INTRODUCTION:

Oxazolones are flexible reagents used for the synthesis of α-keto acids, arylacetic acids, α-amino acids, peptides and also plays a key role in the synthesis of several natural products.^1,2,3 Oxazolones have many biological applications; such as antimicrobial,^4-13 analgesic, antiinflammatory,¹⁴ anticancer,¹⁵ anti-HIV,¹⁶antiangiogenic,anticonvulsant, antitumor,¹⁷ antinociceptive,^14,18,19 antagonistic,²⁰ pesticidal²¹ and cardiotonic activity.²² Applications include their use as immunomodulators,²³ biosensors or photosensitive compositions devices for proteins,^5,8,24,25 also in semiconductor devices as electrophotographic photoreceptors and non-linear optical materials, because of their promising photophysical and photochemical activities.²⁶ The chemistry of unsaturated oxazolone signifies the reactivity of the exocyclic double bond, which operate as a dienophile in the Diels-Alder reaction. In literature, oxazolone also known as azlactone,³ have been used as excellent substrate for synthesizing various oxazolone derivatives involving Michael addition reaction,²⁷ Erlenmeyer reaction and cycloaddition reaction.^28-30In oxazolone, electron donating groups enhance the activity as compared to electron withdrawing groups. Substitutions at the C-4 position and C-2 position in oxazolone ring may affect the activity to a certain extent.²¹ Oxazolone also participates as a key intermediate for the synthesis of oxazoles,^31,32 triazoles,³³ imidazolones,^34-37 pseudo-peptides,¹ imidazolines,³⁸ furanones,³⁹ propenoic acids,⁴⁰ amides,^41,42 imidazolinones,⁴³ quinazolinones,^44,45 pyrrole derivatives,²⁷pyrazoles⁴⁶ and highly functionalized molecules.³In literature, a classical Erlenmeyer azlactone synthesis is an important method, which plays a vital role for producing aromatic α-amino acids and dehydropeptides.^47,48

Some oxazolones also act as NOS inhibitor,⁴⁹ cyclooxygenase-2 inhibitor^14,18,50and tyrosinase inhibitor.^21,51Oxazolone shows interesting behaviour towards polymerization and condensation leading to homopolymers, telomers, condensation reagents, peptides, herbicides,⁵² fungicides, pesticides.^21,53

Oxazolone MDL 27032, a has good smooth muscle vasorelaxant effects and antimetastatic properties linked to its ability to inhibit protein kinase C.⁸A number of antibiotics are available for the cure of various viral infectious diseases. From these, jadomycin is an antibiotic of benzoxazolophenanthridine family, having a potency to inhibit bacteria, yeast and also exhibiting cytotoxicity against cancerous cells.^54,55

David L. Jakeman et al reported jadomycin B, b is a Type-II polyketides derived (glycosylated) natural product, which contains a five-membered oxazolone ring with the extension of aliphatic side chain through the α-carbon, produced by Streptomyces venezuelae. They found that compound b showed excellent activity against methicillin resistant Staphylococcus aureus with minimum inhibitory concentration.⁵⁶Oxazolone is used as a key intermediate for synthesis of sphingofungin F, c by an asymmetric allylic alkylation with gem-diacetate.²⁸Sphingofungin F, is a natural product which has serine palmitoyltransferase inhibiting properties and potent antifungal activity against various Candida species.⁵⁷

Salinosporamide A, d is well known anticancer agent.^58,59 Robert A. Mosey et al synthesised a novel salinosporamide A, d via a tert-alkyl amino hydroxy carboxylic ester, which produced in an ene-type reaction of an oxazolone with an enol ether.⁶⁰ Intramolecular Diels-Alder cycloaddition of N-substituted oxazolones are used for designing the skeleton of alkaloids from trienes such as (±)-2-epi-pumiliotoxin C.⁶¹

Antimicrobial activity:

Vijay Taile et al reported that the carbohydrate containing 4-(4-o-β-d-glucoxybenzylidene)-2-(substituted styryl) oxazol-5-ones 1 have shown good antibacterial activity against pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Klebsiella aerogenes, using ciprofloxacin and sulphacetamide as standard drugs. The results showed maximum antifungal activity of these compounds against Aspergillus niger, Candida albicans, using gentamycin and clotrimazole as standard drugs.⁴

M. A. Pasha et al synthesised 4-arylmethylidene-2-phenyl-5-(4H)-oxazolones 2 and screened their potent antibacterial activity. They indicated that compounds 2a-2d have shown minimum inhibitory concentration (MIC) against Bacillus subtilis at 180.8, 192.0, 179.2, 185.6 and 166.4 µg/50 µL, respectively and compounds 2a, 2c, 2d and 2e also showed minimum inhibitory concentration (MIC) against Escherichia coli at 167.0, 160.0, 182.4 and 160.4 µg/50 µL, respectively. They used streptomycin and ampicillin as standard drugs.⁵

Manish Tandon et al reported that compound 1-{1-[2-(2,4-dichloro-phenyl)-5-oxo-oxazol-4-ylidene]-propyl}-azetidine-2-carboxylic acid [1-carbamoyl-2-(4-hydroxy-phenyl)-ethyl]-amide 3 containing oxazolone ring. They proved that compound 3 showed remarkable antibacterial activity against Staphylococcus aureus methionyl tRNA synthetase and Enterococci faecalis methionyl tRNA synthetase with an IC₅₀ of 18 nM and IC₅₀ of 3.51 µM, respectively.⁶

M. J. Aaglawe et al synthesised some substituted oxazolone derivatives 4 and screened them for their antibacterial activity against E. coli and Xanthomonas citri, using streptomycin as a standard drug. They found that 4-substituted aryl 2,4-substituted phenloxy methyl 4-oxazol-5-ones 4a-4f have shown maximum antibacterial activity against Xanthomonas citri. Compounds 4b, 4d, 4e and 4g have shown highest antibacterial activity against E. coli.⁷

A series of N-substituted oxazolone derivatives 5 were synthesised from cyclic carbonates and evaluated their antimicrobial activity by Elisabete Rodrigues et al. They found that all N-substituted compounds have shown inhibitory activity against Bacillus cereus, Corynebacterium equi and Streptomyces chartreusis. They also observed that compound 5d has shown excellent growth inhibitory effect against S. faecalis and good inhibiting properties towards the sporulation of S. chartreusis (size of sporulation zone inhibition = 18 mm).⁸

N.D. Argades et al synthesised seven derivatives of pyrazole containing 2,4-disubstituted oxazole by microwave assisted synthesis and evaluated them for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. They used ampicillin, streptomycin, fluconazole, ketoconazole and clotrimazole as standard drugs. From all compounds, they found that 4-[3-(4-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-phenyl-4H-oxazol-5-one 6 was the most potent compound of this series as an antimicrobial agent.⁹

R C Tandel et al reported the antibacterial activity of 4-benzylidine-2-phenyl-4H-oxazol-5-one 7 against Micrococcus luteus, Escherichia coli and cytotoxicity against the monocots barley seeds; Hordeum vulgare L and dicots moong seeds; Phaseolus aureus. From all the synthesised compounds, they indicated that 7 was the most potent compound which exhibit antibacterial activity.¹⁰

Mohd. Shahnawaaz et al used most common Erlenmeyer-Polchi reaction for the synthesis of a novel series of 5(4H)-oxazolone derivatives 8. They performed cyclodehydration-condensation reaction of the appropriate aldehyde and hippuric acid in the presence of acetic anhydride. All compounds were screened for their in vitro antibacterial activity against E. coli and Xanthomonas citri, using cup-plate method. Heterocyclic compound 8 containing furan and anthracene moiety, which showed good antibacterial activity with inhibition zone in 9-12mm against streptomycin.¹¹

In literature, oxazolone is related to the structure and chemistry of penicillin. George Brownlee et al reported several oxazolones, which exhibited some antibacterial activity against Streptococcus pyogenes. From all the synthesised compounds, 2-phenyl-4-(ethoxymethylene)-5-oxazolone 9 showed good activity.¹²

Adam M. Gilbert et al synthesised anthranilate 4H-oxazol-5-one derivatives 10 and evaluated them for their biological activity. The results indicated that compounds10a-10c were good inhibitors of acyl carrier protein synthase (AcpS) with IC₅₀ values 1.1 µM, 1.5 µM and 0.27 µM, also showed good antibacterial activity with minimum inhibitory concentrations (MICs) in the range of 12.5-50.0 µM against B. subtilis, E. faecalis and Streptococcus pneumoniae.¹³

Immunomodulatory property:

Muhammad A. Mesaik et al synthesised a series of oxazolone compounds and tested for their phagocyte chemiluminescence, neutrophil chemotaxis, T-cell proliferation, cytokine production from mononuclear cells and their cytotoxicity. They found that compound 4-[(E)-(4-nitrophenyl)methylidene]-2-methyl-1,3-oxazol-5(4H)-one 11 was the most potent immunomodulator of this series.²³

Antiviral activity:

HIV infection is the most prevalent worldwide viral disease. Myriam Witvrouw et al represented a novel class of spirocyclopropyl oxazolone, which has good inhibiting properties against herpes proteases. They indicated that compound 1,2-disubstituted-7-oxo-6-oxa-4-azaspiro[2,4]hept-4-ene 12 inhibit the replication of HIV-1 with an EC₅₀ value of approximately 26.3 µg/ml.¹⁶

Ivan L. Pinto et al synthesised novel inhibitors of herpes viral genes. They reported that spirocyclopropyl oxazolones 13 were submicromolar inhibitors of HSV-2 and HCMV proteases selectively related to standard serine proteases. They found that the orientation of aryl ring with cyclopropyl ring play an important role in the inhibition of herpes proteases. These oxazolones, further gave imidazolone ring containing products, which act as good inhibitors of HCMV proteases.⁶²

Antitumor activity:

Francoise M. Perron-Sierra et al synthesised novel bicyclic oxazolones and evaluated them for the inhibition of proliferation of various tumour cells including A431 (human epidermoid carcinoma) and L1210 (murine leukemia). They determined that the antiangiogenic activity of oxazolone derivatives 14 inhibit the vascular growth in the chick embryo chorioallantoic membrane (CAM assay) at 125 nmol. They found that compounds 14a and 14b were the strong inhibitors in the CAM (with less cytotoxicity).¹⁷

Pesticidal property:

4-Benzylidine-2-methyloxazol-5-one 15a and 4-benzylidine-2-phenyloxazol-5-one 15b, having some pesticidal property as reported by Ahmed S. Abdel-Aty. They synthesised and screened them for their fungicidal effects against Fusarium calmorum, Pythium debarianum, Rhizoctonia solani and Macrofomina phaseoli. They used metalaxyl, N-(2,6-dimethylphenyl-N-methoxyacetyl)-DL-alaninemethylester as a standard fungicide. The results showed that 2-phenyl moiety in compound 15b enhance the fungi toxicity against Pythium debarianum with IC₅₀ of 76.9 μg/ml. They observed that all compounds showed phytocidal and fungicidal activities higher than their insecticidal effects, also excellent in vitro tyrosinase inhibitory properties having IC₅₀ values in the range of 1.23 ± 0.37 to 17.73±2.69 μM, even better than the standard inhibitors 1-mimosine and kojic acid.²¹

Anticancer activity:

Xiao-Xian Han et al synthesised and evaluated biological activity of naturally occurring staurosporine (STA) analog ZHD-0501 16, a novel compound containing oxazolone ring. They proposed that compound 16 biosynthesized from 4'-N-formyl-STA and elucidated their structure by spectroscopic methods. They found that compound 16 strongly inhibit the proliferation of mammalian cancer A549, BEL-7402, HL60, P388 and tsFT210 cells.^15,63

Cardiotonic activity:

Heart failure is a world wide disease and occurs most commonly, when cardiac output is low. Schnetttler et al patented the synthesis of heterocyclic oxazolone derivatives 17 and tested for their cardiotonic activity. From all the compounds, they found that compounds 17a, 17b were strongly enhance the myocardial contractile force and cardiac function, also showed similar activity to digitalis with less toxicity.²²

Analgesic, anti-inflammatory activity:

Mariappan G. et al designed some new oxazolone derivatives. On the basis of results, they found that compound 2 containing NO₂group at ortho position, exhibit potent analgesic and anti-inflammatory activity.¹⁹

Umut Salgin Goksen et al synthesised thiadiazole and hydrazide derivatives, screened their analgesic, anti-inflammatory and antimicrobial activities. Compounds containing oxazolone ring in their structure, such as thiadiazole derivatives 18 and benzylidene hydrazone derivatives 19 showed excellent analgesic effects, even higher than standard drugs aspirin and morphine. They reported that both of these compounds showed significant analgesic, anti-inflammatory activity including compound 18, which exhibited strong inhibitory action against Candida krusei, Candida albicans and Candida parapsilosis.¹⁴

Deniz Songul Dogruer et al synthesised a number of oxazolone derivatives 20 and evaluated them for their biological activity. They found that compounds 20a-20d have more than 60% antinociceptive activity and also performed potent anti-inflammatory activity by carrageenan-induced rat hind paw edema method. They reported that the potency of compound 20a was due to benzoyl moiety at C-6 position and similarly in compound 20b due to morpholino moiety on the side chain.¹⁸

Coffen et al patented several oxazolone derivatives 21 and evaluated these compounds as potent α₁-adrenoreceptor antagonists. They found that all of these compounds are useful in the treatment of the urinary tract dysfunctions, nonciceptive, neurogenic pain without producing the blood pressure lowering effects and the postural hypotension.²⁰

Photophysical properties:

Gulsiye Ozturk et al synthesised novel optical biosensors, which were utilized as alternative indicators for enzymatic neurotransmitter and donepezil sensing.They found that 2,4-diaryl-5-oxazolone derivatives contain an N-phenyl-(aza-15-crown-5) moiety at the C-4 position and electron donating or withdrawing groups at the C-2 position. Compound 2-(4-nitrophenyl)-4-[4-(1,4,7,10-tetraoxa-13-azacyclopentadecyl)benzylidene]-5-oxazolone (CPO-II) 22 was characterised for their photophysical properties, using absorption and fluorescence emission spectroscopies by immobilising it in a polyvinylchloride matrix. They found that compound 22 exhibit excellent photostability and alsofluoresced strongly at the longest wavelength (689 nm) due to the nitro group on phenyl ring.^26,64

Nitric oxide synthase inhibitor:

A series of non-amino based N-substituted benzoxazolones 23 and 24 were synthesised by K. Shankaran et al. Both of these compounds were evaluated for their NOS (nitric oxide synthase) inhibiting properties. Biological evaluation of these inhibitors showed that compound 23 has maximum activity due to morpholino residue. The results also showed that compound 24a was a substrate of the mammalian cytochrome P450 (CYP2E1) isozymes and a type-I inhibitor, which compete with L-arginine. Compound 24b was the strong inhibitor of NOS because of the presence of methyl group on phenyl ring.⁴⁹

Khalid Mohammed Khan et al reported the synthesis of seventeen oxazolone derivatives and screened them for their excellent in vitro tyrosinase inhibitory properties. They found that 2-methyl-4-[(E)-3-phenyl-2-propenyliden]-1,3-oxazol-5(4H)-one 25 was one of the most potent oxazolone due to cinnamyol residue at C-4 position, with remarkable IC₅₀ values in the range of 1.23 ± 0.37 µM.⁵¹

Oxazolone as key intermediate:

Nimesh C. Misra et al reported the formation of various oxazole derivatives 28 from oxazolone 26. They used oxygen, nitrogen and carbon nucleophiles for ring-opening of oxazolone 26 (4-bis(methylthio)methylene-2-phenyloxazol-5-one), further 5-endo cyclization of acyclic adducts 27 in the presence of silver carbonate gave reasonable oxazole derivatives 28.³¹

Rahman Shah Zaib Saleem et al reported the synthesis of 1,2,4-triazolines 31 by the reaction of oxazolones 29 with azodicarboxylates 30. Further they synthesised triazoles 32 from triazolines 31.³³

Anjani Solankee et al synthesised 5-imidazolones 35 from different 5-oxazolones (azlactones) 33. The condensation reaction of oxazolones 33 with 5-bromofuran-2-carbohydrazide 34 in the presence of pyridine gave 5-imidazolones 35, which exhibit potent antibacterial activity against B. subtilis, E. coli and S. paratyphi-B.³⁴

Kalpesh Patel et al synthesised and evaluated the anthelmintic activity of imidazolone derivatives 38. They reported that {(5Z)-5-[4-(dimethylamino)benzylidene]-3-(5-substituted-1,3,4-oxadiazol-2-yl)-2-phenyl-3,5-dihydro-4H-imidazol-4-one} derivatives 38 were prepared by condensation reaction of substituted oxadiazole 36 with oxazolone 37 in the presence of pyridine.³⁵

Thalita G. Barros et al synthesised some novel peptide inhibitors of serine proteases. They reported the synthesis of pseudo-peptides 41 from oxazolone 40 and isomannide derivatives 39. They also evaluated their anti-HCV activity using HCV (Hepatitis C Virus) replicon-based assay.^1,65

Murlidhar P. Wadekar et al reported that substituted oxazolone 43 and hydrazone 42 were responsible for the production of 1-[(2-hydroxy-5-substituted phenyl azo)-benzylidene amino]-2-phenyl-4-benzylidene-5-oxo imidazoline 44 in pyridine. They proved that compound 44 has potent antimicrobial activity against Bacillus magatherium, Bacillus subtilis, Escherichia coli and Proteus vulgaris.³⁸

Maria Luisa Gelmi et al proved that in acidic conditions 4(2-oxa-alkylidene)-5(4H)-oxazolones (azlactones) 45 were transferred into furanones 46.³⁹

Oxazolone derivatives 47 behave as an ene system in (2π+2π) cycloaddition reaction with benzyne. A facile synthesis of 1,4(H)-benzoxazepine-2-ones 49 in good yields confirmed by Ashraf A. Aly et al. They reported that cycloaddition reaction of 4-arylidene-2-phenyl-5(4H)-1,3-oxazolones 47 with excess of benzyne 48 afforded the compound 49 in dry acetonitrile.²

P. P. Haasbroek et al reported the hydrolysis of 4-(4'-acetoxybenzylidine)-2-methyl-5-oxazolone 50 (Z-isomer), which gave unexpected 2-acetoxy-3-(p-hydroxyphenyl)-propenoic acid 52 and on treatment with acetic acid gave 2-acetoxy-3-(p-acetoxyphenyl)-propenoic acid 51.⁴⁰

Ibadur R Sidddiqui et al developed a new facile green protocol for the synthesis of antiviral compounds from oxazolone derivatives 53. They reported that microwave assisted montmorillonite K10 clay catalyzed Michael addition reaction of oxazolone derivatives 53 and (4-oxo-butyl)-dithiocarbamic acid 54, which gave N-{3-(4-hydroxymethyl-butyl)-4-oxo-6-phenyl-2-thioxo[1,3]thiazinan-5-yl}-acetamide 55 under solvent free conditions.⁴¹

Hashmukh Joshi et al reported that 2-phenyl-4-benzylidene-5-oxazolone derivatives 56 were used as an intermediate in the synthesis of 1-N-substituted sulphonyl amino-2-phenyl-4-substituted benzylidene-5-imidazolinones 58 and evaluated their potent antimicrobial activity as well as anticonvulsant activity. They performed condensation reactions of oxazolone derivatives 56 with equimolar quantity of sulphacetamide 57, which produce imidazolinones 58. They indicated their excellent antimicrobial activity against Staphylococcus aureus, Bacillus megaterium, Escherichia coli, Pseudomonas fluorescens, Aspergillus flavus and Candida albicans. They also observed that compound 58 exhibit potent anticonvulsant activity.⁴³

Robert A. Mosey et al reported that quaternary oxazolones 59 were used for the construction of quaternary α-amino acids 60 that play a vital role in synthetic and medicinal chemistry. They proved that nucleophilic ring-opening reaction of quaternary substituted oxazolones 59 gave quaternary substituted α-amino acid derivatives 60 in good yield.²⁸

Piero Dalla Croce et al reported that diastereoisomeric spirocyclic ß-lactams and imidazothiazole derivatives synthesised by the cycloaddition reaction of mesoionic 5H,7H-thiazolo[3,4-c]oxazol-1-one and imines.³⁰ Oxazolone derivatives used as an intermediate for the direct formation of annulated hymenialdisine analog from S-benzylthiourea and lithium hydride.⁶⁶ R. Mazurkiewicz et al found that alkylation of 4-phosphoranylidene-5(4H)-oxazolones gave alkylated products in good yield.⁶⁷ Hydrolysis of some oxazolone derivatives led to the formation of some acids, such as levulenic acid and cinnamic acid, further gave many heterocyclic compounds e.g. pyranones, pyrazoles.^68,69

Some oxazolones have various applications because of their sensitizing nature, so they act as a lead compound for the synthesis and testing of many clinically and biologically useful natural products e.g. 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one.^70-73 Andreas Natsch et al used this novel oxazolone for in vitro testing of their sensitizing nature because these induced antioxidant response element (ARE) dependent genes, they also determined their detoxifying properties and appropriate level of use in cosmetic applications.⁷⁴

CONCLUSION:

Oxazolone nucleus exhibited immense pharmacological activities. Various potential therapeutic applications of oxazolones are reviewed and discussed in brief in this article. Thus, oxazolone nucleus has emerged as one of the potential pharmacophore responsible for diverse pharmacological activities. Oxazolone ring have been explored in past years and used as versatile lead for development of new drugs.

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Received on 17.01.2011 Modified on 02.02.2011

Asian J. Research Chem. 4(5): May, 2011; Page-685-694