Synthesis, characterization and biological evaluation of fused thiazolo[3,2-a]pyrimidine derivatives

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Khanapur, S. Basavoju, R. Bavantula, M. Narra and S. Abbagani, RSC Adv., 2014, DOI:

10.1039/C4RA02514H.

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S

Ar CHO

+

H₂N NH₂

O

2(a-g)

3

1

P(4-VPH)HSO₄

Solvent-free, 120 ^oC

10-20 min

O

Br

O

Ar

N

Ar

Br

Ar

N

R

O

N

NH

(5, 6)

(9)

N

S

N

H

S

AcOH, reflux,

3-6 h

AcOH, reflux, 1-3 h

S

4(a-g)

11(a-g)

5/7(a-g):

R = 4-ClC₆H₄

6/8(a-f): R = 4-BrC₆H₄

O

AcOH, reflux,

2 h

Br

O

(10)

Ar

N

S

12a,b

Ar:

a = C₆H₅

c = 4-FC₆H₄

b = 4-OHC₆H₄

d = 4-OCH₃C₆H₄

e

f

= 4-OH-3-OCH₃C₆H₃

= 3,4-(OCH₃)₂C₆H₃

g = 4-ClC₆H₄

Scheme 1. Synthesis of fused 3,4-dihydropyrimidin-2(1H)-thiones and thiazolo[3,2-

a]pyrimidines.

Figure 1. Biologically potent thiazolo[3,2-a]pyrimidine derivatives.

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Figure 2. ORTEP representation of compound 8e. Thermal ellipsoids are drawn at 50%

probability level.

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Figure 3. DNA cleavage activity of fused thiazolo[3,2-a]pyrimidines (7a-g, 8a-f, 11a-g and

12a,b) at 50 and 100 µg/mL. Where, M-Marker; P-Plasmid pUC18; D-DMSO treated

plasmid; F-FeSO4 (5 mM) treated plasmid; 5-50 µg/mL; 10-100 µg/mL.

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Table 1. Synthesis of fused thiazolo[3,2ꢀa]pyrimidine derivatives.

Product^aAr

Time (h)

Yield^b(%)

82

M.P. (^oC)

C₆H₅

4ꢀOHC₆H₄

5

4

5

4

3

5

6

5

3

4

1

3

2

1

2

319ꢀ320

292ꢀ294

301ꢀ303

260ꢀ262

233ꢀ236

271ꢀ273

317ꢀ318

322ꢀ324

294ꢀ296

298ꢀ300

261ꢀ263

242ꢀ244

280ꢀ282

290ꢀ291

293ꢀ294

277ꢀ279

275ꢀ277

267ꢀ269

261ꢀ263

280ꢀ282

310ꢀ312

264ꢀ266

7a

7b

80

79

82

85

84

82

80

79

80

81

86

84

88

82

80

87

4ꢀFC₆H₄

7c

4ꢀOCH₃C₆H₄

3,4ꢀ(OCH₃)₂C₆H₃

4ꢀOHꢀ3ꢀOCH₃C₆H₃

4ꢀClC₆H₄

7d

7e

7f

7g

C₆H₅

8a

4ꢀOHC₆H₄

8b

4ꢀFC₆H₄

8c

4ꢀOCH₃C₆H₄

3,4ꢀ(OCH₃)₂C₆H₃

4ꢀOHꢀ3ꢀOCH₃C₆H₃

C₆H₅

4ꢀOHC₆H₄

4ꢀFC₆H₄

4ꢀOCH₃C₆H₄

3,4ꢀ(OCH₃)₂C₆H₃

4ꢀOHꢀ3ꢀOCH₃C₆H₃

4ꢀClC₆H₄

C₆H₅

4ꢀOHC₆H₄

8d

8e

8f

11a

11b

11c

11d

11e

11f

11g

12a

12b

89

88

83

80

77

a

Reaction conditions: Fused 3,4ꢀdihydropyrimidinꢀ2(1H)ꢀthiones (4aꢀg, 1 mmol), 4ꢀ

chlorophenacyl bromide/4ꢀbromophenacyl bromide/3ꢀ(2ꢀbromoacetyl)ꢀ2Hꢀchromenꢀ2ꢀone/2ꢀ

(2ꢀbromoacetyl)ꢀ3Hꢀbenzo[f]chromenꢀ3ꢀone (1 mmol), acetic acid (10 mL), reflux.

^bIsolated yields.

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Table 2. Antibacterial activity of fused thiazolo[3,2ꢀa]pyrimidine derivatives.

MIC (ꢁg/mL)

Compound

Bs

75

ꢀ

75

ꢀ

75

ꢀ

Sa

Se

75

ꢀ

Ec

75

ꢀ

Pa

Kp

75

ꢀ

18.75

ꢀ

75

150

75

7b

7d

7e

7f

7g

8a

8b

8c

9.375 37.5

ꢀ

18.75 9.375

37.5 37.5

18.75 9.375

150

37.5

ꢀ

75

ꢀ

75

ꢀ

150

37.5

75

37.5

18.75

37.5

150

ꢀ

18.75

37.5

9.375

75

ꢀ

37.5

ꢀ

75

18.75 18.75

ꢀ

75

8d

8e

8f

150

9.375

75

ꢀ

11a

1.562 1.562

6.25 6.25

3.125 12.5

3.125 6.25

12.5

1.562

6.25

3.125

Penicillin

Streptomycin

Gramꢀpositive bacterial strains:ꢀ Bs: Bacillus subtilis; Sa: Staphylococcus aureus; Se:

Staphylococcus epidermidis;

Gramꢀnegative bacterial strains:ꢀ Ec: Escherichia coli; Pa: Pseudomonas aeruginosa; Kp:

Klebsiella pneumoniae.

“ꢀ” Indicates the concentration >150 ꢁg/mL.

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Table 3. Antioxidant activity of fused thiazolo[3,2ꢀa] pyrimidines.

Compound

IC₅₀( ꢁM)

82.58

80.50

25.79

80.91

66.75

41.29

29.67

44.75

46.57

26.01

74.86

63.32

28.76

64.34

18.25

12.36

53.22

47.54

28.45

47.26

11.12

13.88

14.22

10.32

9.84

7a

7b

7c

7d

7e

7f

7g

8a

8b

8c

8d

8e

8f

11a

11b

11c

11d

11e

11f

11g

12a

12b

Trolox

Curcumin

Quercetin

Ascorbic acid

3.8

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Graphical abstract

Synthesis, characterization and biological evaluation of fused thiazolo[3,2-a]pyrimidine

derivatives

Janardhan Banothu^a, Manjulatha Khanapur^b, Srinivas Basavoju^a, Rajitha Bavantula^a*, Muralikrishna Narra,^c

Sadanandam Abbagan^c*

A series of fused thiazolo[3,2-a]pyrimidines have been synthesized in good yields by reaction

of fused 3,4-dihydropyrimidin-2(1H)-thiones (4a-g) with phenacyl bromides (5,6)/3-(2-

bromoacetyl)coumarins (9,10) under conventional heating in acetic acid. All the synthesized

compounds were characterized by analytical and spectral studies, and screened for their

antibacterial, antioxidant and DNA cleavage activities.

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Synthesis, characterization and biological evaluation of fused thiazolo[3,2-

a]pyrimidine derivatives

Janardhan Banothu^a, Manjulatha Khanapur^b, Srinivas Basavoju^a, Rajitha Bavantula^a*,

Muralikrishna Narra,^cSadanandam Abbagan^c*

^aDepartment of Chemistry, National Institute of Technology, Warangal-506004, A.P., India.

^bDepartment of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad-

500046, A.P., India

^cDepartment of Bio-Technology, Kakatiya University, Warangal-506009, A.P., India.

Corresponding Author

Prof. Rajitha Bavantula

Tel.: 0091ꢀ0870ꢀ2459445

Fax: 0091ꢀ0870ꢀ2459547

Eꢀmail: rajitabhargavi@yahoo.com

Abstract

A series of fused thiazolo[3,2ꢀa]pyrimidines (7a-g, 8a-f, 11a-g and 12a,b) have been

synthesized in good yields by reaction of fused 3,4ꢀdihydropyrimidinꢀ2(1H)ꢀthiones (4a-g)

with phenacyl bromides (5,6)/3ꢀ(2ꢀbromoacetyl)coumarins (9,10) under conventional heating

in acetic acid. Analytical and spectral studies as well as single crystal Xꢀray diffraction data

on the representative compound 8e confirmed the structure of all the reaction products. All

the synthesized compounds were screened for their antibacterial, antioxidant and DNA

cleavage activities. The compound 7e against Escherichia coli, 8a and 8c-e against

Pseudomonas aeruginosa have shown prominent antibacterial activity than the standard drug

Penicillin with MIC 9.375 ꢁg/mL, whereas the compounds 11c, 12a and 12b have shown

very good antioxidant activity compared to the standard drug Trolox with IC₅₀values 12.36,

11.12 and 13.88 ꢂM respectively. Compound 11f and 12b have completely cleaved the DNA

even at 50 ꢁg/mL concentration and remaining compounds have partially cleaved the DNA.

Key words: Antibacterial activity; Antioxidant activity; 3,4ꢀDihydropyrimidinꢀ2(1H)ꢀthiones;

DNA cleavage activity; Thiazolo[3,2ꢀa]pyrimidines.

Introduction

Treatment of bacterial infections still remains an important and challenging therapeutic

problem, due to the emergence of bacteria resistant to current therapeutic agents.¹Reactive

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oxygen species (ROS) are causing damage to nucleic acids, proteins, carbohydrates and lipids

in many types of cells including macrophages,²eventually leading to many chronic diseases.³

Antioxidants exert their effects by preventing the generation of ROS, which can protect the

formation of free radicals and retard the progress of diseases.³These are also useful to extend

the shelf life of food and pharmaceuticals during processing, storage and transportation.⁴

Deoxyribonucleic acid (DNA) is the primary target for most anticancer and antiviral

therapies.⁵Therefore, the investigation towards the development of new antibiotics,

antioxidants and molecules that can exhibit DNA binding and cleaving properties have

become a necessary endeavor.

Dihydropyrimidine (DHPM) derivatives are known to possess diverse pharmacological

properties including calcium channel modulators, mitotic kinesin inhibitors, adrenergic

receptor antagonists, antibacterial and antiviral agents.⁶Hence, much attention has been

focused on the modification of their core synthon. One such modification was observed when

the reaction of dihydropyrimidinꢀthiones is carried out with 1,2ꢀdielectrophiles such as 2ꢀ

bromo ketones,⁷chloroacetyl chloride,⁸chloroacetic acid,⁹methyl chloroacetate¹⁰and 1,2ꢀ

dichloroethane¹¹to form ring annulation products, thiazolo[3,2ꢀa]pyrimidine derivatives. The

synthesis of thiazolo[3,2ꢀa]pyrimidines have recently gained considerable interest due to the

broad spectrum of biological activities that include antiꢀinflammatory,^9a,12antihypertensive,¹³

antifungal,^7aantibiofilm, antibacterial,^9bantiviral,^9cantioxidant,¹⁴anticancer,¹⁵antitumor,¹⁶

antiꢀHIV,¹⁷calcium antagonists^7band group 2 metabotropic glutamate receptor antagonists.¹⁸

They also serve as inhibitors of CDC25B phosphatase,⁸acetylcholinesterase (AChE)

enzymes¹⁹and Bclꢀ2 family proteins.²⁰The structures of thiazolo[3,2ꢀa]pyrimidine

derivatives and their pharmacological activities are given in Figure 1.⁶

(Figure 1)

In continuation of our research towards the synthesis of biologically potent heterocyclic

compounds,²¹herein we report an efficient method for the synthesis of fused thiazolo[3,2ꢀa]

pyrimidine derivatives and to evaluate their antibacterial, antioxidant and DNA cleavage

activities.

Results and discussion

Fused 3,4ꢀdihydropyrimidinꢀ2(1H)ꢀthiones (4a-g) were prepared in good yields via a

modified Biginelli reaction on 1ꢀtetralone (1), aromatic aldehydes (2a-g) and thiourea (3) in

the presence of poly(4ꢀvinylpyridinium)hydrogen sulfate [P(4ꢀVPH)HSO₄] as a catalyst

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under solventꢀfree conditions at 120 ^oC.²²The title compounds, fused thiazolo[3,2ꢀ

a]pyrimidines (7a-g, 8a-f, 11a-g and 12a,b) were obtained by cyclization of 4a-g with 4ꢀ

chlorophenacyl bromide (5)/4ꢀbromophenacyl bromide (6)/3ꢀ(2ꢀbromoacetyl)ꢀ2Hꢀchromenꢀ

2ꢀone (9)/2ꢀ(2ꢀbromoacetyl)ꢀ 3Hꢀbenzo[f]chromenꢀ3ꢀone (10) under reflux in acetic acid

(Scheme 1, Table 1).

(Scheme 1)

(Table 1)

The formation of title compounds 7a-g, 8a-f, 11a-g and 12a,b from fused 3,4ꢀ

1

dihydropyrimidinꢀ2(1H)ꢀthiones (4a-g) were characterized by IR, H NMR, ¹³C NMR and

mass spectral data. From the FTIR spectra, the disappearance of absorption bands ranging

from 3144ꢀ3274 cm^ꢀ1for thioamide (–N–H) in the starting material and the appearance of a

weak band ranging from 1598ꢀ1611 cm^ꢀ1in 7a-g and 8a-f, and 1628ꢀ1636 cm^ꢀ1in 11a-g and

12a,b of imine (–C=N–) group was indicative of formation of the products. Compounds 11a-

g and 12a,b were also shown a strong band ranging from 1710ꢀ1740 cm^ꢀ1confirm the

1

presence of lactone carbonyl (–O–C=O) group. From the H NMR spectra, the absence of

singlets at 8.98ꢀ9.47 ppm and 9.66ꢀ9.81 ppm for thioamide (–N–H) in the starting material,

and from ¹³C NMR the disappearance of a signal at 173.2ꢀ174.3 ppm of cyclic thiourea

carbon (–C=S), and the presence of a signal at 160.9ꢀ163.3 ppm of imine carbon (–C=N)

confirmed the formation of the products. In addition, the molecular ion peak from the mass

spectra, elemental analyses data and single crystal Xꢀray diffraction structure of a compound

8e are further evidences for the formation of products.

Single crystal Xꢀray diffraction analysis of compound 8e was carried out on a crystal

obtained from the reaction mixture. The compound was crystallizes in the triclinic space

group Pꢀ1 with one completely protonated 8e, one partially protonated 8e, one Br^–, one

partially proton transferred HBr and three molecules of acetic acid in the asymmetric unit.

The ORTEP representation of the molecular structure of 8e is shown in Figure 2. A summary

of the crystallographic data, structure refinement details, the geometrical parameters of

hydrogen bonds and packing diagram is given in the supporting file.

(Figure 2)

All the synthesized compounds were screened for their in vitro antibacterial activity

against Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis (Gramꢀ

positive), Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae (Gramꢀ

negative) bacterial strains by micro dilution method recommended by CLSI standard

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protocol²³using Penicillin and Streptomycin as standard drugs. The results are tabulated in

Table 2.

(Table 2)

Evaluation of the antibacterial screening data revealed that, the compound 7e against

Escherichia coli, 8a and 8c-e against Pseudomonas aeruginosa have shown prominent

activity than the standard drug Penicillin (MIC: 12.5 ꢁg/mL) with MIC 9.375 ꢁg/mL (~ 1.33

fold potent than Penicillin, Table 2). The potential activity may be attributed due to the

presence of pharmacologically active moieties like phenyl, 4ꢀfluoro phenyl, 4ꢀmethoxy

phenyl and 3,4ꢀdimethoxy phenyl groups on pyrimidine core and 4ꢀchloro phenyl/4ꢀbromo

phenyl group on thiazole core. Among all the compounds, 8d is active against all the tested

bacterial strains. Remaining compounds derived from 4ꢀchlorophenacyl bromide and 4ꢀ

bromophenacyl bromide has shown weak to moderate activity. Compound 11a (bearing

pyranone moiety) has shown weak activity against Gramꢀpositive bacterial strains whereas

inactive against Gramꢀnegative bacterial strains, rest of the compounds (11b-g and 12a,b)

were inactive against all the tested bacterial strains.

All the synthesized compounds were also screened for free radical scavenging activity in

terms of hydrogen donating or radical scavenging ability by DPPH method.²⁴Methanol

(95%), DPPH solution and standard compounds (Trolox, Curcumin, Quercetin and Ascorbic

acid) were used as blank, control and reference respectively. The IC₅₀values of the

compounds under study for antioxidant results are shown in Table 3.

(Table 3)

There is mounting evidence for the radical scavenging capacity of phenol and coumarin

derivatives.²⁵The free radical scavenging ability of compounds in present study results have

also exhibited good scavenging ability for compounds bearing 4ꢀfluoro phenyl and 2Hꢀ

chromenꢀ2ꢀone (11c, IC₅₀value 12.36 ꢂM), and phenyl/4ꢀhydroxy phenyl and 3Hꢀ

benzo[f]chromenꢀ3ꢀone (12a, IC₅₀value 11.12 ꢂM and 12b, IC₅₀value 13.88 ꢂM). These on

comparison with the standard Trolox with IC₅₀value of 14.22 ꢂM found to be active by ~

1.15 fold for 11c, ~ 1.27 fold for 12a and ~ 1.02 fold for 12b. Compound possessing 4ꢀ

hydroxy phenyl/4ꢀfluoro phenyl/4ꢀhydroxyꢀ3ꢀmethoxy phenyl/4ꢀchloro phenyl on pyrimidine

core, and 4ꢀchloro phenyl/4ꢀbromo phenyl/2Hꢀchromenꢀ2ꢀone on thiazole core (7c, 7g, 8c, 8f,

11b and 11f) have shown moderate scavenging ability with IC₅₀values 25.79, 29.67, 26.01,

28.76, 18.25 and 28.45 ꢂM respectively. Remaining compounds have shown weak

scavenging ability/capacity with IC₅₀values ranging from 41.29ꢀ82.58 ꢂM.

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The DNA cleavage activity of the titled compounds (7a-g, 8a-f, 11a-g and 12a,b) was

determined using agarose gel electrophoresis method.²⁶DNA cleavage is controlled by

relaxation of supercoiled circular form into nicked circular form and linear form. When

circular plasmid DNA is subjected to electrophoresis, relatively fast migration will be

observed for the intact supercoiled form. If one strand is cleaved, the supercoils will relax to

produce a slower moving open circular form. If both strands are cleaved, a linear form will be

generated and migrates between supercoiled and open circular forms. The pictures of the gels

are presented in Figure 3.

(Figure 3)

The gel after electrophoresis clearly revealed that, the plasmid pUC18 having three

forms of DNA, whereas in case of standard FeSO₄(10 mg/1 mL) complete DNA cleavage

was observed. Compared to standard FeSO₄, compound 11f and 12b have completely cleaved

the DNA even at 50 ꢁg/mL, whereas 7c, 7f, 8b and 8e have shown complete cleavage at 100

ꢁg/mL. Remaining compounds have partially cleaved the DNA. From these results we

deduce that, the presence of pyranone moiety on thiazole core, 4ꢀhydroxy phenyl and 4ꢀ

hydroxyꢀ3ꢀmethoxy phenyl groups on pyrimidine core has enhanced the DNA cleavage

activity.

Conclusion

In conclusion, we have synthesized a series of fused thiazolo[3,2ꢀa]pyrimidines under

conventional method in good yields, and evaluated their antibacterial, antioxidant and DNA

cleavage activities. The compound 7e against E.coli, 8a and 8c-e against P.aeruginosa are

shown marked antibacterial activity and the compounds 11c, 12a and 12b are shown very

good antioxidant activity. Similarly, the compound 11f and 12b are shown complete DNA

cleavage even at 50 ꢁg/mL. These results are suggesting that the synthesized compounds can

be better candidates for future investigations.

Experimental

All the reagents and solvents were purchased from Aldrich/Merck and used without

further purifications. Melting points were determined in open capillaries using Stuart SMP30

apparatus (Bibby Scientific Ltd. United Kingdom) and are uncorrected. The progress of the

reactions as well as purity of compounds was monitored by thin layer chromatography with

F₂₅₄silicaꢀgel precoated sheets (Merck, Darmstadt, Germany) using hexane/ethyl acetate 8/2

as eluent; UV light and iodine vapours were used for detection. IR spectra were recorded on a

PerkinꢀElmer 100S spectrometer (PerkinꢀElmer Ltd. United Kingdom) utilizing KBr pellets;

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values are expressed in cm^ꢀ1. ¹H NMR and ¹³C NMR spectra were obtained at 400 MHz and

100 MHz respectively on Bruker spectrometer (Bruker Corporation Ltd., Germany) using

DMSOꢀd₆as solvent and TMS as internal standard, chemical shifts are expressed in parts per

million. Elemental analyses were performed on a CarloꢀErba model EA1108 analytical unit

(Triad Scientific Ltd., New Jersey, USA) and the values are ± 0.4% of theoretical values.

Mass spectra were recorded on a Jeol JMSDꢀ300 spectrometer (Jeol Ltd., Tokyo, Japan).

Synthesis of 4-aryl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thiones (4a-g)

To a clean and dry round bottom flask were added 1ꢀtetralone (1, 1 mmol), aromatic

aldehyde (2a-g, 1 mmol), thiourea (3, 1.2 mmol) and P(4ꢀVPH)HSO₄(0.015 g). The resulting

o

mixture was heated at 120 C under solventꢀfree conditions for 10ꢀ20 min. After completion

of the reaction (monitored by TLC), water (5 mL) was added and the mixture was stirred at

room temperature for an additional 10 min. The solid separated out was filtered, washed with

water, dried and the crude product was crystallized from ethanol to afford the pure product.

The aqueous layer containing catalyst was recovered under reduced pressure, washed with

dichloromethane, dried and reused for subsequent runs.

4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a)

o

Yellow solid; Yield: 92%; Mp.: 258ꢀ259 C; IR (KBr) υ_max(cm^ꢀ1): 3159 (NH), 1194 (C=S);

¹H NMR (400 MHz, DMSOꢀd₆): δ 1.80ꢀ1.88 (m, 1H), 2.15ꢀ2.23 (m, 1H), 2.55ꢀ2.62 (m, 1H),

2.69ꢀ2.77 (m, 1H), 4.95 (s, 1H), 7.17ꢀ7.22 (m, 3H), 7.31ꢀ7.41 (m, 5H), 7.68 (d, J = 7.2 Hz,

1H), 9.08 (s, 1H), 9.76 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 174.2, 142.8, 135.4,

128.6, 127.9, 127.7, 127.5, 126.9, 126.6, 126.3, 121.6, 111.1, 58.4, 27.3, 23.6; MS (ESI) m/z:

293 [M+H]⁺; Anal. Calcd. for C₁₈H₁₆N₂S: C, 73.94; H, 5.52; N, 9.58; Found: C, 73.67; H,

5.71; N, 9.64.

4-(4-Hydroxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4b)

o

White solid; Yield: 88%; Mp.: 270ꢀ272 C; IR (KBr) υ_max(cm^ꢀ1): 3445 (OH), 3263, 3144

(NH), 1171 (C=S); ¹H NMR (400 MHz, DMSOꢀd₆): δ 1.79ꢀ1.87 (m, 1H), 2.09ꢀ2.18 (m, 1H),

2.57ꢀ2.63 (m, 1H), 2.67ꢀ2.73 (m, 1H), 4.82 (s, 1H), 6.75 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4

Hz, 2H), 7.15ꢀ7.22 (m, 3H), 7.67 (d, J = 7.2 Hz, 1H), 8.98 (s, 1H), 9.47 (s, 1H), 9.67 (s, 1H);

¹³C NMR (100 MHz, DMSOꢀd₆): δ 173.8, 157.1, 135.4, 133.3, 128.3, 127.8, 127.6, 127.5,

126.4, 126.3, 121.6, 115.3, 111.6, 58.0, 27.3, 23.6; MS (ESI) m/z: 309 [M+H]⁺; Anal. Calcd.

for C₁₈H₁₆N₂OS: C, 70.10; H, 5.23; N, 9.08; Found: C, 70.25; H, 5.17; N, 9.22.

4-(4-Fluorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4c)

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o

White solid; Yield: 91%; Mp.: 252ꢀ254 C; IR (KBr) υ_max(cm^ꢀ1): 3179 (NH), 1220 (CꢀF),

1

1190 (C=S); H NMR (400 MHz, DMSOꢀd₆): δ 1.79ꢀ1.87 (m, 1H), 2.14ꢀ2.22 (m, 1H), 2.58ꢀ

2.64 (m, 1H), 2.69ꢀ2.73 (m, 1H), 4.99 (s, 1H), 7.17ꢀ7.24 (m, 5H), 7.34ꢀ7.37 (m, 2H), 7.69 (d,

J = 7.2 Hz, 1H), 9.09 (s, 1H), 9.78 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 174.2, 162.9,

139.1, 135.4, 129.0, 128.9, 127.8, 127.5, 126.7, 126.3, 121.7, 115.6, 115.4, 110.9, 57.6, 27.3,

23.5; MS (ESI) m/z: 311 [M+H]⁺; Anal. Calcd. for C₁₈H₁₅FN₂S: C, 69.65; H, 4.87; N, 9.03;

Found: C, 69.52; H, 4.95; N, 9.16.

4-(4-Methoxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4d)

o

Yellow solid; Yield: 93%; Mp.: 211ꢀ212 C; IR (KBr) υ_max(cm^ꢀ1): 3274, 3196 (NH), 1253

1

(CꢀOꢀC), 1172 (C=S); H NMR (400 MHz, DMSOꢀd₆): δ 1.79ꢀ1.87 (m, 1H), 2.12ꢀ2.20 (m,

1H), 2.55ꢀ2.63 (m, 1H), 2.68ꢀ2.74 (m, 1H), 3.74 (s, 3H), 4.88 (s, 1H), 6.93ꢀ6.95 (m, 2H),

7.15ꢀ7.24 (m, 5H), 6.67 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H), 9.69 (s, 1H); ¹³C NMR (100 MHz,

DMSOꢀd₆): δ 173.9, 158.9, 135.4, 134.9, 128.2, 127.7, 127.6, 127.5, 126.5, 126.3, 121.6,

114.0, 111.4, 57.8, 55.1, 27.3, 23.6; MS (ESI) m/z: 323 [M+H]⁺; Anal. Calcd. for

C₁₉H₁₈N₂OS: C, 70.78; H, 5.63; N, 8.69; Found: C, 70.89; H, 5.54; N, 8.58.

4-(3,4-Dimethoxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4e)

Yellow solid; Yield: 94%; Mp.: 207ꢀ209 ^oC; IR (KBr) υ_max(cm^ꢀ1): 3196 (NH), 1258 (CꢀOꢀC),

1

1138 (C=S); H NMR (400 MHz, DMSOꢀd₆): δ 1.87ꢀ1.93 (m, 1H), 2.16ꢀ2.21 (m, 1H), 2.61ꢀ

2.65 (m, 1H), 2.69ꢀ2.75 (m, 1H), 3.73 (s, 6H), 4.89 (s, 1H), 6.82ꢀ6.85 (m, 1H), 6.92ꢀ6.97 (m,

2H), 7.16ꢀ7.23 (m, 3H), 7.66 (d, J = 7.2 Hz, 1H), 8.98 (s, 1H), 9.71 (s, 1H); ¹³C NMR (100

MHz, DMSOꢀd₆): δ 174.0, 148.7, 148.5, 135.4, 135.2, 127.8, 127.7, 127.6, 126.6, 126.3,

121.6, 119.0, 111.9, 111.3, 111.0, 58.1, 55.6, 55.5, 27.4, 23.6; MS (ESI) m/z: 353 [M+H]⁺;

Anal. Calcd. for C₂₀H₂₀N₂O₂S: C, 68.16; H, 5.72; N, 7.95; Found: C, 68.02; H, 5.88; N, 8.06.

4-(4-Hydroxy-3-methoxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione

(4f)

o

Yellow solid; Yield: 90%; Mp.: 230ꢀ232 C; IR (KBr) υ_max(cm^ꢀ1): 3347 (OH), 3177 (NH),

1

1272 (CꢀOꢀC), 1195 (C=S); H NMR (400 MHz, DMSOꢀd₆): δ 1.85ꢀ1.93 (m, 1H), 2.12ꢀ2.21

(m, 1H), 2.59ꢀ2.74 (m, 2H), 3.73 (s, 3H), 4.85 (s, 1H), 6.71ꢀ6.89 (m, 3H), 7.71ꢀ7.22 (m, 3H),

7.67 (d, J = 7.2 Hz, 1H), 8.97 (s, 1H), 9.06 (s, 1H), 9.69 (s, 1H); ¹³C NMR (100 MHz,

DMSOꢀd₆): δ 173.9, 147.5, 146.4, 135.4, 133.8, 127.8, 127.6, 127.5, 126.5, 126.3, 121.6,

119.4, 115.5, 111.5, 58.2, 55.6, 27.4, 23.6; MS (ESI) m/z: 339 [M+H]⁺; Anal. Calcd. for

C₁₉H₁₈N₂O₂S: C, 67.43; H, 5.36; N, 8.28; Found: C, 67.31; H, 5.49; N, 8.35.

4-(4-Chlorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4g)

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o

White solid; Yield: 94%; Mp.: 262ꢀ264 C; IR (KBr) υ_max(cm^ꢀ1): 3269, 3194 (NH), 1195

(C=S), 775 (CꢀCl); ¹H NMR (400 MHz, DMSOꢀd₆): δ 1.79ꢀ1.87 (m, 1H), 2.15ꢀ2.22 (m, 1H),

2.56ꢀ2.64 (m, 1H), 2.69ꢀ2.77 (m, 1H), 4.98 (s, 1H), 7.18ꢀ7.23 (m, 3H), 7.33 (d, J = 8.4 Hz,

13

2H), 7.46 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.2 Hz, 1H), 9.10 (s, 1H), 9.81 (s, 1H); C NMR

(100 MHz, DMSOꢀd₆): δ 174.3, 141.7, 135.4, 132.4, 128.8, 128.7, 127.8, 127.6, 126.9, 126.3,

121.7, 110.7, 57.6, 27.2, 23.4; MS (ESI) m/z: 327 [M+H]⁺; Anal. Calcd. for C₁₈H₁₅ClN₂S: C,

66.15; H, 4.63; N, 8.57; Found: C, 66.24; H, 4.51; N, 8.69.

Synthesis

of

9-(4-chlorophenyl)-7-aryl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]

quinazolines (7a-g)

4ꢀArylꢀ3,4,5,6ꢀtetrahydrobenzo[h]quinazolineꢀ2(1H)ꢀthione (4a-g, 1 mmol) and 4ꢀchloro

phenacyl bromide (5, 1 mmol) were dissolved in 5 mL of glacial acetic acid and stirred at its

reflux temperature for 3ꢀ5 h. After completion of the reaction (monitored by TLC), the

mixture was kept a room temperature for 4 h, the solid separated out was filtered and

quenched with cold acetic acid. The crude products obtained were purified by

recrystallization from acetic acid.

9-(4-Chlorophenyl)-7-phenyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline (7a)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1604 (C=N), 824 (CꢀCl); ¹H NMR (400 MHz, DMSOꢀd₆):

δ 1.76 (t, J = 7.6 Hz, 1H), 2.33 (t, J = 8.0 Hz, 1H), 2.57ꢀ2.79 (m, 2H), 6.16 (s, 1H), 6.84 (d, J

= 6.4 Hz, 2H), 7.17ꢀ7.46 (m, 11H), 7.65 (d, J = 6.8 Hz, 1H); MS (ESI) m/z: 427 [M+H]⁺;

Anal. Calcd. for C₂₆H₁₉ClN₂S: C, 73.14; H, 4.49; N, 6.56; Found: C, 73.26; H, 4.59; N, 6.45.

4-(9-(4-Chlorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)phenol

(7b)

1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 3244 (OH), 1609 (C=N), 836 (CꢀCl); H NMR (400

MHz, DMSOꢀd₆): δ 1.75ꢀ1.82 (m, 1H), 2.26ꢀ2.32 (m, 1H), 2.61 (t, J = 8.0 Hz, 1H), 2.78 (t, J

= 7.6 Hz, 1H), 6.04 (s, 1H), 6.52 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 7.25ꢀ7.40 (m,

6H), 7.50 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.2 Hz, 1H), 9.63 (s, 1H); MS (ESI) m/z: 443

[M+H]⁺; Anal. Calcd. for C₂₆H₁₉ClN₂OS: C, 70.50; H, 4.32; N, 6.32; Found: C, 70.37; H,

4.50; N, 6.44.

9-(4-Chlorophenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazoline (7c)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1604 (C=N), 1236 (CꢀF), 837 (CꢀCl); ¹H NMR (400 MHz,

DMSOꢀd₆): δ 1.70ꢀ1.77 (m, 1H), 2.31 (t, J = 8.4 Hz, 1H), 2.59ꢀ2.64 (m, 1H), 2.75ꢀ2.79 (m,

1H), 6.20 (s, 1H), 6.89ꢀ7.03 (m, 4H), 7.25 (d, J = 8.4 Hz, 3H), 7.32ꢀ7.48 (m, 5H), 7.64 (t, J =

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6.8 Hz, 1H); MS (ESI) m/z: 445 [M+H]⁺; Anal. Calcd. for C₂₆H₁₈ClFN₂S: C, 70.18; H, 4.08;

N, 6.30; Found: C, 70.09; H, 4.23; N, 6.44.

9-(4-Chlorophenyl)-7-(4-methoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazoline (7d)

1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1607 (C=N), 1246 (CꢀOꢀC), 822 (CꢀCl); H NMR (400

MHz, DMSOꢀd₆): δ 1.75ꢀ1.82 (m, 1H), 2.28ꢀ2.35 (m, 1H), 2.60 (t, J = 8.4 Hz, 1H), 2.75ꢀ2.83

(m, 1H), 3.67 (s, 3H), 6.09 (s, 1H), 6.69ꢀ6.75 (m, 4H), 7.26ꢀ7.40 (m, 6H), 7.49 (d, J = 8.4 Hz,

2H), 7.63 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.3, 159.5, 138.5, 135.3,

134.9, 131.3, 130.6, 128.8, 128.5, 128.2, 128.1, 126.7, 123.7, 121.3, 114.0, 112.4, 110.1,

62.1, 55.1, 26.7, 23.2; MS (ESI) m/z: 457 [M+H]⁺; Anal. Calcd. for C₂₇H₂₁ClN₂OS: C, 70.96;

H, 4.63; N, 6.13; Found: C, 70.84; H, 4.72; N, 6.27.

9-(4-Chlorophenyl)-7-(3,4-dimethoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]

quinazoline (7e)

1

Pale yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1609 (C=N), 1245 (CꢀOꢀC), 834 (CꢀCl); H NMR

(400 MHz, DMSOꢀd₆): δ 1.77ꢀ1.82 (m, 1H), 2.31 (t, J = 7.6 Hz, 1H), 2.59ꢀ2.79 (m, 2H), 3.47

(s, 3H), 3.67 (s, 3H), 6.13 (s, 1H), 6.56ꢀ6.58 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.25ꢀ7.40 (m,

13

7H), 7.50 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.6 Hz, 1H); C NMR (100 MHz, DMSOꢀd₆): δ

161.1, 148.9, 147.9, 138.6, 135.3, 134.9, 131.5, 131.1, 128.8, 128.5, 128.1, 126.9, 126.7,

121.3, 119.5, 112.4, 112.1, 110.9, 109.8, 62.4, 55.4, 54.9, 26.7, 23.1; MS (ESI) m/z: 488

[M+H]⁺; Anal. Calcd. for C₂₈H₂₃ClN₂O₂S: C, 69.05; H, 4.76; N, 5.75; Found: C, 69.30; H,

4.68; N, 5.81.

4-(9-(4-Chlorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)-2-

methoxyphenol (7f)

1

White solid; IR (KBr) υ_max(cm^ꢀ1): 3306 (OH), 1605 (C=N), 1242 (CꢀOꢀC), 821 (CꢀCl); H

NMR (400 MHz, DMSOꢀd₆): δ 1.78ꢀ1.84 (m, 1H), 2.26ꢀ2.34 (m, 1H), 2.59ꢀ2.65 (m, 1H),

2.75ꢀ2.81 (m, 1H), 3.47 (s, 3H), 6.09 (s, 1H), 6.42ꢀ6.45 (m, 1H), 6.63 (d, J = 8.4 Hz, 2H),

7.25ꢀ7.40 (m, 6H), 7.51 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 9.20 (s, 1H); MS (ESI)

m/z: 473 [M+H]⁺; Anal. Calcd. for C₂₇H₂₁ClN₂O₂S: C, 68.56; H, 4.48; N, 5.92; Found: C,

68.71; H, 4.36; N, 5.98.

7,9-Bis(4-chlorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline (7g)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1611 (C=N), 826 (CꢀCl); ¹H NMR (400 MHz, DMSOꢀd₆):

δ 1.72ꢀ1.79 (m, 1H), 2.31 (t, J = 8.0 Hz, 1H), 2.59ꢀ2.64 (m, 1H), 2.75ꢀ2.79 (m, 1H), 6.19 (s,

1H), 6.89 (d, J = 8.4 Hz, 2H), 7.23ꢀ7.35 (m, 7H), 7.39 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.4

Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.5, 138.3, 137.5,

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135.3, 135.0, 133.5, 131.4, 128.9, 128.7, 128.5, 128.1, 126.7, 121.4, 111.5, 110.1, 61.8, 26.6,

23.0; MS (ESI) m/z: 462 [M+H]⁺; Anal. Calcd. for C₂₆H₁₈Cl₂N₂S: C, 67.68; H, 3.93; N, 6.07;

Found: C, 67.51; H, 4.05; N, 6.19.

Synthesis

of

9-(4-bromophenyl)-7-aryl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazolines (8a-f)

A mixture of 4ꢀarylꢀ3,4,5,6ꢀtetrahydrobenzo[h]quinazolineꢀ2(1H)ꢀthione (4a-f, 1 mmol)

and 4ꢀbromo phenacyl bromide (6, 1 mmol) were taken in 5 mL of glacial acetic acid and

stirred at its reflux temperature for 3ꢀ6 h. After completion of the reaction shown by TLC, the

mixture was kept a room temperature for 4 h, the solid separated out was filtered, washed

with cold acetic acid and recrystallized from acetic acid to afford the pure product.

9-(4-Bromophenyl)-7-phenyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline (8a)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1603 (C=N), 578 (CꢀBr); ¹H NMR (400 MHz, DMSOꢀd₆):

δ 1.72ꢀ1.80 (m, 1H), 2.28ꢀ2.34 (m, 1H), 2.59 (t, J = 8.0 Hz, 1H), 2.75ꢀ2.81 (m, 1H), 6.15 (s,

1H), 6.84 (d, J = 7.6 Hz, 2H), 7.15ꢀ7.40 (m, 9H), 7.58 (d, J = 8.4 Hz, 3H); MS (ESI) m/z: 472

[M+H]⁺; Anal. Calcd. for C₂₆H₁₉BrN₂S: C, 66.24; H, 4.06; N, 5.94; Found: C, 66.15; H, 4.23;

N, 5.78.

4-(9-(4-Bromophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)phenol

(8b)

1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 3253 (OH), 1609 (C=N), 631 (CꢀBr); H NMR (400

MHz, DMSOꢀd₆): δ 1.76ꢀ1.84 (m, 1H), 2.26ꢀ2.34 (m, 1H), 2.58ꢀ2.65 (m, 1H), 2.76ꢀ2.84 (m,

1H), 6.05 (s, 1H), 6.52 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 7.20ꢀ7.38 (m, 6H), 7.61ꢀ

7.69 (m, 3H), 9.61 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.2, 157.8, 138.6, 135.3,

131.5, 131.4, 128.9, 128.8, 128.2, 127.1, 126.7, 126.6, 123.6, 123.4, 121.3, 115.3, 112.6,

110.0, 62.3, 26.7, 23.2; MS (ESI) m/z: 487 [M]⁺; Anal. Calcd. for C₂₆H₁₉BrN₂OS: C, 64.07;

H, 3.93; N, 5.75; Found: C, 63.95; H, 4.04; N, 5.85.

9-(4-Bromophenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazoline (8c)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1604 (C=N), 1227 (CꢀF), 632 (CꢀBr); ¹H NMR (400 MHz,

DMSOꢀd₆): δ 1.72ꢀ1.78 (m, 1H), 2.27ꢀ2.34 (m, 1H), 2.59ꢀ2.64 (m, 1H), 2.75ꢀ2.81 (m, 1H),

13

6.19 (s, 1H), 6.89ꢀ7.03 (m, 5H), 7.16ꢀ7.40 (m, 6H), 7.61 (d, J = 8.4 Hz, 2H); C NMR (100

MHz, DMSOꢀd₆): δ 163.1, 161.5, 138.4, 135.3, 134.9, 131.5, 131.4, 129.2, 128.9, 128.1,

126.9, 126.7, 123.7, 121.2, 115.6, 115.4, 111.7, 61.8, 26.6, 23.0; MS (ESI) m/z: 490 [M+H]⁺;

Anal. Calcd. for C₂₆H₁₈BrFN₂S: C, 63.81; H, 3.71; N, 5.72; Found: C, 63.90; H, 3.87; N,

5.56.

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9-(4-Bromophenyl)-7-(4-methoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazoline (8d)

1

White solid; IR (KBr) υ_max(cm^ꢀ1): 1606 (C=N), 1245 (CꢀOꢀC), 634 (CꢀBr); H NMR (400

MHz, DMSOꢀd₆): δ 1.75ꢀ1.81 (m, 1H), 2.27ꢀ2.35 (m, 1H), 2.56ꢀ2.64 (m, 1H), 2.75ꢀ2.81 (m,

1H), 3.67 (s, 3H), 6.09 (s, 1H), 6.72 (d, J = 8.0 Hz, 4H), 7.19ꢀ7.40 (m, 7H), 7.63 (d, J = 8.4

Hz, 2H); MS (ESI) m/z: 502 [M+H]⁺; Anal. Calcd. for C₂₇H₂₁BrN₂OS: C, 64.67; H, 4.22; N,

5.59; Found: C, 64.52; H, 4.45; N, 5.68.

9-(4-Bromophenyl)-7-(3,4-dimethoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-

b]quinazoline (8e)

1

Pale yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1598 (C=N), 1266 (CꢀOꢀC), 630 (CꢀBr); H NMR

(400 MHz, DMSOꢀd₆): δ 1.77ꢀ1.83 (m, 1H), 2.31 (t, J = 8.0 Hz, 1H), 2.57ꢀ2.65 (m, 1H),

2.75ꢀ2.83 (m, 1H), 3.47 (s, 3H), 3.67 (s, 3H), 6.12 (s, 1H), 6.57ꢀ6.59 (m, 1H), 6.81 (d, J = 8.4

Hz, 2H), 7.21ꢀ7.40 (m, 7H), 7.64 (d, J = 8.8 Hz, 2H); MS (ESI) m/z: 532 [M+H]⁺; Anal.

Calcd. for C₂₈H₂₃BrN₂O₂S: C, 63.28; H, 4.36; N, 5.27; Found: C, 63.36; H, 4.49; N, 5.06.

4-(9-(4-Bromophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)-2-

methoxyphenol (8f)

1

White solid; IR (KBr) υ_max(cm^ꢀ1): 3306 (OH), 1600 (C=N), 1277 (CꢀOꢀC), 634 (CꢀBr); H

NMR (400 MHz, DMSOꢀd₆): δ 1.76ꢀ1.84 (m, 1H), 2.25ꢀ2.33 (m, 1H), 2.59ꢀ2.65 (m, 1H),

2.75ꢀ2.81 (m, 1H), 3.48 (s, 3H), 6.07 (s, 1H), 6.44ꢀ6.46 (m, 1H), 6.63 (d, J = 8.0 Hz, 2H),

7.22ꢀ7.40 (m, 6H), 7.60ꢀ7.66 (m, 3H), 9.21 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ

160.9, 146.9, 146.8, 138.6, 135.3, 131.6, 131.4, 129.5, 128.7, 128.1, 127.3, 126.7, 123.6,

123.5, 121.3, 119.7, 116.1, 112.6, 111.5, 109.8, 62.5, 55.1, 26.7, 23.2; MS (ESI) m/z: 518

[M+H]⁺Anal. Calcd. for C₂₇H₂₁BrN₂O₂S: C, 62.67; H, 4.09; N, 5.41; Found: C, 62.40; H,

4.25; N, 5.58.

Synthesis

of

3-(7-aryl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-

chromen-2-one (11a-g)

To a mixture of 4ꢀarylꢀ3,4,5,6ꢀtetrahydrobenzo[h]quinazolineꢀ2(1H)ꢀthione (4a-g, 1

mmol) and 3ꢀ(2ꢀbromoacetyl)ꢀ2Hꢀchromenꢀ2ꢀone (9, 1 mmol) in 25 mL of round bottom

flask; 5 mL of glacial acetic acid was added and refluxed for 1ꢀ3 h. The progress of the

reaction was monitored by TLC. After completion of the reaction, the solid separated out was

filtered and washed with hot acetic acid to afford the pure product.

3-(7-Phenyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-chromen-2-one

(11a)

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1

Pale yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1711 (C=O of lactone), 1630 (C=N); H NMR (400

MHz, DMSOꢀd₆): δ 1.76 (t, J = 6.4 Hz, 1H), 2.28ꢀ2.36 (m, 1H), 2.57ꢀ2.65 (m, 1H), 2.77ꢀ2.81

(m, 1H), 6.25 (s, 1H), 7.16ꢀ7.26 (m, 6H), 7.34ꢀ7.49 (m, 5H), 7.64ꢀ7.89 (m, 4H); MS (ESI)

m/z: 461 [M+H]⁺Anal. Calcd. for C₂₉H₂₀N₂O₂S: C, 75.63; H, 4.38; N, 6.08; Found: C, 75.47;

H, 4.49; N, 6.15.

3-(7-(4-Hydroxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-

chromen-2-one (11b)

1

Pale yellow solid; IR (KBr) υ_max(cm^ꢀ1): 3430 (OH), 1727 (C=O of lactone), 1633 (C=N); H

NMR (400 MHz, DMSOꢀd₆): δ 1.74ꢀ1.79 (m, 1H), 2.26 (t, J = 8.0 Hz, 1H), 2.62 (t, J = 8.0

Hz, 1H), 2.76ꢀ2.80 (m, 1H), 6.10 (s, 1H), 6.52 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H),

7.24ꢀ7.51 (m, 6H), 7.68ꢀ7.74 (m, 3H), 7.92 (s, 1H), 9.61 (s, 1H); ¹³C NMR (100 MHz,

DMSOꢀd₆): δ 161.1, 158.5, 158.0, 153.5, 146.4, 135.4, 133.5, 133.4, 129.4, 129.1, 128.8,

128.5, 128.1, 126.6, 125.0, 121.4, 118.0, 116.2, 115.9, 115.5, 113.4, 112.0, 62.4, 26.7, 23.1;

MS (ESI) m/z: 477 [M+H]⁺; Anal. Calcd. for C₂₉H₂₀N₂O₃S: C, 73.09; H, 4.23; N, 5.88;

Found: C, 73.15; H, 4.38; N, 5.60.

3-(7-(4-Fluorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-

chromen-2-one (11c)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1740 (C=O of lactone), 1634 (C=N), 1226 (CꢀF); ¹H NMR

(400 MHz, DMSOꢀd₆): δ 1.76 (t, J = 6.4 Hz, 1H), 2.30 (t, J = 8.0 Hz, 1H), 2.60ꢀ2.66 (m, 1H),

2.76ꢀ2.83 (m, 1H), 6.27 (s, 1H), 7.02 (t, J = 8.4 Hz, 2H), 7.23ꢀ7.26 (m, 3H), 7.32ꢀ7.50 (m,

5H), 7.63ꢀ7.75 (m, 3H), 7.93 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 163.3, 161.4, 160.9,

158.4, 153.5, 146.9, 135.4, 135.2, 133.6, 133.1, 129.5, 129.4, 128.9, 128.1, 126.6, 125.0,

124.1, 121.5, 117.9, 116.2, 115.9, 115.7, 113.6, 111.3, 61.8, 26.6, 22.9; MS (ESI) m/z: 479

[M+H]⁺; Anal. Calcd. for C₂₉H₁₉FN₂O₂S: C, 72.79; H, 4.00; N, 5.85; Found: C, 72.54; H,

4.21; N, 5.72.

3-(7-(4-Methoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-

chromen-2-one (11d)

1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1716 (C=O of lactone), 1608 (C=N), 1248 (CꢀOꢀC); H

NMR (400 MHz, DMSOꢀd₆): δ 1.74ꢀ1.79 (m, 1H), 2.28 (t, J = 7.6 Hz, 1H), 2.61 (t, J = 8.0

Hz, 1H), 2.79 (t, J = 7.6 Hz, 1H), 3.58 (s, 3H), 6.18 (s, 1H), 6.69 (d, J = 8.4 Hz, 2H), 7.70 (d,

J = 8.8 Hz, 2H), 7.24ꢀ7.51 (m, 6H), 7.66ꢀ7.87 (m, 4H); MS (ESI) m/z: 491 [M+H]⁺; Anal.

Calcd. for C₃₀H₂₂N₂O₃S: C, 73.45; H, 4.52; N, 5.71; Found: C, 73.27; H, 4.72; N, 5.63.

3-(7-(3,4-Dimethoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-

2H-chromen-2-one (11e)

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1

White solid; IR (KBr) υ_max(cm^ꢀ1): 1734 (C=O of lactone), 1636 (C=N), 1261 (CꢀOꢀC); H

NMR (400 MHz, DMSOꢀd₆): δ 1.76ꢀ1.83 (m, 1H), 2.29 (t, J = 8.0 Hz, 1H), 2.61ꢀ2.66 (m,

1H), 2.76ꢀ2.80 (m, 1H), 3.26 (s, 3H), 3.59 (s, 3H), 6.15 (s, 1H), 6.68 (s, 1H), 6.75 (s, 2H),

7.25ꢀ7.50 (m, 6H), 7.66ꢀ7.65 (m, 3H), 7.88 (s, 1H); MS (ESI) m/z: 521 [M+H]⁺; Anal. Calcd.

for C₃₁H₂₄N₂O₄S: C, 71.52; H, 4.65; N, 5.38; Found: C, 71.39; H, 4.84; N, 5.47.

3-(7-(4-Hydroxy-3-methoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-

9-yl)-2H-chromen-2-one (11f)

Pale yellow solid; IR (KBr) υ_max(cm^ꢀ1): 3256 (OH), 1738 (C=O of lactone), 1638 (C=N),

1

1247 (CꢀOꢀC); H NMR (400 MHz, DMSOꢀd₆): δ 1.77ꢀ1.81 (m, 1H), 2.27 (t, J = 8.0 Hz,

1H), 2.60ꢀ2.66 (m, 1H), 2.77 (t, J = 7.6 Hz, 1H), 3.23 (s, 3H), 6.09 (s, 1H), 6.61 (d, J = 7.6

Hz, 3H), 7.24ꢀ7.50 (m, 6H), 7.61ꢀ7.74 (m, 3H), 7.93 (s, 1H), 9.18 (s, 1H); ¹³C NMR (100

MHz, DMSOꢀd₆): δ 161.0, 158.5, 153.5, 147.2, 146.4, 135.4, 133.6, 129.7, 129.4, 128.8,

128.1, 126.7, 125.0, 123.7, 121.4, 120.0, 118.0, 116.2, 112.0, 111.8, 62.7, 54.9, 26.7, 23.0;

MS (ESI) m/z: 507 [M+H]⁺; Anal. Calcd. for C₃₀H₂₂N₂O₄S: C, 71.13; H, 4.38; N, 5.53;

Found: C, 71.02; H, 4.55; N, 5.41.

3-(7-(4-Chlorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H-

chromen-2-one (11g)

White solid; IR (KBr) υ_max(cm^ꢀ1): 1740 (C=O of lactone), 1636 (C=N), 840 (CꢀCl); ¹H NMR

(400 MHz, DMSOꢀd₆): δ 1.73ꢀ1.78 (m, 1H), 2.27ꢀ2.35 (m, 1H), 2.60ꢀ2.66 (m, 1H), 2.76ꢀ2.80

(m, 1H), 6.27 (s, 1H), 7.22ꢀ7.26 (m, 5H), 7.34ꢀ7.51 (m, 5H), 7.64ꢀ7.75 (m, 3H), 7.94 (s, 1H);

¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.5, 158.4, 153.5, 147.0, 137.8, 135.4, 133.9, 133.7,

133.0, 129.4, 129.0, 128.9, 128.1, 126.7, 125.0, 121.5, 117.9, 116.3, 115.7, 113.6, 111.1,

61.8, 26.6, 22.9; MS (ESI) m/z: 495 [M+H]⁺; Anal. Calcd. for C₂₉H₁₉ClN₂O₂S: C, 70.37; H,

3.87; N, 5.66; Found: C, 70.50; H, 3.79; N, 5.74.

Synthesis

of

2-(7-aryl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-3H-

benzo[f]chromen-3-one (12a,b)

4ꢀArylꢀ3,4,5,6ꢀtetrahydrobenzo[h]quinazolineꢀ2(1H)ꢀthione (4a,b, 1 mmol) and 2ꢀ(2ꢀ

bromoacetyl)ꢀ3Hꢀbenzo[f]chromenꢀ3ꢀone (10, 1 mmol) were dissolved in 10 mL of glacial

acetic acid and stirred at its reflux temperature for 2 h. After completion of the reaction

(monitored by TLC), the solid separated out was filtered and washed with hot acetic acid to

afford the pure product.

2-(7-Phenyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-3H-

benzo[f]chromen-3-one (12a)

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1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 1729 (C=O of lactone), 1637 (C=N); H NMR (400

MHz, DMSOꢀd₆): δ 1.72ꢀ1.79 (m, 1H), 2.27ꢀ2.34 (m, 1H), 2.61 (t, J = 8.0 Hz, 1H), 2.77ꢀ2.83

(m, 1H), 6.28 (s, 1H), 7.13ꢀ7.41 (m, 8H), 7.52 (s, 1H), 7.64ꢀ7.76 (m, 4H), 8.11 (d, J = 8.0 Hz,

1H), 8.31ꢀ8.34 (m, 2H), 8.72 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.4, 158.4, 153.8,

143.0, 138.7, 135.4, 135.1, 133.5, 129.9, 129.0, 128.8, 128.6, 128.1, 127.0, 126.7, 126.4,

122.4, 121.4, 116.4, 114.8, 113.5, 112.4, 111.4, 62.9, 26.6, 23.1; MS (ESI) m/z: 511 [M+H]⁺;

Anal. Calcd. for C₃₃H₂₂N₂O₂S: C, 77.62; H, 4.34; N, 5.49; Found: C, 77.74; H, 4.45; N, 5.33.

2-(7-(4-Hydroxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-3H-

benzo[f]chromen-3-one (12b)

1

Yellow solid; IR (KBr) υ_max(cm^ꢀ1): 3358 (OH), 1710 (C=O of lactone), 1613 (C=N); H

NMR (400 MHz, DMSOꢀd₆): δ 1.75ꢀ1.81 (m, 1H), 2.22ꢀ2.30 (m, 1H), 2.60ꢀ2.66 (m, 1H),

2.76ꢀ2.83 (m, 1H), 6.16 (s, 1H), 6.48 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 7.25ꢀ7.41

(m, 3H), 7.51 (s, 1H), 7.64ꢀ7.70 (m, 4H), 8.12 (d, J = 8.0 Hz, 1H), 8.33ꢀ8.41 (m, 2H), 8.82 (s,

1H), 9.56 (s, 1H); ¹³C NMR (100 MHz, DMSOꢀd₆): δ 161.0, 158.4, 158.0, 153.8, 142.7,

135.4, 135.0, 133.6, 129.9, 129.1, 128.9, 128.8, 128.7, 128.6, 128.1, 126.7, 126.4, 123.9,

122.5, 121.3, 116.4, 115.5, 115.0, 113.4, 112.5, 112.0, 62.6, 26.7, 23.2; MS (ESI) m/z: 527

[M+H]⁺; Anal. Calcd. for C₃₃H₂₂N₂O₃S: C, 75.27; H, 4.21; N, 5.32; Found: C, 75.11; H, 4.43;

N, 5.40.

Determination of minimum inhibitory concentration (MIC)

The MIC values for all the synthesized compounds as well as positive control drugs

Penicillin and Streptomycin were determined against the three gramꢀpositive and three gramꢀ

negative bacterial strains by micro dilution method recommended by CLSI Standard Protocol

in liquid medium (Nutrient agar) distributed in 96ꢀwell plates. Serial dilutions of the test

compounds as well as standards were performed at concentrations ranging from 150 to 0.97

ꢁg/mL in a 200 ꢁL culture medium final volume; afterwards each well was seeded with a 50

ꢁL microbial suspension of 0.5 MacFarland density. In each test a microbial culture control

and a sterility control (negative) were performed. The plates were incubated for 24 h at 37 ^oC.

The lowest concentration which inhibited the visible microbial growth was considered the

MIC.

Diphenylpicrylhydrazyl (DPPH) method

Free radical scavenging activity was done by DPPH method. Briefly, 0.004% w/v of

DPPH radical solution was prepared in methanol and then 900 ꢁL of this solution was mixed

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with 100 ꢁL of solution containing 10 ꢁg/mL of test compound. The absorbance was

measured at 517 nm after 30 min of incubation.

Agarose gel electrophoresis method

Cleavage products were analyzed by agarose gel electrophoresis method. Test samples

(10 mg/mL) was prepared in DMSO. The samples at two different concentrations (50 and

100 ꢂg) were added to the isolated pUC18 (200 ꢂg/mL) plasmid. The samples were

incubated for 2 h at 37 ^oC and then 20 ꢂL of DNA sample (mixed with bromophenol blue dye

at 1:1 ratio) was loaded carefully into the electrophoretic chamber wells along with standard

DNA marker containing TAE buffer (4.84 g Tris base, pH 8.0, 0.5 M EDTA/1 L) and finally

loaded on agarose gel and constant 50 V of electricity was passed for around 30 min. Gel is

removed and stained with 10 ꢂg/mL ethidium bromide for 10ꢀ15 min and the bands were

observed under UV transilluminator and photographed to determine the extent of DNA

cleavage and the results were compared with standard FeSO₄.

Acknowledgments

We would like to thank the Director, National Institute of Technology, Warangal for

providing facilities, and wish to thanks Dr. U.S.N. Murthy, Head, Biology division, Indian

Institute of Chemical Technology, Hyderabad, for screening the antibacterial activity of the

synthesized compounds. We thank Dr. Hari Prasad Kokatla, Assistant professor, Department

of Chemistry, NITꢀWarangal for his valuable suggestions. One of the authors JB thanks the

Ministry of Human Resource Development for senior research fellowship.

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