL (50, 75, and

100 μg/well) were added into the wells by using sterile

pipettes. The standard antibiotic, Chloramphenicol, for

antibacterial activity (as positive control) was

simultaneously tested against the pathogens. The samples

were dissolved in DMSO, which showed no zone of

inhibition acts as a negative control. The plates were

incubated at 37°C for 24 h. After appropriate incubation,

the diameter of zone of inhibition of each well was

measured. Duplicates were maintained, and the average

values were calculated for eventual antibacterial activity.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

yl)-6-chloroquinazolin-2-amine (16d). Yield 76%; mp 157–

159°C; IR (KBr): 3288 (NH), 1553(C═N), 1600, 1474,

1

1448 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

δ 11.92 (bs, 2H, Imidazole-NH), 8.98 (bs, 1H, NH),

6.78–8.17 (m, 11H, Ar─H), 2.43 (s, 3H, Ar─CH₃) ppm;

¹³C NMR (100 MHz, DMSO-d₆): δ 170.1 (C-2), 155.4

(C-4), 154.8 (C-2⁰), 149.2 (C-2″), 24.6 (CH₃), 145.6,

136.5, 133.6, 131.2, 130.4, 128.9, 122.2, 121.6, 118.4,

116.1, 110.8, 108.6 (aromatic carbons) ppm; MS: (m/z):

423.49 [M⁺]. Anal. Calcd for C₂₃H₁₇N₇S: C, 65.23; H,

4.05; N, 23.15; found: C, 65.36; H, 4.09; N, 23.35%.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

Minimum inhibitory concentration assay.

Broth

dilution test was used to determine MIC of the above-

mentioned samples [29,30]. Freshly prepared nutrient

broth was used as diluents. The 24-h old culture of the

test bacteria S. aureus, B. subtilis, P. aeruginosa, and

K. pneumoniae were diluted 100-fold in nutrient broth

(100-μL bacterial cultures in 10-mL NB). The stock

solution of the synthesized compounds was prepared in

DMSO by dissolving 5 mg of the compound in 1 mL of

DMSO. Increasing concentrations of the test samples

(1.25, 2.5, 5, 10, 20, and 40 μL of stock solution contain

6.25, 12.5, 25, 50, 100, and 200 μg of the compounds)

were added to the test tubes containing the bacterial

cultures. All the tubes were incubated at 37°C for 24 h.

The tubes were examined for visible turbidity and using

NB as control. Control without test samples and with

solvent was assayed simultaneously. The lowest

concentration that inhibited visible growth of the tested

organisms was recorded as MIC.

yl)-6-methoxyquinazolin-2-amine (16e).

Yield 77%; mp

168–170°C IR (KBr): 1548 (C═N), 3284 (NH), 1607,

1485, 1467 (Ar, C═C) cm^ꢀ^{1 1}H NMR (400 MHz,

;

DMSO-d₆): δ 11.85 (bs, 2H, Imidazole-NH), 8.94 (bs,

1H, NH), 6.72–8.26 (m, 11H, Ar─H), 3.74 (s, 3H,

Ar─OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ

168.6 (C-2), 153.8 (C-4), 152.3 (C-2⁰), 147.1 (C-2″), 54.5

(OCH₃), 151.6, 146.5, 138.3,128.3, 126.5, 123.9, 120.4,

119.6, 118.6, 113.1, 107.2, 101.3 (aromatic carbons)

ppm; MS: (m/z): 439.49 [M⁺]. Anal. Calcd for

C₂₃H₁₇N₇OS: C, 62.86; H, 3.90; N, 22.31; found: C,

62.94; H, 3.91; N, 22.47%.

4-(1H-benzo[d]imidazol-2-ylthio)-N-(1H-benzo[d]imidazol-2-

yl)-6-nitroquinazolin-2-amine (16f). Yield 79%; mp 173–

Minimum bactericidal concentration.

For the

determination of the MBC [31] for each set of test tubes

in the MIC determination, a loopful of broth was

collected from those tubes, which did not show any

growth and inoculated on sterile nutrient broth (for

bacteria) by streaking. Plates inoculated with bacteria

were incubated at 37°C for 24 h. After incubation, the

lowest concentration was noted as MBC at which no

visible growth was observed.

175°C; IR (KBr): 3312 (NH), 1578 (C═N), 1597, 1486,

1

1463 (Ar, C═C) cm^ꢀ1; H NMR (400 MHz, DMSO-d₆):

δ 12.22 (bs, 2H, Imidazole-NH), 9.11 (bs, 1H, NH),

6.87–8.39 (m, 11H, Ar─H) ppm; ¹³C NMR (100 MHz,

DMSO-d₆): δ 173.6 (C-2), 159.3 (C-4), 158.3 (C-2⁰),

154.3 (C-2″), 150.5, 143.6, 141.3, 132.1, 127.6, 126.2,

123.6, 122.4, 121.6, 117.3, 116.2, 108.6 (aromatic

carbons) ppm; MS: (m/z): 454.46 [M⁺]. Anal. Calcd for

C₂₂H₁₄N₈O₂S: C, 58.14; H, 3.11; N, 24.66; found: C,

58.54; H, 3.14; N, 24.84%.

Acknowledgments. The authors are thankful to Council of

Scientiﬁc and Industrial Research (CSIR), New Delhi, India, for

the sanction of Major Research Project. One of the authors Mr.

L. Mallikarjuna Reddy is thankful to CSIR, New Delhi, India,

for the sanction of Senior Research Fellowship. The authors are

also thankful to Department of Bio-Chemistry, S.V. University,

Tirupati, for providing necessary facilities to carry out the anti-

bacterial activity.

Antibacterial assays.

The compounds 8–16 were

evaluated for antibacterial activity at three different

concentrations: 50, 75, and 100 μg/well. Bacterial strains

S. aureus, Bacillus subtilis, Pseudomonas aeruginosa,

and Klebsiella pneumoniae were obtained from the

Department of Microbiology, S.V. University, Tirupati.

The in vitro antibacterial studies were carried out by agar

well diffusion method against test organisms [27,28].

Nutrient broth (NB) plates were swabbed with 24-h old

broth culture (100 μl) of test bacteria. Using the sterile

cork borer, wells (6 mm) were made into each petriplate.

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Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles

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