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SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL HETEROCYCLES DERIVED FROM 2-ARYLIDENE-1-TETRALONES

 

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About Authors:
Roshni Patel*, Prof. Arun Parikh, Prof. Vijayalakshmi  Gudaparthi
Department of Pharmaceutical Chemistry, L.J.Institute of Pharmacy,
S.G.Highway, Ahmedabad-382210
*roshanimpharm@gmail.com

ABSTRACT
Medicinal chemistry involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. Indazoles have an important role in medicinal chemistry. Indazole  nucleus is an important class of nitrogen containing heterocyclic widely used as key building block for the synthesis of various pharmaceutically important agents. Indazole possess wide range of biological activities such as bactericidal, fungicidal, analgesic, antihypertensive, anti-inflammatory and antitumor. In the present study we have synthesized some novel 3,3a,4,5-tetrahydro-2-(substituted benzenesulphonyl)-3-(substituted phenyl)-2H-benzo[g]indazoles, by condensation of  1-tetralone with different substituted aromatic aldehydes and the resulted 2-(substituted benzylidene)-3,4,-dihydronaphtalen-1-ones on reaction with hydrazine hydrate in methanol followed by treatment with different substituted sulfonyl chlorides in pyridine gave the titled compounds.The synthesized compounds were characterized by IR, NMR and Mass spectral analysis. All newly synthesized derivatives were evaluated for antibacterial activity against  gram + ve and gram-ve bacteria B.cereus, S.aureus and E.coli respectivelyand antifungal activity againstC.albicans and all the synthesized compounds showed significant antibacterial and antifungal activity.

Reference Id: PHARMATUTOR-ART-1385

INTRODUCTION
The indazole ring is an important pharmacophore in medicinal chemistry. Benzannulated nitrogen heterocycles are ubiquitous in pharmaceutical research. As part of a continuing effort to develop novel heterocyclic compounds with potential therapeutic biological activity, we are currently involved in the synthesis of a large number of indazole derivatives.  Over the past decade, the indazole structural variant (benzo[c]pyrazole) has received much attention due to a broad range of biological activity. The synthesis of the indazole core, as well as the functionalization of the indazole ring system has recently been reviewed.1 Despite the many useful applications of indazole derivatives, indazole chemistry remains less studied compared to other heteroaromatic compounds, such as indole or benzimidazole. The indazole ring has two nitrogen atoms and presents annular tautomerism with regards to the position of the NH hydrogen atom. Due to the difference in energy between the tautomers, the 1H-tautomer (the benzenoid form) predominates in the gas-phase, solution and solid state, and its derivatives are usually thermodynamically more stable than the corresponding 2H-forms.

The regioselectivity of the reaction is also dependent on the nature of the alkylating agents used. The substitution at the different atoms of the six- and five membered rings with side chains with different length and functionalisation, can afford a large number of indazole derivatives, presenting a promising field to provide new derivatives with biological/therapeutical properties.2

Moreover, the increasing biological importance of indazole derivatives particularly in chemotherapy, promoted us to develop and synthesize new molecules with indazole moiety, with the aim of obtaining some novel heterocyclic systems with potentially enhanced biological properties. Indazoles constitute an important class of heterocycles that display interesting biological properties, such as anti-emetic 3,anticancer4, antimicrobial5, and anti-inflammatory activities6. The indazole ring system is also present in many other compounds such as herbicides, dyes or sweeteners like guanidine-1H indazole.

Recently, indazole derivative7, ABT-102 (1), has been identified as a potent vanilloid receptor (VR1) antagonist. This compound is currently undergoing advanced clinical development for the treatment of chronic pain, Axitinib (2),   was synthesized by Pfizer and WO/2007/056170 (3), was developed by Baeyer US as potent IGF-1R kinase inhibitors.

The synthesis of new hexahydroindazoles containing pharmacophore fragments and groups was carried out and their stereochemistry and bioactivity were investigated. The hexahydroindazole derivatives shared a larger part of the report for their use in pharmaceutical compositions as nonestrogenic antifertility agents and antihypertensive agents.

MATERIAL AND METHODS
Material:

The chemicals and reagentsused in the project work were of AR and LR grade, procured from Astron chemicals, Ahmedabad and they are used as they obtained.

Equipments:  
Purity of compounds was checked by thin layer chromatography. Melting points of synthesized compounds were determined by open capillary method. The IR spectra of synthesized compounds were recorded on a Fourier-Transform IR spectrophotometer (model-DRS 8400, Shimadzu) in the range of 400-4000 cm-1 using KBr pellets. The 1H-NMR spectra of synthesized compounds were recorded on Bruker Avance II 500MHz FT-NMR spectrophotometer (TOPSPIN 1.3 version) using DMSO-d6 as solvent.Mass spectrum was recorded by MDS SCIEX API 2000 LCMS/MS (Applied Biosystems) instrument.

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Method:
Step-1: Synthesis of (E)-2-(substituted benzylidene)-3,4-dihydronaphthalen-1-(2H)-one 8

The solution of substituted aromatic aldehyde (0.02 mole) and 1-tetralone (0.02 mole) in 18 ml PEG 600 was added to KOH (0.02 mole) and few ml of water. The reaction mixture was stirred for 1 hrs at room temperature. After stirring, the mixture was cooled in refrigerator overnight , filtered and washed with cooled ethanol, dried in air and recrystallized from ethanol.

Step-2: Synthesis of 3,3a,4,5-tetrahydro -3-(substituted phenyl) -2H- benzo [g] indazole
The solution of  hydrazine hydrate (0.03 mole) and step-1 compound,(E)-2-(substituted benzylidene)-3,4-dihydronaphthalen-1-(2H)-one (0.01 mole) in methanol (100 ml) was refluxed for 3 hrs. The above reaction mixture was kept in refrigerator for 24 hrs. The precipitated product was filtered, washed with methanol and recrystallized from methanol.

Step-3: Synthesis of 3,3a,4,5-tetrahydro 2-(substituted benzene sulphonyl)-3-(substituted phenyl) -2H-benzo[g]indazole
To the solution of 3,3a,4,5-tetrahydro-3-(substituted phenyl)-2H-benzo[g]indazole (0.004 mole) in pyridine (20 ml) was added of substituted benzene sulphonyl chloride (0.004 mole), and the mixture was heated on a water bath for 3 hrs. Then the reaction mixture was cooled, poured into dilute hydrochloric acid and the solid thus obtained was filtered, washed with water and recrystallized from rectified spirit.

SCHEME

Table 1: Physical  data table of  synthesized compounds

No.

 Name of sSubstituent ((R)

 Name of substituent (R1)

Molecular formula

 Melting

 point(°C)

Yield %

Rf  Value

1

4-Methoxy     phenyl

Benzene sulphonyl

C24H19N2O3S

188-1900C

66%

              0.77

Toluene:Ethyl acetate

              (7:3)

2

3,4-Dimethoxy

phenyl

Benzene sulphonyl

C25H22N2O4S

180-1820C

71%

              0.48

Toluene:Ethyl acetate

              (5:5)

3

 

Vanillin sulphonate

 

Benzene sulphonyl

C30H24N2O6S2

118-1200C

48%

0.54

n-Hexane:Ethyl acetate

               (7:3)

4

4-Chloro

phenyl

Benzene sulphonyl

C22H17N5O2Cl

186-1880C

70%

0.78

Toluene:Methanol

(6:4)

5

        2-Nitro

phenyl

 

Benzene sulphonyl

C22H17N3O4S

148-1500C

68%

0.49

Toluene:Methanol

(5:5)

6

      3-Niro

phenyl

Benzene sulphonyl

C23H17N3O4S

216-2180C

55%

0.65

Toluene:Ethyl acetate

(7:3)

7

2,3,4-         Trimethoxy

        phenyl

Benzene sulphonyl

C23H17N3O4S

170-1720C

75%

0.58

Toluene:Ethyl acetate

(7:3)

8

4-Dimethylamino phenyl

Benzene sulphonyl

C26H24N2O5S

178-1800C

56%

0.62

Toluene:Ethyl acetate

(5:5)

9

Vanillin sulphonate

2-Methoxy,5-carboxy benzene sulphonyl

C32H28N2O9S2

110-1120C

66%

0.61

Toluene:Methanol

(7:3)

10

4-Methoxy phenyl

2-Methoxy,5-carboxy benzene sulphonyl

C26H24N2O6S

86-890C

52%

0.55

Toluene:Ethyl acetate

(6:4)

11

3-Nitro

 phenyl

2-Methoxy,5-carboxy benzene sulphonyl

C25H21N3O7S

102-1040C

60%

0.55

Toluene:Ethyl acetate

(6:4)

12

2,3,4-         Trimethoxy

phenyl

2-Methoxy,5-carboxy benzene sulphonyl

C28H28N2O8S

68-700C

72%

0.55

Toluene:Ethyl acetate

(5:5)

(IIIa) 3,3a,4,5-Tetrahydro-2-(benzenesulphonyl)-3-(4-methoxyphenyl)-2H benzo[g] indazole
IR (KBr, cm-1):(3050) C-H str; (1425) C=C str; (1253) C-O-C str(sym); (1030)C-O-C str (asym) ; (1612) C=N str;.(1089) S=O str; (831) N-SO2 str ;1H NMR (δ ppm, DMSO): 3.8(S,3H,Ar-OCH3);1.5-2.6(M,5H,-CH2-CH2-CH);6.8-7.8(M,10H,Ar-H);4.1(S,1H,Ar-CH); Mass: (m/e) 418 (M+); 419.44; (M+1).

(IIIb)3,3a,4,5-Tetrahydro-2-(benzene sulphonyl)-3-(3,4-dimethoxyphenyl)-2H-benzo[g] indazole
IR (KBr, cm-1):(3045) C-H str;  (1454) C=C str; (1263) C-O-C str(sym);  (1022) C-O-C str (asym) ; (1595) C=N str; (1168) S=O str; (866) N-SO2 str;1H NMR (δ ppm, DMSO): 1.5-2.6 (M,5H,-CH2-CH2-CH);6.8-7.8(M-10H,Ar-H); 4.1(S,1H,Ar-CH) Mass: (m/e) 449.12;(M+1).

 (IIIc) 5-(3,3a,4,5-Tetrahydro-2(benzene sulphonyl)-2H-benzo[g]indazole -3-yl)-2-methoxyphenyl benzenesulfonate
IR (KBr, cm-1):(3064) C-H str; (1508) C=C str; (1263) C-O-C str(sym); (1029)C-O-C str (asym) ; (1602) C=N str;.(1159) S=O str; (941) N-SO2 str ; 1H NMR (δ ppm, DMSO): 3.8( S,3H,Ar-OCH3);1.5-2.6(M,5H,-CH2-CH2-CH);6.8-7.8(M-15H,Ar-H);4.1(S,1H,Ar-CH)Mass: (m/e) 574 (M+),575-(M+1).

(IIId) 3,3a,4,5-Tetrahydro-2-(benzene sulphonyl)-3-(4-chlorophenyl)-2H-benzo[g] indazole
IR (KBr, cm-1):(3000) C-H str; (1492) C=C str; (798) C-Cl str ; (1039) C=N str;.(1091) S=O str; (823) N-SO2 str ;  1H NMR (δ ppm, DMSO): 1.5-2.6(M,5H,-CH2-CH2-CH);6.8-7.8(M,11-Ar-H);4.1(S,1H,Ar-CH); Mass: (m/e).424.11(M+2).

(IIIe) 3,3a,4,5-Tetrahydro-2-(benzene sulphonyl)-3-(2-nitrophenyl)-2H-benzo[g]indazole
IR (KBr, cm-1):(3058) C-H str; (1490) C=C str; (1253)  ; (1602) C=N str; (1159) S=O str; (941) N-SO2 str ;  

(IIIf)3,3a,4,5-Tetrahydro-2-(benzene sulphonyl)-3-(3-nitrophenyl)-2H-benzo[g]indazole
IR (KBr, cm-1): (3055) C-H str; (1480) C=C str; (1253)  ; (1610) C=N str; (1162) S=O str; (955) N-SO2 str ; Mass: (m/e) 478 (M+2) 434.45-M+1

(IIIg) 3,3a,4,5-Tetrahydro-2-(benzene sulphonyl)-3-(2,3,4-trimethoxyphenyl)-2H-benzo [g]indazole
IR (KBr, cm-1):(3063) C-H str;  (1482) C=C str; (1261) C-O-C str(sym);  (1045) C-O-C str (asym) ; (1599) C=N str; (1174) S=O str; (829) N-SO2 str ;1H NMR (δ ppm, DMSO): 1.5-2.6(M,5H,-CH2-CH2-CH);6.8-7.8(M-12H,Ar-H);4.1(S,1H,Ar-CH); Mass: (m/e)  479.16 (M+1).

(IIIh) 4-(3,3a,4,5-Tetrahydro-)-2-(benzene sulphonyl)-2H-benzo[g]indazole-3-yl)-N,N-dimethyl benzenamine
IR (KBr, cm-1):(3055) C-H str;  (1480) C=C str; (1610) C=N str; (1162) S=O str; (955) N-SO2 str ; Mass: (m/e) 431.45(M) ,432.17(M+1)

(IIIi)5-(3,3a,4,5-Tetrahydro-2-(2methoxy,5-carboxy benzene sulphonyl)-2H-benzo[g]indazole-3-yl)-2-methoxyphenyl benzenesulfonate
IR (KBr, cm-1):(3061) C-H str; (1504) C=C str; (1274) C-O-C str(sym); (1030)C-O-C str (asym) ; (1579) C=N str;.(1178) S=O str; (831) N-SO2 str ; (1637) C=O str.

 (IIIj)3,3a,4,5-Tetrahydro-2-(2-methoxy,5-carboxy benzene sulphonyl)-3-(4-methoxyphenyl)-2H-benzo[g]indazole
IR (KBr, cm-1):(3053) C-H str; (1420) C=C str; (1240) C-O-C str(sym); (1034)C-O-C str (asym) ; (1628) C=N str;.(1089) S=O str; (828) N-SO2 str ;Mass: (m/e) 493.51(M+1).

(IIIk)3,3a,4,5-Tetrahydro-2-(2-methoxy,5-carboxy benzene sulphonyl)-3-(3-nitrophenyl) -2H-benzo[g]indazole
1H NMR (δ ppm, DMSO): 3.8( S,3H,Ar-OCH3);1.5-2.6(M,5H,-CH2-CH2-CH);6.8 7.8(M,12H,Ar-H);4.1(S,1H,Ar-CH); Mass: (m/e)  508.1(M+1)

(IIIl)3,3a,4,5-Tetrahydro-2-(2-methoxy,5-carboxy benzene sulphonyl)-3-(2,3,4 trimethoxyphenyl)-2H benzo[g]indazole
IR (KBr, cm-1):(3063) C-H str; (1496) C=C str; (1240) C-O-C str(sym); (1045)C-O-C str (asym) ; (1599) C=N str; Mass: (m/e)  552.18-(M),553.18(M+1)

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RESULTS AND DISCUSSION
Biological Evaluations Microbial Screening:

The synthesized compounds were screened for their anti-microbial activity by Agar diffusion method and Disc diffusion method using medium F and Sabouraud’s agar medium for bacteria and fungi respectively. Antimicrobial activity was evaluated by measuring the diameter of zone of inhibition against test organisms. Based on the results it is refered that synthesis of some indazole derivatives have significant inhibition effect on the growth of bacteria like Bacillus cereus, Staphylococus aureus and Escherichia coli and fungi likeCandida albicans. The results were tabulated in table. The results showed that the compound IIIc, IIId,  and IIIl showed  significant  antibacterial activity when compare to that the standard (Streptomycin and Tetracycline) and compound IIIc and IIId showed significant  antifungal activity when compare to that the standard (Miconazole).

Table-2 Antibacterial activity (zones of inhibition) of synthesised compound

Compound code

Conc(µg/mL)

Zone of inhibition(mm)

Gram +ve

Gram -ve

B.Cereus

S.aureus

E.coli

3a

64

7.10

7.0

6.93

80

8.4

8.1

7.12

100

9.45

9.3

8.18

125

14.32

13.98

13.52

165

19.45

19.58

18.40

3b

64

7.2

6.9.

6.1

80

9.66

8.7

7.71

100

12.75

11.9

10.87

125

15.44

15.7

13.2

165

19.55

18.2

16.4

3c

64

9.2

8.9

7.8

80

12.86

12.7

11.68

100

17.20

17.1

17.98

125

19.6

18.9

18.92

165

22.1

20.1

20.1

3d

64

9

7.9

7.5

80

12.5

12

10.9

100

16.7

14.9

16.9

125

17.5

16.8

18.1

165

21.5

18.1

19.7

3e

64

8.2

7.6

6.5

80

11.2

9.2

9.8

100

14.2

13.4

13.8

125

16.24

14.9

15

165

18.1

16.8

16.9

3f

64

7.8

6.8

5.9

80

10.9

10.8

9.8

100

13.6

12.2

13.1

125

15.9

14.4

14.2

165

17.85

16

16.4

3g

64

7.5

6.5

6.12

80

11.66

11.5

9.8

100

12.1

10.9

11.3

125

15.23

14.5

15.5

165

16.9

15.7

15.9

3h

64

6.55

5.5

4.9

80

7.81

6.9

5.9

100

8.26

9.8

6.33

125

13.4

12

12.1

165

18.5

14.3

15

3i

64

6.85

5.9

5.9

80

8.0

7.8

6.89

100

8.25

8.1

7.2

125

13.8

12.4

12.5

165

18

16.4

15.88

3j

64

8.4

7.4

7.1

80

11.6

10.5

10.9

100

15.82

14.8

14.9

125

17.2

16.9

15.7

165

19.6

18

17.5

3k

64

8.7

7.8

6.88

80

12

13.4

10.75

100

16.22

17

13.2

125

17.2

16.3

15.8

165

19

18.7

16.9

3l

64

7.11

7

6.3

80

11.04

12.1

9

100

12.5

13.2

14

125

15.2

14

15.2

165

19.5

16.4

17.1

Streptomycin

25

15

12.9

-

50

19.7

18

-

75

21.8

19.5

-

100

24.3

21

-

 

Tetracycline

25

-

-

13.5

50

-

-

15.2

75

-

-

18.7

100

-

-

22

Degree of activity was measured by the zone of inhibition (mm), (--) No inhibition

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Table-3 Antifungal activity (zones of inhibition) of synthesised compounds

Compound code

Conc.

(µg/ml)

Zone of inhibition

(mm)

Compound   code

Conc.

(µg/ml)

Zone of inhibition

(mm)

C. albicans

C. albicans

3a

50

4.5

3g

50

6.1

100

7.9

100

9.7

150

8.3

150

10.4

200

14.1

200

15.7

3b

50

5.6

3h

50

2.9

100

10.7

100

5.9

150

16.3

150

10.7

200

14.6

200

15.1

 

3c

50

6.3

3i

50

4.7

100

13.5

100

11.4

150

16.0

150

13.5

200

18.2

200

13.7

3d

50

6.9

3j

50

5.5

100

8.5

100

9.2

150

10.7

150

10.6

200

18.5

200

13.5

3e

50

6.3

3k

50

8.7

100

9.1

100

9.9

150

10.9

150

11.8

200

18

200

16.7

3f

50

8.4

3l

50

9.9

100

12.5

100

11.2

150

14.0

150

13.8

200

16.4

200

15.9

Miconazole

25

9.7

Miconazole

75

15.3

50

12.1

100

20.4

Degree of activity was measured by the zone of inhibition (mm), (--) No inhibition

Fig.5:Antifungal activity chart of C. albicans fungiof synthesized test compounds.

CONCLUSION
Among all synthesized compounds, most of them showed significant antibacterial activity within the series against both of Gram +ve and Gram –ve bacteria at 125 and 156 μg/ml concentrations and antifungal activity at 150 and 200 μg/ml concentrations.

ACKNOWLEDGEMENTS
The authors are thankful to L.J.Institute of Pharmacy for providing facilities for synthesis and biological screening.

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