Design, Synthesis and Biological Evaluation of Methyl-2-(2-(Arylideneamino) Oxazol-4- Ylamino) Benzoxazole-5-Carboxylate Derivatives as New Antiinflammatory Agents

 

Nageshwar Rao Chilumula1, Srinivas Ampati2, Rajyalaxmi Gudipati2, Sarangapani Manda2 and Dayakar Gaday1*

1Departmet of Chemistry, Kakatiya University, Warangal, A.P-India, 506009          

2University College of Pharmaceutical Sciences, Kakatiya University, Warangal, A.P.-India, 506009

*Corresponding Author E-mail: profgdayakar@gmail.com

 

ABSTRACT:

A series of novel methyl-2-(arylideneamino)oxazol-4ylamino)benzoxazole-5-carboxylate derivatives synthesized. The structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass spectral data and elemental analysis. Compounds were evaluated for their anti-inflammatory activity. Derivatives VIId and VIIe exhibited very good and almost equal anti-inflammatory activity in carrageenan-induced rat paw edema method compared with the standard drug Diclofenac Sodium.

 

KEYWORDS: Benzoxazole derivatives, IR, 1H NMR and Mass spectroscopy, methyl-2- (arylideneamino)oxazol-4ylamino) benzoxazole -5-carboxylate and anti inflammatory.

 


INTRODUCTION:

Non-steroidal anti-inflammatory drugs (NSAID) are one of the most widely used drug category against inflammation, mild to moderate pain, and fever. Specific uses also include the treatment of headaches, arthritis, sports injuries, and menstrual cramps. Their use is mainly restricted by their well known and serious adverse gastrointestinal side effects such as gastroduodenal erosions and ulcerations1–5. NSAID-induced gastropathy are estimated to affect up to half of chronic NSAID users, with major world health implications6. Therefore, search for better and safer anti-inflammatory agents is always going on at a rapid pace. The ring system in which a benzene ring is fused to the 4,5-positions of oxazole is designated as Benzoxazole7. Recent observations suggest that substituted benzoxazoles and related heterocycles, possess potential activity with lower toxicities in the chemotherapeutic approach in man8,9. Careful literature survey revealed that targets containing benzoxazole moiety, either isolated from plants or accessed by total synthesis, have remarkable biological activities10. For example, antimicrobial11, antihistaminic12, antiparasitics13, herbicidal14 antiviral15 antiallergic16, and antihelmintic acticivities17.Anti-inflammatory activity of benzoxazole derivatives were also reported in the literature.

 

Previously in our laboratory we have synthesized methyl-2- (arylideneamino) benzoxazole -5-carboxylate derivatives proved as potent anti-inflammatory agents18. Therefore, it was thought worthwhile to explore anti-inflammatory potential of some methyl-2- (arylideneamino)oxazol-4ylamino) benzoxazole -5-carboxylate derivatives. Accordingly the present work is concerned with the synthesis of different methyl-2- (arylideneamino)oxazol-4ylamino) benzoxazole -5-carboxylate derivatives with the objective of discovering novel and potent anti-inflammatory agents that might be devoid of side effects. The compounds were evaluated for their acute anti-inflammatory activity using carrageenan-induced rat paw edema model. Moreover, the test compounds showing potent anti-inflammatory activity. The title compounds were synthesized by treating the methyl-2-(2-aminooxazol-4-ylamino) benzoxazole-5-carboxylates with appropriate aromatic aldehydes to get a new series of methyl-2- (arylideneamino) oxazol-4ylamino) benzoxazole-5-carboxylate derivatives.

 

MATERIALS AND METHODS:

All melting points were taken in open capillaries on a veego VMP-1 apparatus and are uncorrected IR spectra were recorded as KBr pellets on a Perkin-Elmer FT IR 240-c spectrometer. The 1H NMR spectra were recorded on Varian-Gemini 200 MHz spectrometer in DMSO-d6 using TMS as an internal standard and mass spectras were recorded on Schimadzu QP 5050A spectrometer.

 

I.         Synthesis of 4-Carbomethoxy-2-nitrophenol (II):

To a solution of aluminium nitrate (40g) in acetic acid- acetic anhydride (1:1) mixture (160ml), was added an appropriate phenol (I, 40g) in small portions, while cooling and shaking occasionally. The reaction mixture was left at room temperature for 1.5 h while shaking the contents intermittently to complete the nitration. The resulting brown solution was diluted to complete the nitration. The resulting brown solution was diluted with ice-cold water and acidified with concentrated Nitric acid to get a bulky, yellow precipitate. It was filtered washed with small quantity of methanol and purified by recrystallization from alcohol to get a yellow crystalline solid (44g, 85%), m.p 73OC19.

 

II. Synthesis of 4-carbomethoxy-2-aminophenol (III):

4-carbomethoxy-2-nitrophenol (II, 10 g) was dissolved in boiling alcohol (50%, 100ml) and sodium dithionite was added to this boiling alcohol solution until it becomes almost colourless. Then the alcohol was reduced to one-third of its volume by distillation and the residual liquid was triturated with crushed ice. The resulting colourless, shiny product was filtered, washed with cold water and dried in the air. Its purification was effected by recrystallization from benzene to get colourless, shiny scales (5.1 g; 60%) m.p 143 C20.

 

III.Synthesis of methyl 2-aminobenzoxazole-5-carboxylate (IV):

1.3 mol of 4-carbomethoxy-2-aminophenol (III) was dissolved in 1lit. methyl alcohol and cooled the solution to 5 C by adding chopped ice. A cold suspension of 1.5 mol of cyanogenbromide in 1lit of water was added over a period of 5min with rapid stirring. Continued the stirring for 0.75h at room temperature, 1.3 mol of solid sodium bicarbonate in small portions over a period of 1.5 h was added to bring the pH 6.5 -7.0. Stirring was continued for another 1h. The solid was separated by filtration, washed with cold water and on recrystallization from ethyl alcohol has resulted white solid, yield 70% m.p 238 C.

 

IV. Synthesis of methyl-2-(2-chloroacetamido) benzoxazole-5-carboxylate (V):

A mixture of methyl-2-aminobenzoxazole-5-carboxylate (IV, 0.01mol) and chloroacetyl chloride (0.01mol) was taken in 20 ml of dry benzene and the reaction mixture was refluxed for 5h on a water bath. The solvent was evaporated and the residue was washed first with benzene and then with petroleum ether. The compound was recrystallized from suitable solvent(s). The compound was found to be containing yield 72% and m.p is 177 C.

 

IV. Synthesis of methyl-2-(2-aminooxazol-4-ylamino) benzoxazole-5-carboxylate (VI):

Methyl-2-(2-chloroacetamido) benzoxazole-5-carboxylate (VI, 0.01mol) and urea (0.01mol) were dissolved in 10ml of absolute alcohol in conical flask. The conical flask was hanged with a funnel and was subjected to microwave irradiation at 480 Watts for 5min in LG-Microwave oven. The reaction was monitored by TLC.  After the completion of the reaction the contents were cooled and triturated with crushed ice the separated solid was filtered, washed with 1% NaHCO3 solution and purified by recrystallization from ethanol and water mixture found to be containing yield 97% and m.p 199 C.

 

V. Synthesis of methyl-2-(2-(arylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate (VII):

Methyl-2-(2-aminoxazol-4-ylamino) benzoxazole-5-carboxylate (XII,0.01mol) and appropriate aromatic aldehydes viz. Benzaldehyde, salicyladehyde, p-hydroxybenzaldehyde, anisaldehyde, p-dimethylaminobenzaldehyde, p-chlorobenzaldehyde, veratraldehyde, cinnamaldehyde, 3,4,5-trimethylbenaldehyde (0.015mol) were taken into a conical flask and were dissolved in 10ml of absolute alcohol.  The conical flask was hanged with a funnel and was subjected to microwave irradiation at 480 Watts for 7min in LG-Microwave oven. The reaction was monitored by TLC. The reaction mixture was cooled and triturated with crushed ice; the separated solid was filtered, washed with 1% NaHCO3 solution and purified by recrystallization from ethanol and water mixture. The compounds were characterized by spectral data.

 

Compound VIIa: Methyl-(2-(4-(dimethylamino) benzylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3133(NH), 1693 (C=N), 1610 (C=C), 1582 (C=N), 1249 (C-O-C).

1H-NMR (DMSO-d6) δ: 8.8 (s, 1H, CH), 8.6 (s, 1H, Ar-H), 8.1(d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.6(s, 1H, Ar-H oxazole ring), 7.5(d, 2H, Ar-H), 6.8(d, 2H, Ar-H) 5.3(s, 1H, NH), 3.8(s, 3H, OCH3), 3.0(s, 6H, CH3).

MS (m/z): M+: 406.1

 

Compound VIIb: Methyl-2-(2-(benzylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3138(NH), 1696 (C=N), 1602 (C=C), 1576 (C=N), 1233 (C-O-C).

1H-NMR (DMSO-d6) δ: 8.6 (s, 1H, CH), 8.5 (s, 1H, Ar-H), 8.1(d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.8 (d, 2H, ArH), 7.7 (s, 1H, Ar-H oxazole ring), 7.5(t, 3H, Ar-H), 6.8(d, 2H, Ar-H) 5.3(s, 1H, NH), 3.8(s, 3H, OCH3)

MS (m/z): M+: 363.1

 

 

Compound VIIc: methyl-2-(2-(2-hydroxybenzylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3137(NH), 1669 (C=N), 1620 (C=C), 1585 (C=N), 1241 (C-O-C).

1H -NMR (DMSO-d6) δ: 11.2(s, 1H, OH), 8.8 (s, 1H, ArH), 8.3 (s, 1H, CH), 8.1(d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.9 (s, 1H, ArH oxazole ring), 7.7 (d, 1H, Ar-H), 7.5(t, 1H, Ar-H), 7.1(t, 1H, Ar-H), 7.0(d, 1H, Ar-H), 5.5(s, 1H, NH), 3.9(s, 3H, OCH3)

MS (m/z): M+: 379.1

 


Table 1: Physical data of methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates (VII).

 

S. No

Compound

Ar

Chemical formula

Melting Point (OC)

Yield (%)

Elemenyal analysis (C; N; H; O)

1

VIIa

4-dimethylaminophenyl

C21H19N5O4

228

94

62.22;4.72;17.27;15.79

2

VIIb

Phenyl

C19H14N4O4

211

95

62.98; 3.89; 15.46; 17.66

3

VIIc

2-hydroxyphenyl

C19H14N4O5

229

90

60.23; 3.73; 14.81; 21.14

4

VIId

4-chlorophenyl

C19H13N4O4Cl

204

91

57.51; 3.30; 14.12, 16.13, 8.94(Cl)

5

VIIe

4-methoxyphenyl

C20H16N4O5

235

96

61.22; 4.11; 14.28; 20.39

6

VIIf

4-hydroxyphenyl

C19H14N4O5

236

98

60.23; 3.73; 14.81; 21.14

7

VIIg

2-hydroxy-4-methoxyphenyl

C20H16N4O6

222

92

58.82; 3.95; 13.72; 23.51

8

VIIh

Cinnamalyl

C21H16N4O4

233

95

64.64; 4.15; 14.43; 16.48

9

VIIi

3,4,5-trimethylphenyl

C22H20N4O4

207

93

65.34; 4.98; 13.85; 15.82

 

Table 2a: Showing the Mean ± SD of the paw volume of the Compounds in Scheme – I (methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates) by Carrageenan induced rat paw oedema method. (n  = 6)

 

Time

1.0hr

2.0hr

3.0hr

4.0hr

Carraggenan

2.74±0.213

2.87±0.254

3.12±0.218

3.15±0.284

DFS

1.14±0.236

1.2±0.236

0.85±0.274

0.62±0.265

VIIa

2.67±0.398

2.03±0.341

1.56±0.358***

0.71±0.319***

VIIb

2.54±0.361

2.33±0.398

1.73±0.350***

1.04±0.347***

VIIc

2.53±0.398

2.31±0.367

1.34±0.387***

0.94±0.381***

VIId

2.39±0.374

2.07±0.329

1.41±0.358***

0.61±0.384***

VIIe

2.58±0.381

2.14±0.393

1.52±0.317***

0.67±0.309***

VIIf

2.52±0.393

2.45±0.380

1.59±0.331***

1.02±0.322***

VIIg

2.59±0.381

2.19±0.392

1.62±0.329***

1.05±0.339***

VIIh

2.53±0.391

2.36±0.366

1.85±0.311***

0.98±0.355***

VIIi

2.47±0.356

2.23±0.311

1.76±0.365***

1.01±0.391***

*** = p<0.001, ** = p<0.01, * = p<0.05

 

Table 2b: Percentage inhibition of paw volume of the Compounds in Scheme – I (methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates) by Carrageenan induced rat paw oedema method.      (n = 6)

 

Time

1hr %red

2 hr %red

3hr %red

4hr %red

Carraggenan

NA

NA

NA

NA

DFS

32.84

54.00

66.34

80.31

VIIa

2.55

29.26

50.00

77.46

VIIb

7.29

18.81

44.55

66.98

VIIc

7.66

19.51

57.05

70.15

VIId

12.77

27.87

54.80

80.63

VIIe

5.83

25.43

51.28

78.73

VIIf

8.02

14.63

49.03

67.61

VIIg

5.47

23.69

48.07

66.66

VIIh

7.66

17.77

40.70

68.88

VIIi

9.85

22.29

43.58

67.93

 

Scheme-1

 


Compound VIId: methyl-2-(2-(4-chlorobenzylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3112(NH), 1685 (C=N), 1609 (C=C), 1564 (C=N), 1223 (C-O-C).

1H -NMR (DMSO-d6) δ: 8.6(s, 1H, ArH), 8.3 (s, 1H, CH), 8.2(d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.9 (s, 1H, ArH oxazole ring), 7.8 (d, 2H, Ar-H), 7.5(d, 2H, Ar-H), 5.1(s, 1H, NH), 3.6(s, 3H, OCH3)

MS (m/z): M+: 397.1

 

Compound VIIe: methyl-2-(2-(4-methoxybenzylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3114(NH), 1647 (C=N), 1615 (C=C), 1543 (C=N), 1212 (C-O-C).

1H -NMR (DMSO-d6) δ: 8.8(s, 1H, ArH), 8.5 (s, 1H, CH), 8.0(d, 1H, Ar-H), 7.8(d, 1H, Ar-H), 7.6 (s, 1H, ArH oxazole ring), 7.4 (d, 2H, Ar-H), 7.3(d, 2H, Ar-H), 5.4(s, 1H, NH), 3.9(s, 3H, OCH3), 3.6(s, 3H, OCH3)

MS (m/z): M+: 393.1

 

Compound VIIf: methyl-2-(2-(4-hydroxybenzylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3133(NH), 1690 (C=N), 1602 (C=C), 1592 (C=N), 1259 (C-O-C).

1H -NMR (DMSO-d6) δ: 9.4(s, 1H, OH), 8.8(s, 1H, ArH), 8.6(s, 1H, CH), 8.1(d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.9 (s, 1H, ArH oxazole ring), 7.8 (d, 2H, Ar-H), 6.8(d, 2H, Ar-H), 5.0(s, 1H, NH), 3.6(s, 3H, OCH3)

MS (m/z): M+: 379.1

 

Compound VIIg: methyl-2-(2-(2-hydroxy-4-methoxybenzylideneamino)oxazol-4-ylamino)benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3141(NH), 1659 (C=N), 1612 (C=C), 1568 (C=N), 1217 (C-O-C).

1H -NMR (DMSO-d6) δ: 11.5(s, 1H, OH), 8.8(s, 1H, ArH), 8.7(s, 1H, CH), 8.4(d, 1H, Ar-H), 8.3(d, 1H, Ar-H), 7.7 (s, 1H, ArH oxazole ring), 7.6 (d, 1H, Ar-H), 6.6(d, 1H, Ar-H), 6.4(s, 1H, ArH), 5.2(s, 1H, NH), 3.9(s, 3H, OCH3), 3.3(s, 3H, OCH3)

MS (m/z): M+: 409.0

 

CompoundVIIh: methyl-2-(2-(3-cinnamylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3103(NH), 1640 (C=N), 1600 (C=C), 1590 (C=N), 1219 (C-O-C).

1H -NMR (DMSO-d6) δ: 8.6 (s, 1H, ArH), 8.1 (d, 1H, Ar-H), 8.0(d, 1H, Ar-H), 7.7(s, 1H, Ar-H oxazole ring), 7.6(d, 2H, Ar-H),7.5 (s, 1H, CH), 7.4(t, 1H, Ar-H), 7.3(t, 1H, Ar-H), 7.0 (s, 1H, CH), 5.3 (s, 1H, CH), 4.6 (s, H, NH), 3.8(s, 3H, OCH3).

MS (m/z): M+: 389.0

 

CompoundVIIi: methyl-2-(2-(3, 4, 5-trimethylbenzylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylate:

IR (KBr, cm-1): 3201(NH), 1670 (C=N), 1628 (C=C), 1588 (C=N), 1219 (C-O-C).

1H -NMR (DMSO-d6) δ: 8.8 (s, 1H, ArH), 8.5 (d, 1H, CH), 8.1(d, 1H, Ar-H),8.0(s, 1H, ArH), 7.8(s, 1H, Ar-H oxazole ring), 7.3(s, 2H, Ar-H), 5.2 (s, 1H, CH), 5.3 (s, H, NH), 3.9(s, 3H, OCH3), 2.3(s, 6H, CH3), 2.13.9(s, 3H, CH3)

MS (m/z): M+: 405.0

 

Anti inflammatory activity21:

Carrageenan - induced rat paw edema method21 was employed for evaluating the anti inflammatory activity of the synthesized compounds.

 

Wister Albino rats of either sex weighing approx 200- 350 gm, were housed in clean polypropylene cages and kept under room temperature (25±2 C), and relative humidity 40-50% in a 12 h light-dark cycle. Food was withdrawn 12 h before and during experimental hours. In this study, the animals were divided into groups as shown in the Table-2. Acute inflammation was produced by sub plantar injection of 0.1ml of 1% suspension of Carrageenan with 2% gum acacia in normal saline, in the right hind paw of the rats. After oral administration of the test compounds, the paw volume was measured Plethysmometrically at 1, 2, 3, and 4 h intervals. Diclofenac sodium 10mg/ml of 2% gum acacia in normal saline was used as standard drug.

 

RESULTS AND DISCUSSION:

The target compounds were synthesized according to the Scheme-1. The required starting material, methyl-3-amino-4-hydroxybenzoate (III) was prepared in good yield (85%) according to reported procedure. The methyl-3-amino-4-hydroxybenzoate (III) on cyclization with cyanogen bromide in methyl alcohol and water on rapid stirring at room temperature gave the product, methyl-2-aminobenzoxazole-5-carboxylate (IV).The methyl-2-aminobenzoxazole-5-carboxylate on reaction with chloroacetylchloride gave the product methyl-2-(2-chloroacetamido) benzoxazole-5-carboxylate(V), which on treatment with urea gave methyl-2-(2-aminooxazol-4-ylamino) benzoxazole-5-carboxylate(VI).  Further, the desired compounds (VIIa-VIIi), methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates were obtained by reacting methyl-2-(2-aminooxazol-4-ylamino) benzoxazole-5-carboxylate (VI) with different aromatic aldehydes. The yields, melting points and physical data of newly synthesized compounds are summarized in Table-1. The formation of methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates were confirmed by means of IR, 1HNMR, mass spectral analysis. The investigation of anti inflammatory acivity revealed that  the tested compounds VIIa-VIIi were significantly (p<0.0001) reduced the inflammation there by showed a promising anti-inflammatory activity, where as the compound VIIb, VIIf, VIIg, VIIh and VIIi moderately reduced the inflammation towards Carrageenan – induced paw edema rat model when compared to the standard drug Diclofenac Sodium (10mg/ml).Compound VIIb with simple phenyl group the activity is moderate where as in case of VIIc the inhibitory activity was increased with the presence of a hydroxyl group at 2nd position of the phenyl ring. In case compound VIIa the inhibitory activity was increased by substituion of dimethylamino group at 4th position of the phenyl group when comparing with compound VIIb. Compound VIId was showed almost eaqual activity with the presence of a chloro group at 4th position of the phenyl group and also the good activity was observed with the compound VIIe by substitution of methoxy group at 4th position of the phenyl group. Therefore by the presence of electron withdrawing groups, the activity was increased.

 

CONCLUSION:

This study reports the successful synthesis of the title compounds in good yields and moderate to potent anti inflammatory activity of these derivatives containing benzoxazole moiety which is comparable with standard drug.

 

Figure 1: Percentage inhibition of paw volume of the Compounds in Scheme – I methyl-2-(2-(arylideneamino) oxazol-4-ylamino) benzoxazole-5-carboxylates)by Carrageenan induced rat paw oedema method

 

ACKNOWLEDGEMENTS:

The authors thank Prof. E.Ram Reddy for IR spectra, Kakatiya University, Mr. Sudhakar, IICT for NMR spectra and Mr. Mahesh for mass spectra.

 

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Received on 09.07.2010          Modified on 23.07.2010

Accepted on 31.07.2010         © RJPT All right reserved

Research J. Pharm. and Tech. 4(2): February 2011; Page 302-307