Int J Pharm Pharm Sci, Vol 7, Issue 1, 16-23Review Article


BENZOXAZOLE: THE MOLECULE OF DIVERSE PHARMACOLOGICAL IMPORTANCE

AVNEET KAUR*, SHARAD WAKODE, DHARAM PAL PATHAK

Delhi Institute of Pharmaceutical Sciences and Research, New Delhi.
Email: avneetkaur1986@gmail.com

Received: 25 Sep 2014 Revised and Accepted: 20 Oct 2014

ABSTRACT

Benzoxazole nucleus is one of the most important heterocyclic compounds exhibiting remarkable pharmacological activities. The present review provides a broad overview of the synthesis and pharmacological activities such as antimycobacterial, anticonvulsant, anti-inflammatory, anticancer, DNA topoisomerase inhibitor, cholesterol ester transfer protein inhibitor and miscellaneous activities.

Keywords: Benzoxazole, Synthesis, Pharmacological activity.

INTRODUCTION

The practice of medicinal chemistry is devoted to the discovery and development of new agents for treating disease [1]. An important aspect of medicinal chemistry has been to establish a relationship between chemical structure and pharmacological activity. The chemistry of heterocyclic compounds is the most important in the discovery of new drugs. The study of these compounds is of great interest both in theoretical as well as practical aspects [2].

Various compounds such as alkaloids, essential amino acids, vitamins, haemoglobin, hormones, large number of synthetic drugs and dyes contain heterocyclic ring systems. There are the large number of synthetic heterocyclic compounds like pyrrole, pyrrolidine, furan, benzoxazole, piperidine, pyridine and benzimidazole having important application and many are important intermediates in synthesis [3].

Among all the heterocyclic compounds, benzoxazole is one of the most important heterocycles exhibiting remarkable pharmacological activities. Benzoxazole is an organic compound, which has benzene fused with an oxazole ring. Oxazole (Fig.1) is 1, 3 azole having oxygen atom and a pyridine type nitrogen atom at the 3-position in a five member ring. A slight change in the substitution pattern of benzoxazole nucleus causes distinguishable difference in their pharmacological activities.

Fig. 1

Synthesis of benzoxazole

Several protocols for the synthesis of benzoxazole have been developed due to their biological and synthetic significance. 2-substitued benzoxazole was prominently studied trusting that this position is decisive for the biological activity whereas position 5 prevailing intensity of the activity. Benzoxazoprofen and Zoxazolamine are also kind of benzoxazole derivative which are substituted at both 2 and 5 position [4].

Moghaddam et al. synthesized 2-substituted benzoxazoles (Fig.2) via condensation reaction of 2-aminophenol with various aldehydes using molecular iodine as a catalyst in solvent-free conditions under microwave irradiation at 130°C in short time of span gives excellent yield [5].

Fig. 2

Batley et al. carried out a copper catalyzed one-pot synthesis of benzoxazole (Fig. 3) using bromoaniline and acyl hallides in the presence of a base and solvent giving intermediates which finally gave pure benzoxazole (21–97%) isolated yield, exhibiting a broad range of biological activity. They can also be used as precursors in the synthesis of drugs [6-8].

Fig. 3

Lokhwani et al. prepared benzoxazole (Fig. 4) by the reaction of orthoesters with o-aminophenols in the presence of silica sulfuric acid under heterogeneous and solvent–free conditions [9].

Fig. 4

Yang et al. synthesized benzoxazole (Fig. 5) by treatment of N-(2-hydroxyaryl) cyclopropyl amides with PPh3/CBr4 in acetonitrile to yield 2-substituted benzoxazole [10].

Fig. 5

Do et al. carried out copper catalyzed arylation of benzoxazole (Fig. 6) at 2- carbon with aryliodides in DMF with very high yields. This method involves direct functionalization of heterocycle C-H bonds [11].

Fig. 6

Mardolla et al. synthesized substituted benzoxazoles (Fig. 7) by condensing a variety of carboxylic acids with 2-aminophenol, 2- aminothiophenol and 1, 2-phenylenediamines respectively using the ionic liquid 1-butyl 3-methyl imidazolium tetraflouroborate [(bmim) BF4] at higher temperatures.Ionic liquid acts as a reaction medium and promoter [12].

Fig. 7

Yoshida et al. prepared 2-cyclicamine benzoxazole (Fig. 8) by the reaction of 2-mercapto benzoxazole or 2-chlorobenzoxazole with cyclicamine under different reaction conditions [13].

Fig. 8

Prakash et al. reported synthesis of 2-benzoxazoles (Fig. 9) using hypervalent iodine (iodobenzene diacetate) mediated oxidative cyclization of Schiff’s bases in methanol as anoxidant. Schiff’s bases were prepared by the reaction of o-aminophenols and aldehydes [14].

Fig. 9

Ozdemira et al. prepared 5-amino-2-arylbenzoxazoles (Fig. 10) by the reaction of 2, 4-diaminophenol dihydrochloride and various aryl carboxylic acids in polyphosphoric acid (PPA) [15].

Fig. 10

Pharmacological activity

Antimicrobial activity

The rapidly increasing occurrence of multiple drug-resistant microbial strains is a serious problem. Since the emergence of anti resistant bacteria is inevitable, there is urgency for the discovery of novel active agents, which is of the highest priority [16, 17].

Yalcin et al. synthesized 5- substituted-2-cyclohexyl methyl benzoxazoles (Fig. 11) by the reaction of 2–hydroxy–5-substituted aniline and cyclohexyl carboxylic acid with sodium bicarbonate. The synthesized compounds showed moderate to good antibacterial and anti-fungal activity as compared to standard [18].

R= H

Fig. 11

Ozdemira et al. synthesized a series of twelve novel 5-[2-(morpholin-4-yl) acetamido] and 5-[2-(4-substituted piperazine-1-yl)acetamido]-2-(p-substituted phenyl] benzoxazole derivatives (Fig. 12) and were tested for their in vitro activities against certain strains of Gram-positive, Gram-negative bacteria as well as the yeasts Candida albicans, Candida krusei, and Candida glabrata. Microbiological results showed that the newly synthesized compounds possessed a broad spectrum of activity, showing MIC values of 3.12-50 μg/mL against the Candida species [19].

Fig. 12

Yildiz et al. synthesized a new series of 5 (or 6)-nitro/amino-2-(substituted phenyl) benzoxazole derivatives (Fig. 13) and evaluated for their antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and drug-resistant isolates. The compounds synthesized were found to exhibit appreciable antibacterial activity [16].

Fig. 13

Zitouni et al. synthesized some 2-[(benzoxazole-2-yl) thioacetylamino] thiazole derivative (Fig. 14) by reacting 4-methyl-2-(chloroacetylamino)thiazole derivatives with benzazol-2-thiole in acetone in the presence of K2CO3. The chemical structures of the compounds were elucidated by 1H NMR and FAB+-MS spectral data. The prepared compounds showed mild to significant antimicrobial activity and toxicity [20].

Fig. 14

Yildiz et al. synthesized series of 5-ethylsulphonyl-2-(substituted-phenyl/substituted-benzyl and/or phenylethyl) benzoxazole (Fig. 15) derivatives and evaluated for in vitro antimicrobial activity of the compounds against Gram-positive, Gram-negative bacteria, a fungi Candida albicans and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicated that the synthesized compounds possessed a broad spectrum of activity with MIC values 250-7.81 mg/ml [21].

Fig. 15

Kim et al. synthesized benzoxazole amides (Fig. 16) and evaluated for their antifungal activity against Malassezia furfur. Twelve benzoxazole amides were prepared through the cyclization of the substituted 2-hydroxy aniline with N-(bis-methylsulfanylmethylene) amides. Among the prepared compounds, few showed in vitro antifungal activity [22].

Fig. 16

Kabilan et al. synthesized some novel benzoxazolyl ethoxypiperidones (Fig. 17) and screened for their antibacterial activity against Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and antifungal activity against Candida albicans, Aspergillus niger, Candida-51 and Aspergillus flavus. Some compounds exerted potent in vitro antibacterial activity against Streptococcus faecalis while rest compounds exhibited potent in vitro antifungal activity against Candida-51 [23].

Fig. 17

Elnima et al. synthesized 2- substituted benzoxazole derivatives (Fig. 18, 19) and studied in vitro antibacterial and antifungal activities against E. coli, P. aeruginosa and S. aureus. Among the fifty nine prepared derivatives only two derivatives were found to be effective against S. aureus isolates. Their minimal inhibitory concentration was found to be 25 and 50 μg/ml[24].

Fig. 18 Fig. 19

Goker et al. synthesized a number of substituted 2-anilinobenzimidazoles, benzothiazoles and benzoxazoles (Fig. 20) evaluated for their anti-staphylococcal activity [25].

Fig. 20

Vinsova et al. synthesized a series of lipophilic new 2-substituted 5, 7-di-tert-butylbenzoxazoles (Fig. 21) by the reaction of 3, 5-di-tert-butyl-1, 2-benzoquinone with amino acids and dipeptides, bearing N-terminal glycine. Dipeptides having other N-terminal amino acids undergo oxidative deamination. 5, 7-di-tert-butylbenzoxazoles have shown antituberculotic activity against Mycobacterium tuberculosis comparable with or higher than the standard drug isoniazid [26].

Fig. 21

Klimesova et al. synthesized a set of 2-benzylsulfanyl derivative of benzoxazole (Fig. 22) and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosi, non-tuberculous mycobacteria and multidrug-resistant M. tuberculosi notable activity was obtained [27].

Fig. 22

Singh et al. prepred 4-(Benzoxazole-2-yl)-N-substituted Benzylidine aniline derivatives (Fig. 23) by reaction of 2-aminophenol with p- amino benzoic acid and various aldehydes in presence of polyphosphoric acid and evaluated for their antibacterial activity against E. coli, P. aeruginosa and S. aureus [28].

Fig. 23

Jayananna et al. synthesised a new class of 5,7-dichloro-1,3-benzoxazole derivatives (Fig. 24) by fusing 5,7-dichloro-2-hydrazino-1,3-benzoxazole nucleus with aliphatic acids, active methylene compounds, and with selected esters to form heterocyclic ring systems like 1,2,4-triazoles, pyrazoles, and triazine moieties and screened for cytotoxic, antimicrobial, antioxidant, and antilipase activities [29].

Fig. 24

Anticonvulsant activity

Pujar et al. synthesized 2-mercapto benzoxazole (Fig. 25) and 2-mercapto benzimidazole and screened for in vivo anticonvulsant activity by PTZ induced convulsions in albino mice. Most of the compounds showed ability to protect against the pentylenetetrazol-induced convulsions. Some compounds exhibited maximum activity as compared to standard drug [30].

Fig. 25

Siddiqui et al. synthesized a series of 5-carbomethoxybenzoxazole (Fig. 26) derivatives by using methyl-p-hydroxybenzoate and evaluated for their anticonvulsant and neurotoxicity effect and was found to possess considerable anticonvulsant activity [31].

Fig. 26

Quan et al. synthesized a series of 2-substituted-6-(4H-1, 2, 4-triazol-4-yl) benzo[d]oxazoles. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. Further, it was observed that 2-phenyl- 6- (4H-1, 2, 4-triazol-4 yl) benzo[d]oxazole (Fig. 27) was the most active and also had the lowest toxicity [32].

Fig. 27

Anti inflammatory activity

Non-steroidal anti-inflammatory drugs (NSAIDs) are a main-stay in the treatment of inflammation and they owe their therapeutic and side effects in large part to the inhibition of cyclooxygenase (COX). The separation of the therapeutic effects from the side effects has been a major challenge in the design and synthesis of these drugs. The discovery of a second isoform of cyclooxygenase, namely COX-2, has opened a new line of research based on the assumption that pathological prostaglandins are produced by the inducible isoform COX-2 while physiological prostaglandins are produced by the constitutive isoform COX-1 [33].

Rao et al. synthesized the series of 2-[[2-alkoxy-6-pentadecylphenyl (methyl)]thio]-1H benzoxazole (Fig. 28) and investigated their ability to inhibit human cyclooxygenase-2 enzyme which showed anti-inflammatory activity [34].

Fig. 28

Ampati et al. synthesised a series of methyl-2-{(2-(dialkylamino) acetamido)}-benzoxazole-5- carboxylates (Fig. 29) from Methyl 3-amino-4-hydroxybenzoate and investigated their ability to inhibit human cyclooxygenase-2 enzyme (COX-2). The IC50 values were found to be comparable to that of standard - refecoxib. Thus, this class of compounds serves as excellent candidates for selective COX-2 inhibition [35].

Fig. 29

Srinivas et al. synthesized a series of methyl 2- (arylideneamino) benzoxazole -5-carboxylate derivatives (Fig. 30) by the reaction of Schiff bases of methyl 2-aminobenzoxazole-5-carboxylate with appropriate aromatic aldehydes. The chemical structures of the synthesized compounds were confirmed by means of IR, 1H NMR, mass spectral analysis and evaluated for COX-2 inhibitory activity. In conclusion, this class of compounds serves as remarkable class for COX-2 inhibition [36].

Fig. 30

Sondhi et al. synthesized a series of N-(acridin-9-yl)-4-(benzo [d]imidazol/oxazol-2-yl) benzamides (Fig. 31) by the condensation of 9- amino acridine derivatives with benzoxazole derivatives. All these compounds were characterized by correct FT-IR, 1H NMR, MS and elemental analysis. These compounds were found to possess appreciable anti-inflammatory activity [37].

Fig. 31

Analgesic activity

Erdogan et al. synthesized a novel series of mannich bases of 5-nitro-3-substitutedpiperazinomethyl-2-benzoxazolinones (Fig. 32). The compounds were screened for their anti-inflammatory activity. Among the tested compounds most promising results were obtained for the compounds bearing electron withdrawing substituents (F, Cl, COCH3) in the ortho/para position of the phenyl ring at the third position of benzoxazolinone moiety. The analgesic activity of the entire compounds is higher than their anti-inflammatory activity [38].

Fig. 32

Safac et al. synthesized a series of 3-(2-pyridylethyl) benzoxazolinones (Fig. 33) derivatives which exhibited anti-inflammatory and analgesic activity [39].

Fig. 33

Anticancer activity

Many of the major classes of anticancer drugs in current use owe their overall therapeutic effectiveness but lack of selectivity for tumor cells over normal cells can lead to severe side effects. Design and synthesis of novel small molecules which can specifically block some targets in tumor cells are in perspective direction in modern medicinal chemistry. Therefore there is an urgent need to establish processes to assess anticancer drug action (i. e, safety, efficacy and mechanism of action). From the different groups of heterocycles, many synthetic small molecules with cytotoxic activity have been reported and several of them under gone for the clinical trials [40].

Murty et al. synthesized 2-substituted -1, 3-benzoxazoles (Fig. 34) with the influence of the presence of cyclic amine moiety in the benzoxazole scaffold and evaluated with respect to their cytotoxic effects toward four human cancer cell lines. Substitution was done at the second and third position of benzoxazole moiety to know the influence of cytotoxic effect towards these cell lines [41].

Fig. 34

Kamal et al. synthesized a series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates (Fig. 35) and screened for their anticancer activity, DNA thermal denaturation studies, restriction endonuclease digestion assay and flow cytometric analysis in human melanoma cell line (A375). One of the compounds of the series 7-methoxy-8-{5-[4-(1,3-benzothiazol-2-yl)-2methoxy phenoxy] pentyl}oxy-(11aS)1,2,3,11a-tetra-hydro-5H-pyrrolo-[2,1-c][1,4] benzodiazepin-5-one (24) showed significant anticancer activity with promising DNA-binding ability and apoptosis which caused G0/G1 phase arrest at sub-micromolar concentrations [42].

Fig. 35

DNA topoisomerase inhibitor

Akbay et al. synthesized 5-phenylacetamidosubstituted-2-phenylbenzoxazole derivatives (Fig. 36) by reaction of 5-amino substituted-2-phenylbenzoxazole and excess of thionyl chloride, sodium bicarbonate & diethyl ether in water. Derivative compounds inhibits reverse transcriptase (RT) activity, binding of the RT enzyme exhibiting IC50 values between 6.3×105 μ mol/1-0.34 μ mol/l and their activities were compared to standard drug such as 3’-azido-2’,3’-dideoxythymidine triphosphate and dideoxythymidine triphosphate. Since DNA topoisomerases are considered as important targets for cancer chemotherapy, the present findings may provide future opportunities to design and develop new chemotherapeutic agents [43].

Fig. 36

Oksuzoglu et al. investigated the inhibitory effects of some novel fused heterocyclic compounds (Fig. 37) on eukaryotic DNA topoisomerase II in a cell free system. He pointed out that in addition to the very well-known bi- and ter-benzimidazoles, compounds with single bicycled fused ring systems in their structure such as benzoxazole derivatives also exhibited significant DNA topoisomerase II inhibitory activity having IC50 values of 22.3, 17.4, 91.41 μM, respectively, showing higher potency than the reference drug etoposide [44].

Fig. 37

Cholestrol ester transfer protein inhibitor

Smith et al. reported a series of 2-arylbenzoxazole as inhibitors of the cholesterol ester transfer protein (CETP). Structure–activity studies revealed variation of the substitution of the benzoxazole moiety. Substitution at the 5- and 7-positions of the benzoxazole moiety was found to be beneficial for CETP inhibition. While, compound N-{4-[5-Cyano-7-(1–hydroxy -1- methyl- ethyl)- benzoxazol-2-yl]-phenyl}-2-o-tolyloxy-acetamide (Fig. 38) was found to be the most potent inhibitor in this series and inhibited CETP with an IC50 of 28 Nm [45].

Fig. 38

Hunt et al. Synthesized a series of 2-arylbenzoxazole α-alkoxyamide and β-alkoxyamine inhibitors of cholesteryl ester transfer protein (CETP). Highly fluorinated α-alkoxyamides proved to be potent inhibitors of CETP in vitro, and the highly fluorinated 2-arylbenzoxazole β-alkoxyamine (Fig. 39) showed a desirable combination of in vitro potency (IC50 = 151 nM) and oral bioavailability in the mouse [46].

Fig. 39

Herbicidal activity

Youseef et al. synthesized 6-Amino-5-(benzoxazole-2-yl)-4-aryl-3- cyanopyridine-2-(1H)-thiones (Fig. 40). The herbicidal activity of the newly synthesized compounds was evaluated against wheat as pattern for monocotyledonous plants. Three plant parameters were studied, seed germination, root and shoot growth under laboratory conditions. Compounds that showed an observable inhibition on one or more of the growth parameters under study were considered as promising compounds and needs more studies from the toxicological, soil, environmental and formulation points of view to stand on the most potent derivative that can be formulated in a suitable formulation form to be used in the field of pest control [47].

Fig. 40

Miscellaneous

Potashman et al. synthesized a series of 2-aminobenzimidazole and benzoxazole (Fig. 41) and evaluated for their selective vascular endothelial growth factor-2 receptor kinase inhibitor activity displaying good pharmacokinetic profile [48].

Fig. 41

Tamagnan et al. synthesized 5- and 6-substituted 2-(4-dimethylaminophenyl)-1, 3-benzoxazoles (Fig. 42) and evaluated in vitro and in vivo imaging agents for Alzheimer’s disease (AD)-related amyloid plaque [49].

Fig. 42

Swahn et al. synthesized and evaluated 2-pyridylbenzoxazole derivatives (Fig. 43) asC-PET imaging agents for β-amyloid plaques for Alzheimer’s disease [50].

Fig. 43

Medebielle et al. synthesized fluorine containing benzoxazole derivative (Fig. 44) and tested for activity against HIV-I for used in AIDS treatment [51].

Fig. 44

Raok et al. synthesized benzoxazole containing thiazolidinedione derivatives. 5- [4-[2-(Benzoxazol-2-yl-alkylamino) ethoxy] benzyl] thiazolidine-2, 4-diones (Fig. 45) have been prepared by Mitsunobu reaction of benzoxazolylalkylamino ethanol and hydroxyl benzyl thiazolidinedione [52, 53].

Fig. 45

Sun LQ et al. prepared a novel series of benzoxazole derivatives and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT (1) and MT (2) receptors was determined using 2-[(125) I]-iodomelatonin as the radioligand. This work also established the benzoxazole nucleus as a melatoninergic pharmacophore [54].

CONCLUSION

Benzoxazole moiety is expanding their pharmaceutical importance and is associated with several biological activities. The article has outlined the biological activities of the Benzoxazole scaffold. The benzoxazole derivative has beneficial effects on microbacterial infection, inflammatory disorders, and COX-2 mediatory responses and on DNA topoisomerases activity. The broad spectrum antibacterial and antifungal activity of these compounds could lead to a new series of antimicrobials activity. Further investigation of this scaffold may lead to development of the new drug to be used against the variety of diseases.

CONFLICT OF INTERESTS

Declared None

REFERENCES

  1. Delgado JN, Remers WA. Wilson and Giswold’s Textbook of Organic Chemistry Medicinal and Pharmaceutical Chemistry. 10th ed. Philadelphia: Lipincott Raven; 1998.
  2. Dinakaran VS, Fused pyrimidines. The heterocycle of diverse biological and pharmacological significance. Der Pharm Chem 2012;4(1):255-65.
  3. Pratyusha C, Poornima G, Rani KS, Krishnaveni A, Brahmaiah B. An overview on synthesis and biological activity of pyrimidines. Int J Pharm Rev Res 2013;13(2):86-90.
  4. Wang L, Zhang P, Zhang X, Zang YLi. Synthesis and biological evaluation of a novel series of 1, 5-benzothiazepine derivatives as potential antimicrobial agents. Eur J Med Chem 2009;44:2815-21.
  5. Moghaddam FM, Bardajee GR, Ismaili H, Taimoory SMD. Facile and efficient one pot protocol for the synthesis of benzoxazole and benzthiazole derivative using molecular iodine as a catalyst. Syn Comm 2006;36:2543.
  6. Rohet F, Rubat C, Coudert P, Couquelet J. Synthesis and analgesic effects of 3-substituted 4, 6-diarylpyridazine derivatives of the arylpiperazine class. Bioorg Med Chem 1997;5:655-9.
  7. Unlu S, Baytas SN, Kupeli E, Yesilada E. Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and antiinflammatory agents. Arch Pharm 2003;336:310-21.
  8. Viaud MC, Jamoneau P, Flouzat C, Espiard JG, Pfeiffer B, Renard P, et al. N-Substituted oxazolo[5,4-b]pyridin-2(1H)-ones: a new class of non-opiate antinociceptive agents. J Med Chem 1995;38:1278-86.
  9. Lokhwani P, Nagori BP, Batra N, Goyal A, Gupta S. Benzoxazole: The molecule of diverse biological activity. J Pharmacol Online 2011;1:236-45.
  10. Yang YH, Shi M. Selective synthesis of benzoxazoles and N-(2-hydroxyaryl) pyrrolidin-2-ones from corresponding cyclopropylamides with PPh3/CX4. Tetrahedron Lett 2006;62:2420.
  11. Do HQ, Daugulis O. Copper catalyzed arylation of heterocycle C−H bonds. J Amer Chem Soc 2007;129:12404.
  12. Maradolla MB, Allam SK, Mandha A, Chandramouli GVP. One pot synthesis of benzoxazoles, benzthiazoles and benzimidazoles from carboxylic acids using ionic liquids. Arkivoc 2008;15:42-6.
  13. Yoshida S, Shiokawa S, Kawano K, Ito T, Murakami H, Suzuki H, et al. Orally active benzoxazole derivative as 5-HT3 receptor partial agonist for treatment of diarrhoea-predominant irritable bowel syndrome. J Med Chem 2005;48:7075-9.
  14. Prakash O, Pannu K, Kumar A. Synthesis of some new 2-(3-Aryl-1-phenyl-4-pyrazolyl)-benzoxazoles using hypervalent iodine mediated oxidative cyclization of schiff’s bases. J Molecule 2006;11:43-8.
  15. Temiz AO, Ozdemira A, Yalcin I, Yildiz I, Aki-Senera E. Synthesis and Antimicrobial Activity of some 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl) benzoxazoles. Arch Pharm Chem Life Sci 2005;338:105−11.
  16. Norrby R. Linezolid-A review of the first oxazolidinone. Expert Opinion Pharmacother 2001;2(2):293-302.
  17. Tomasz AN. Multiple-antibiotic resistant pathogenic bacteria. New Eng J Med 1994;330:1247-9.
  18. Yalcin I, Sener E, Temiz O, Oren I. Synthesis and structure-activity relationships of some 2,5-disubstituted benzoxazoles and benzimidazoles as antimicrobial agents. IL Farmaco 1997;52(2):99-103.
  19. Ertan T, Yildiz I, Tekiner-gulbas B, Bolelli K, Temiz-Arpacıa O, Yalcin I, et al. Synthesis biological evaluation and 2D-QSAR analysis of benzoxazoles as antimicrobial agents. Eur J Med Chem 2009;44:501-10.
  20. Zitouni GT, Demirayak S, Ozdemir A, Kaplancikli ZA, Yıldız MT. Synthesis of some 2-[(benzoxazole-2-yl)thioacetylamino] thiazole derivatives and their antimicrobial activity and toxicity. Eur J Med Chem 2004;39(3):267–72.
  21. Temiz-Arpaci O, Yildiz I, Ozkan S, Kaynak F, Sener E, Yalcin I. Synthesis and biological activity of some new benzoxazoles. Eur J Med Chem 2008;43:1423-31.
  22. Kim BJ, Kim J, Kim YK, Choi SY, Choo HYP. Synthesis of benzoxazole amides as novel antifungal agents against Malassezia furfur. Bull Korean Chem Soc 2010;31:1270-5.
  23. Ramalingan C, Balasubramanian S, Kabilan S, Vasudevan M. Synthesis and study of antibacterial and antifungal activities of novel 1-[2-(benzoxazol-2-yl)ethoxy]-2,6 diarylpiperidin-4-ones. Eur J Med Chem 2004;39:527–33.
  24. Elnima E, Zubair MU, Badr AA. Antibacterial and antifungal activities of benzimidazole and benzoxazole derivatives. Antimicrob Agents Chemother 1981;19(1):29-32.
  25. Ozden O, Atabey D, Yıldız S, Goker H. Synthesis, potent anti-staphylococcal activity and QSARs of some novel 2-anilinobenzazoles. Eur J Med Chem 2008;43:1390-402.
  26. Vinsova J, Cermakova K, Tomeckova A, Ceckova M, Jampilek J, Cermak P, et al. Highly lipophilic benzoxazoles with potential antibacterial activity. J Molecule 2005;10:783-93.
  27. Kliomesova V, Koci J, Waisser K, Kaustova J, Mollmann U. Preparation and in vitro evaluation of benzylsulfanyl benzoxazole derivatives as potential antituberculosis agents. Eur J Med Chem 2009;44(5):2286-93.
  28. Singh G, Kaur M, Mohan C, Prashar S. Synthesis and antimicrobial activity of benzoxazole derivatives. Indo Am J Pharm Res 2013;3(8):6113-8.
  29. Jayanna ND, Vagdevi HM. Dharshan JC, Prashith TR, Hanumanthappa BC, Gowdarshivannanavar BC. Synthesis and biological evaluation of novel 5,7-dichloro-1,3-benzoxazole derivatives. J Chem 2013;1-9.
  30. Pujar GV, Synesh C, Purohit MN, Srinivasalu N, Udupi RH. Synthesis, anticonvulsant and antibacterial activities of some novel pyrrolines derived from benzaxazole and benzimidazoles. Ind J Hetero Chem 2008;17:387-8.
  31. Siddiqui N, Sarafaroz M, Alam M, Ahsan W. Synthesis, anticonvulsant and neurotoxicity evaluation of 5-Carbomethoxybenzoxazole derivatives. Acta Polo Pharm Drug Res 2008;65(4):449-55.
  32. Wei CX, Guan LP, Jia JH, Chai KY, Quan ZS. Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents. Arch Pharmacal Res 2009;1:23-31.
  33. Dannhardt G, Kiefer W. Cyclooxygenase inhibitors-current status and future prospects. Eur J Med Chem 2001;36:109.
  34. Paramashivappa P, Kumar P, Subba Rao PV, Srinivas Rao A. Design, synthesis and biological evaluation of benzimidazole/benzothiazole and benzoxazole derivatives as cyclooxygenase inhibitors. Bioorg Med Chem Lett 2003;13:657-60.
  35. Ampati S, Vidyasagar JV, Swathi K, Sarangapani M. Synthesis and in vitro evaluation of novel benzoxazole derivatives as specific cyclooxygenase–2 inhibitors. J Chem Pharm Res 2010;2(2):213-9.
  36. Srinivas A, Sagar JV, Sarangapani M. Design, synthesis and biological evaluation of benzoxazole derivatives as cyclooxygensase-2 inhibitors. Int J Pharm Sci 2010;2(1):7-12.
  37. Sondhi MS, Singh N, Kumar A, Lozach A, Meijer L. Synthesis, anti-inflammatory, apnalgesic and kinase(CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of banzimidazole/ benzoxazole derivatives and some schiff’s bases. Bioorg Med Chem 2006;14:3758–65.
  38. Koksal M, Gokhan N, Kupeli E, Yesilada E, Erdogan H. Analgesic and anti-inflammatory activities of some new mannich bases of 5-nitro-2-benzoxazolinones. Arch Pharm Res 2007;30:19-424.
  39. Safak C, Erdogan H, Palaska E, Sunal R, Duru S. Synthesis of 3-(2-pyridylethyl)benzoxazolinone derivatives: potent analgesic and antiinflammatory compounds inhibiting prostaglandin E2. J Med Chem 1992;35(7):1296-9.
  40. Lesyk R, Vladzimirska O, Holota S, Zaprutko L, Gzella A. New 5-substituted thiazolo[3,2-b][1,2,4]triazol-6-ones: synthesis and anticancer evaluation. Eur J Med Chem 2007;42:641.
  41. Murty MSR, Ram KR, Rao RV, Yadav JS, Rao JV, Cheriyan VT, et al. Synthesis and prelimnary evaluation of 2-substituted-1,3-benzoxazole and 3-[(3-substituted)propyl]-1,3-benzoxazol-2(3H)-one derivatives as potent anticancer agents. J Med Chem Res 2011;20:576-86.
  42. Kamal A, Reddy KS, Khan MNA, Shetti R, Ramaiah MJ, Pushpavalli SNC, et al. Synthesis, DNA-binding ability and anticancer activity of benzthiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates. Bioorg Med Chem 2010;18:4747–61.
  43. Akbay A, Oren I, Arpaci OT, Sener EA, Yalcin I. Synthesis and HIV-1 reverse transcriptase inhibitor activity of some 2, 5, 6-substituted benzoxazole, benzimidazole, benzothiazole and oxazolo(4,5-b)pyridine derivatives. Arzneim Forsch Drug Res 2003;53(4):266-71.
  44. Oksuzoglu E, Gulbas BT, Alper S, Arpaci OT, Ertan T, Yildiz I, et al. Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors. J Enz Inhib Med Chem 2008;23(1):37-42.
  45. Smith CJ, Ali Chen L, Hammonda ML, Anderson MS, Chen Y, Eveland SS, et al. 2-Arylbenzoxazoles as CETP inhibitors: Substitution of the benzoxazole moiety. Bioorg Med Chem Lett 2010;20:346–9.
  46. Hunt JA, Gonzalez S, Kallashi F, Hammond ML, Pivnichny JV, Tong X, et al. 2-Arylbenzoxazoles as CETP inhibitors: substitution and modification of the alpha-alkoxyamide moiety. Bioorg Med Chem Lett 2010;20:1019–22.
  47. Youssef MA, Sherif SMA, Elkady AMA, Hamouda SES. Synthesis of some new benzoxazole acetonitrile derivatives and evaluation of their herbicidal efficiency. J Am Sci 2010;12(6):1080-9.
  48. Potasman MH, Bready J, Coxon A, Dipetro L, Deorr N. Design synthesis and evaluation of orally active benzimidazole and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors. J Med Chem 2007;50:4351-73.
  49. Hausner HS, Alagille D, Koren AO, Amici L, Staley JK, Cosgrove KP, et al. Synthesis of 5-and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque. Bioorg Med Chem 2009;19:543–5.
  50. Swahn BM, Wensbo D, Sandell J, Sohn D, Slivo C, Pyring D, et al. Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as [11]C-PET imaging agents for β-amyloid plaques. Bioorg Med Chem Lett 2010;20:1976–80.
  51. Medebielle M, Ait-Mohand S, Burkhloder C, Dolbier WR, Laumond G, Aubertin AM. Syntheses of new difluoromethylene benzoxazole and 1, 2,4-oxadiazole derivatives, as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. J Flourine Chem 2005;126:535-54.
  52. Aronoff S, Rosenblatt S, Braithwaite S. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000;23:1605-11.
  53. Cantello BC, Cawthorne MA, Cottam GP, Duff PT. [[o-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as Potent Antihyperglycemic Agents. J Med Chem 1994;37:3977-85.
  54. Sun LQ, Chen J, Takaki K, Johnson G. Design and synthesis of benzoxazole derivatives as novel melatoninergic ligands. Bioorg Med Chem Lett 2004;14(5):1197-2000.