A comprehensive review on biological activities of oxazole derivatives

The utility of oxazole as intermediates for the synthesis of new chemical entities in medicinal chemistry have been increased in the past few years. Oxazole is an important heterocyclic nucleus having a wide spectrum of biological activities which drew the attention of researchers round the globe to synthesize various oxazole derivatives and screen them for their various biological activities. The present review article aims to review the work reported on therapeutic potentials of oxazole scaffolds which are valuable for medical applications during new millennium.


Background
Heterocyclic systems are a part of large number of drugs and biologically relevant molecules. Often the presence of hetero atoms or groupings imparts preferential specificities in their biological responses. The chemistry and biological study of heterocyclic compounds has been interesting field for a long time [1] and oxazole is one such moiety which has gained attention in recent times due to its increasing importance in the field of medicinal chemistry. Oxazoles is a doubly unsaturated 5-membered ring having one oxygen atom at position 1 and a nitrogen at position 3 separated by a carbon in-between. It was first prepared in 1947, has a boiling point of 69 °C and is a stable liquid at room temperature [2]. Substitution pattern in oxazole derivatives play a pivotal role in delineating the biological activities like antimicrobial [3], anticancer [4], antitubercular [5] anti-inflammatory [6], antidiabetic [7], antiobesity [8] and antioxidant [9] etc. Oxazoles and its derivatives are a part of number of medicinal compounds (Fig. 1) which includes aleglitazar (1, antidiabetic), ditazole (2, platelets aggregation inhibitor), mubritinib (3, tyrosine kinase inhibitor), and oxaprozin (4, COX-2 inhibitor) [10].
From the literature, it was found that various types of review articles have been written on synthesized/natural oxazole compounds which are focused on their pharmacological significance in medicinal filed. Some of the reported review articles on oxazole moiety includes the work done by Joshi et al. who have presented a review on systematic scientific study of 1, 3-oxazole derivatives as a useful lead for pharmaceuticals [11], Swellmeen, prepared a review on 1,3-oxazole derivatives exhibiting their biological activities as antipathogenic [2] whereas Singh and Tilvi, have presented a review on synthesis of oxazole, oxazoline and isoxazoline derived marine natural products [12]. The current review is concentrates on the diverse biological potential of oxazole derivatives in the new millennium, as no such extensive review article is reported recently.

Biological activities of oxazole
Pharmacological interventions of oxazole derivatives are voluminous, but this article covers the most relevant ones. potential against S. aureus, E. coli, P. aeruginosa and C. albicans. Ampicillin and streptomycin (10 and 25 µg/ ml) were used as reference drugs for antibacterial activity and fluconazole, ketaconazole and clotrimazole (10, 20 and 30 µg/ml) were used for antifungal activity. Compound 8 showed highest activity amongst all the synthesized derivatives (Table 2) [13].
Tanitame et al. prepared a range of novel pyrazole, oxazole and imidazole derivatives and checked for its antibacterial potential against various strains such as Staphylococcus aureus FDA 209P, S. aureus KMP 9, Escherichia Coli NIHJ JC-2 and, E. coli W3110 ∆acrA. Sparfloxacin and novobiocin have been used as reference drugs. Among the tested oxazole derivatives, compound 9 was found to possess maximum antibacterial activity but was less potent as compared to pyrazole and imidazole derivatives (Table 3) [14].
Aagalwe et al. carried out the preparation of4-substituted aryl 2-4-disubstituted phenoxy methyl 4-oxazol-5-one derivatives (10) and screened their antibacterial potential against E. coli and Xanthomonas citri using cup-plate method against the standard drug streptomycin. Amongst all the compounds, 10b, 10c, 10e, 10f showed highest activity against E. coli and compounds   oxazoles and evaluated its antifungal potential against various strains using 5-flourocytosine as a reference drug. The activity of compound 11 and 12 was found to be superior or comparable to reference drug (Table 5) [16].
Singh et al. carried out the synthesis of substituted oxa/ thiazoles and evaluated its antibacterial potential against various bacterial strains using the reference drugs ampicillin and ciprofloxacin. Antibacterial activity of the compound (13) revealed that 13a had good activity against E. coli (20 mm); 13b, 13d and 13e had equipotent activity as standard compound and 13c exhibited good antibacterial potential. In case of antibacterial activity of compound 14, the derivatives 14a, 14c, 14d showed good antibacterial activity and 14b exhibited better antibacterial activity than standard drugs. Results are presented in Table 6 [17].
Benzoxazole-5-carboxylatederivatives were prepared and their antimicrobial activity was evaluated by Chilumula et al. against Gram positive and Gram negative bacterial (S. typhi, E. coli, S. aureus and B. subtilis) and fungal strains (C. albicans and A. niger). The results were evaluated using ampicillin and clotrimazole as a reference drugs for antimicrobial activity. Compound 17 showed     the highest activity whereas compound 18 had much higher potency than other tested compounds. Results are mentioned in Table 8 [19]. Synthesis of series of heterocyclic derivatives and its antibacterial potential against various organisms such as B. subtilis, S. aureus, E. coli and K. pneumonia using standard drug ampicillin was done by Kaspady et al. 2-tert-Butyl-4-(4-chlorophenyl)oxazole (19) and 4-(4-bromophenyl)-2-tert-butyloxazole (20) were found to be the most active compounds (Table 9) [20].
Shamsuzzaman et al. synthesized a series of 2ˈ-amino-5α-cholest-6-eno [6,5-d] oxazole derivatives (21). Disk diffusion assay was used to examine the antimicrobial activity using various bacterial and fungal strains against chloramphenicol and nystatin which were used as reference drugs for the study. Out of all the compounds, 21b was found to be the most active one. Results are presented in Tables 10 and 11 [21].
Tomi et al. synthesized new derivatives of five membered heterocyclic compounds containing oxazole and benzothiazole rings and then screened them for their antimicrobial activity using ofloxacin and ketoconazole as standard drugs. Amongst the tested oxazole derivatives (22), three compounds, 22a, 22b, 22c came out to be active against bacterial and fungal strains (Table 12) [22].
A chain of 1,3-oxazole derivatives was prepared and examined for microbial inhibition potential against various bacterial and fungal strains by Sadek et al. Ofloxacin and ketoconazole were used as reference drugs for antimicrobial study. The 1,3oxazole derivative (23) showed notable activity at higher concentration (200 µg/ml) ( Table 13) [23].
Synthesis of a number of multi-substituted oxazoles containing a heterocyclic moiety was carried out and checked for antibacterial activity by Babulreddy et al. against different bacterial strains (S. aureus, E. coli, B. subtilis, K. pneumonia). Ampicillin was used as reference drug for antibacterial activity. Out of all the derivatives investigated, 24, 25, 26 and 27 showed pronounced antibacterial activity whose results are mentioned in Table 14 [24].
Some new aryl oxazoles were prepared by Dawood et al. and then assessed its antimicrobial potential. Reference drugs used were chloramphenicol and fluconazole. Compound 29 was found to have the highest antibacterial and antifungal activity (Table 16) [26].
Taile et al. prepared a series of oxazol-5-ones and screened its antibacterial potential against various pathogenic bacteria using ciprofloxacin and sulphacetamide as reference drugs. The prepared derivatives were also examined for their antifungal potential against Aspergillus niger and Candida albicans. The zone of inhibition was checked in comparison with gentamycin and clotrimazole. Compounds 34 and 35 exhibited good antibacterial activity whereas the compounds 36 and 37 showed good antifungal activity. Results are given in Table 18 [28].
A series of new oxazole derivatives were prepared and assayed for their antibacterial activity against Grampositive bacteria and Gram-negative bacteria by Reddy et al. using penicillin and streptomycin as reference drugs. The compounds 49 and 50 were found to possess good antibacterial activity as compared to standard drugs. Results are shown in Table 24 [34].
Several new spiroindoline-based heterocycles were made by Rahman et al. and examined for their antimicrobial potential. Among the tested derivatives, compound 51 was found to be the most effective against Bacillus subtilis, Bacillus megatherium, E. coli, Aspergillus niger and Aspergillus oryzae. Ampicillin, chloramphenicol and fluconazole were used as reference drugs (Table 25) [35].

Anticancer activity
Cantalejo et al. synthesized bisoxazoles and evaluated their anticancer activity against the cancer cell line HT-29. As well as tested in an ex vivo system using recombinant human choline kinase (ChoK) to assess   the inhibitory potency of the derivatives towards ChoK. Compound 52 was found to possess the maximum antiproliferative activity with an IC 50 value of 0.84 ± 0.005 whereas compound 53 was found to be most active in case of ex vivo study (IC 50 = 0.30 ± 0.003) [36]. The molecular interactions of three ruthenium complexes were studied by Barca et al. in isolated mammalian nuclei. The complexes were chemotherapeutic agents that are effective in reducing metastatic tumours in vivo and were compared with antitumour drug cis-diamminedichloroplatinum (CDDP) (57). Na trans-RuCl 4 (DMSO) imidazole (NAMI) (54), Na       (64) and HXDV (65) and evaluated its antiproliferative potential against various cell lines. Cytotoxicity was evaluated using MTT assay and the IC 50 values are shown in Table 29 [40].
Ohnmacht et al. reported some bisoxazole derivatives and evaluated them for anticancer potential. The analogue 66 was found to be the most effective in the series having high selectivity for the HSP90A over HSP90B quadruplexes. The compound 66 was evaluated for anticancer activity against various cell lines and the IC 50 values are mentioned in Table 30 [41].        Table 31 [42].
Savariz et al. prepared a range ofoxazol-5-one derivatives and carried out the in vitro antitumor evaluation. Doxorubicin was used as a positive control. Among all the synthesized compounds, 69 was found to possess maximum activity against prostate (PC-3) and ovarian (OVCAR-03) cancer cell lines with IC 50 values of 1.50 and 1.07 µM respectively [43].
Three series of novel oxo-heterocyclic fused naphthalimide derivatives were made by Tan et al. and were evaluated for antiproliferative potential using various tumor cell lines. Among the synthesized oxazole derivatives, 70 and 71 were found to be the most active ones (Table 32) [44].
Biersack et al. reported that oxazole-linked combretastatin A-4 analogues (possessing anti-vascular and anti-angiogenic activity) when linked to Ru(η 6 -arene) complex fragments shows additional cytotoxic activity. MTT tests with the oxazoles and their ruthenium complexes revealed them to be effective against cells of human518A2 melanoma and HL-60 leukaemia. Compound 72 showed the highest activity [45].   Hernández et al. did the synthesis of several analogues of the cytotoxic thiopeptide IB-01211 or mechercharmycin A. The cytotoxicity of synthesized analogues was checked against three human tumour cell lines. The peptide heterocycles 73 and 74 were found to be the most active ones (Table 33) [46].
A series of oxazole derivatives were prepared by Lin et al. and the EGFR and Src inhibition activities were checked using gefitinib as reference compound. In vitro cell cytotoxicity of the synthesized derivatives was evaluated against KB and A498 cells using MTT assay. Among all the screened compounds, 75 was found to be the most effective with IC 50 values 0.82 and 3.0 µM against KB and A498 cells respectively [47].
The structures of the most active anticancer compounds (52-75) are shown in Fig. 6, 7.
Moraski et al. carried out the synthesis of several oxazoline-and oxazole-containing compounds, which were tested for inhibition of Mycobacterium tuberculosis H 37 Rv in two different culture media, GAS and GAST using rifampicin as a positive control. Tween 80 is present in GAST but not in GAS whereas GAST is more iron deficient medium than GAS. Among all the synthesized oxazole derivatives, 78 and 79 were found to be most potent against MtbH 37 Rv whose results are presented in Lu et al. carried out the synthesis of a series of substituted thiazole, oxazole and imidazole derivatives. The derivatives were examined for in vitro antitubercular potential using M. tuberculosis, and were also evaluated for antibacterial activities. The results for the antimycobacterial activity of oxazole derivatives 82, 83 are shown in Table 37 [51].
The structures of the most active antitubercular compounds (76-83) are shown in Fig. 8.

Anti-inflammatory activity
Dündar et al. prepared a range of oxazole derivatives and evaluated them for COX-2 inhibition. Homeostasis and gastro protective effects involve COX-1 which is the constitutive form, whereas inflammatory sites involve COX-2. Among the synthesized compounds, 84 was found to possess the highest selective COX-2 inhibition (70.14% ± 1.71) [52].
Eren et al. synthesized a chain of diaryl heterocyclic derivatives and carried out the evaluation of in vitro inhibitory activities against COX-1 and COX-2 isoforms. Among the oxazole derivatives, compound 85 was found to possess the maximum COX-2 inhibition of 47.10% ± 1.05 against the standard drug indomethacin and rofecoxib [6].
Kuang et al. discovered the substituted quinolyl oxazoles as highly effective phosphodiesterase 4 (PDE4) inhibitors. Inflammatory and immune cells involve the expression of PDE4 which is one of the cAMP specific PDE enzymes. Among the investigated compounds, 86 and 87 were found to be most effective with PDE4 IC 50 values of 1.4 nm and 1 nm, respectively [53].
Kuang et al. carried out the synthesis of series of oxazole derivatives. Among the potent carboxamides, the N-benzylcarboxamide was found to exhibit good selectivity for phosphodiesterase 4 over phosphodiesterase 10 and phosphodiesterase 11. Further optimization of this series of potent compounds was carried out which led to the discovery of highly selective PDE4 inhibitors with picomolar potency. Compounds 88, 89, 90 and 91 were found to be the most effective PDE4 inhibitors whose IC 50 values are given in Table 38 [54].    . 9 Structures of the most active anti-inflammatory compounds Rusch et al. carried out the synthesis of 2-α-keto oxazoles and evaluated them for fatty acid amide hydrolase (FAAH) inhibition. FAAH is a membrane-bound serine hydrolase and is responsible for pain and inflammation. Out of all the tested compounds, 93 was found to be the most effective having an IC 50 value of 290 nm [56].
Singh et al. prepared some oxazole derivatives and evaluated them for anti-inflammatory potential against carrageenan induced oedema in albino rats. Out of all the
A chain of oxazole derivatives were synthesized by Kumar et al. and checked for PTP-1B inhibitory activity. Protein tyrosine phosphatase-1B (PTP-1B) has been found important for the treatment of diabetes and obesity. Out of all compounds, 97 and 98 exhibited the most promising activity (Table 40) [58].
Pingali et al. designed and synthesized 1,3-dioxane carboxylic acid derivatives and combined this with substituted oxazole and evaluated them for in vitro PPAR agonistic potential and in vivo sugar lowering and lipid lowering efficacy in animal models using rosiglitazone and tesaglitazar as standard compounds. Compound 99 was found to be the most active (EC 50 = 0.0015 µM) [59].
Raval et al. designed and synthesized novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives as highly potent PPAR α/γ dual agonists. Peroxisome proliferator-activated receptors (PPARs) play a very important role in metabolic syndrome whose major manifestations are hyperglycemia, dyslipidemia and obesity. Compound 100 was found to be the most efficacious PPAR α/γ dual agonist and showed the glucose reduction of 72% [60].
The structures of the most active antidiabetic compounds (96-100) are shown in Fig. 10.

Antiobesity activity
Jadhav et al. prepared and checked a range of derivative shaving oxazole units for their hDGAT1 inhibition. Diacylglycerol acyltransferase (DGAT1) is an enzyme in obesity which is involved in triglyceride synthesis. Among all the tested oxazole derivatives, 101 was found to possess maximum in vivo plasma triglyceride reduction (91%) [8].
Ok et al. found a range of substituted oxazole derivatives that are effective β3 agonists. Compound 102 was found to be the best β3AR agonist (EC 50 = 14 nM, 84% activation) [61].
Griebenow et al. prepared a range of novel squalene synthase inhibitors and evaluated them for lipid lowering activity. Squalene synthase is an enzyme which is involved in one of the steps of cholesterol biosynthesis. Compound 103 was found to be most effective. Results are mentioned in Table 41 [62].
The structures of the most active antiobesity compounds (101-103) are shown in Fig. 10.

Anti progesterone activity
Synthesis of novel oxazole analogs was done by Jin et al. and assessed their antagonist hormonal properties using mifepristone as standard drug. Compounds 106 and 107 showed highly potent antiprogestational activity. Results are mentioned in Table 42 [64].

Prostacyclin receptor antagonist
Brescia et al. carried out the synthesis and evaluated the prostacyclin (IP) receptor antagonistic activity of oxazole derivatives. Prostacyclin (PGI 2 ), which is an eicosanoid, plays an important role in inhibition of platelet  aggregation, vasodilatation, and also acts as an antagonist of thromboxane A 2 . Out of all the tested compounds, 108 was found to be the most effective one. Results are shown in Table 43 [65].

T-type calcium channel blocker
Lee et al. synthesized a number of oxazole derivatives substituted with arylpipera-zinylalkylamines and biologically evaluated against α 1G (Ca v 3.1) T-type calcium channel. Out of all the synthesized derivatives the most active one was 109 with an IC 50 value of 0.65 µM, which was found to be comparable with the reference drug mibefradil [66].

Conclusion
In summary, the present article aims to review the work reported on therapeutic potentials of oxazole derivatives which are valuable for medical applications during new millennium. This review article is based on synthesized oxazole derivatives which displays wide spectrum of biological potentials i.e. antibacterial, analgesic, anti-inflammatory, antidepressant, anticancer, antimicrobial, antidiabetic, antiobesity, antioxidant, adrenergic receptor ligand, antiprogesterone activity, prostacyclin receptor antagonist, T-type calcium channel blocker and transthyretin amyloid fibril inhibitory. The heterocyclic moiety being so versatile in nature offers the medicinal chemist to explore more about it in medicinal field and the data mentioned in this article will be a great help to prospective researchers working in this area for further study of this scaffold.
Oxazole moiety is an important heterocyclic compound as they are being an essential constituent of large number of marketed drugs. Having such diverse spectrum of biological activities, oxazoles has immense potential to be investigated for newer therapeutic