Oxazole Analogues as Potential Therapeutic Agents: A Comprehensive Review

Abstract

Oxazole, a five-membered heterocyclic motif composed of three carbon atoms, one oxygen atom, and one nitrogen atom with one carbon atom between the oxygen and nitrogen atoms, has attained remarkable notice in medicinal chemistry because of its diverse and potent biological effects. The unique structural features of oxazole make it a valuable scaffold for the generation of novel therapeutic agents. Over the years, oxazole derivatives have demonstrated a wide range of therapeutic actions, including anti-inflammatory, antitumor, antidepressant, analgesic, antidiabetic, diuretic, antibacterial, and anticonvulsant effects. These biological activities make them promising candidates for the treatment of various diseases. As a result, there has been an increasing interest in synthesizing new oxazole-based compounds with enhanced efficacy and selectivity for therapeutic applications. The present review aimed to provide a comprehensive overview of the chemical characteristics of oxazole and its congeners, highlighting their biological roles and potential for drug development. In addition, structure–activity relationship analysis explored the key substituents that favor the pharmacological potential against a range of clinical disorders. By consolidating current knowledge on the therapeutic potential of oxazole, this review seeks to stimulate further research and innovation in the pharmaceutical industry, material science, and academia, with the goal of addressing unmet medical needs.

Keywords

oxazole - antibacterial - anticancer - anti-inflammatory - analgesic

Introduction

The history of medicine is intertwined with the history of disease, as humans have long sought to understand and combat various illnesses.[1] From the earliest times, medicines were derived from natural sources, such as plants, animals, and minerals. However, the limited effectiveness and potential toxicity of these natural remedies underscored the need for new, more effective drugs.[1] [2]

Among these, heterocyclic compounds, particularly those with five-membered rings like oxazole, thiazole, oxadiazole, and triazine, have gained prominence due to their diverse pharmacological and therapeutic activities.[3] [4] Oxazole, a heterocyclic aromatic compound as depicted in [Fig. 1], is characterized by a five-membered ring structure composed of three carbon atoms, one oxygen atom, and one nitrogen atom, with one carbon atom between the oxygen and nitrogen atoms.[5] First synthesized in 1962, oxazole gained particular attention during World War II, when it was speculated that penicillin contained an oxazole ring system. The compound was eventually characterized through Diels–Alder reactions as well as 1,3-dipolar cycloaddition methodologies, leading to the discovery of its mesoionic heterocyclic structure.[6] Due to its unique chemical structure, oxazole and its analogues presented a wide range of therapeutic effects such as antibacterial, anti-inflammatory, antifungal, anti-inflammatory, anticancer, antidiabetic, and antiepileptic effects. These attributes make oxazole an important scaffold to design and generate novel therapeutic candidates, contributing significantly to the treatment of various diseases.[7] [8]

Fig. 1 Structures of oxazole nucleus-bearing marketed drugs.

Properties of Oxazole

Oxazole is a five-membered heterocyclic compound with a chemical formula of C₃H₃NO and a molecular mass of 69.06 g/mol. Oxazole typically exists as a colorless to pale yellow liquid at room temperature (boiling point 69–70°C) and has a density of 1.050 g/mL. The synonym name of oxazole is 3-azafuran. It has a relatively low acidity, with a pK_a of 0.8 at 33°C for its conjugate acid, and a basicity with a pK_b of 13.20. Oxazole undergoes phase transitions between solid, liquid, and gas phases.[9] The compound exhibits notable nuclear magnetic resonance (NMR) and the ¹H NMR chemical shifts appear at downfield (δ 7–8) due to the strong deshielding effect of the aromatic ring. Its vapor pressure is 132.01 mm Hg, indicating moderate volatility. The compound's octanol/water partition coefficient (log P) is 0.12, indicating low hydrophobicity. Oxazole is water-soluble and has a melting point of −82°C. It shows distinct spectral features in ultraviolet, infrared (IR), NMR, and mass spectrometry (MS) analyses. The heat of vaporization is 29.8 kJ/mol, and its refractive index at 17.5°C is 1.4285. These show the aromatic features, but less than thiazole. It is a weak base, having pK_a −0.8 as compared with imidazole, having 7.[9] [10] There are numerous synthetic routes leading to oxazole and its analogs, and some important methods of them have been known as name reactions of oxazole synthesis.[11] These include Robinson–Gabriel synthesis,[12] Fischer oxazole reaction,[7] [13] Bredereck synthesis,[14] Van Leusen synthesis,[15] and cycloisomerization of certain propargyl amides[16] as illustrated in [Scheme 1].

Scheme 1 Synthetic routes to produce oxazole-based compounds.

Marketed Drugs with Oxazole Ring

Oxazole-containing approved drugs cover a wide range of therapeutic areas, including inflammation, infectious diseases, oncology, central nervous system disorders, and so on.[17] The marketed drugs with oxazole ring are listed in [Fig. 1]. In this context, valdecoxib is a selective cyclooxygenase (COX)-2 inhibitor belonging to the class of nonsteroidal anti-inflammatory drugs and used to treat osteoarthritis, rheumatoid arthritis, and primary dysmenorrhea.[18] Further, oxaprozin is a propionic acid-derived nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis such as inflammation, swelling, stiffness, and joint pain, and hence, employed in osteoarthritis and rheumatoid arthritis.[19] In the antidiabetic field, Aleglitazar is an oxazole containing PPAR-α/γ dual agonist, which is designed to treat type 2 diabetes mellitus (DM) by improving glucose and lipid control.[20] Furthermore, merimepodib (VX-497) is a potent inosine monophosphate dehydrogenase inhibitor with broad-spectrum antiviral properties.[21] In contrast, ditazole is a platelet aggregation inhibitor from the class of non-NSAID antithrombotics, i.e., used in the past to prevent thromboembolic events.[22] Moreover, mubritinib (TAK-165) is an HER2 tyrosine kinase inhibitor that is currently being investigated for HER2-positive breast cancer.[23] To exhibit antibacterial properties, oxacillin is a β-lactam antibiotic under the penicillin class, which is specifically used against penicillinase-producing staphylococci, whereas sulfisoxazole is a sulfonamide antibiotic used in urinary tract infections, otitis media, and chancroid.[24] [25] In case of inhibitory potential against viruses, pleconaril remains an effective option, which targets picornaviruses like enteroviruses and rhinoviruses by inhibiting viral uncoating.[26] Beside this, leflunomide is a disease-modifying antirheumatic drug, i.e., used in rheumatoid and psoriatic arthritis via inhibition of dihydroorotate dehydrogenase and pyrimidine biosynthesis.[27] Whereas, isocarboxazid is a nonselective and irreversible monoamine oxidase inhibitor used to treat atypical and treatment-resistant depression.[28] Also, broxaterol acts as a β₂-adrenergic receptor agonist and is used as a bronchodilator in chronic obstructive pulmonary disease and asthma. Its oxazole-containing structure facilitates the selectivity toward bronchial smooth muscle β₂-receptors with reduced cardiovascular side effects.[29]

Preclinical or Clinical Trial Candidates Bearing Oxazole Scaffold

Numerous oxazole-based molecules are currently under preclinical and clinical investigation due to their promising biological activities and favorable pharmacokinetic profiles ([Fig. 2]). These investigational agents target a wide range of diseases, with the oxazole ring playing a critical role in receptor binding, enzymatic inhibition, or protein degradation pathways.[30] In this sequence, PRT3789 is an SMARCA2-targeting degrader having an oxazole core incorporated within a proteolysis-targeting chimera (PROTAC). Currently, it is being evaluated in a Phase I dose-escalation trial (NCT05639751) for adult patients with advanced or metastatic solid tumors harboring SMARCA4 mutations. This trial assesses safety, tolerability, pharmacokinetics, pharmacodynamics, and suggests the recommended Phase II dose for both monotherapy and in combination with docetaxel. The study is actively recruiting patients under the sponsorship of Prelude Therapeutics.[31] A planned Phase II follow-on study combining PRT3789 with pembrolizumab (Keytruda) for SMARCA4-mutated cancers is listed in collaboration with Merck & Co.[32] Further, MK-4409 is a 1,3-oxazole-based FAAH inhibitor, i.e., developed by Merck for potential treatment of neuropathic and inflammatory pain. According to the Food and Drug Administration and pipeline records, MK-4409 reached Phase I trials for neuropathic pain around 2009 and is currently in early clinical development.[33] Next, luminespib (NVP-AUY922) is a 1,2-oxazole-based Hsp90 inhibitor originally discovered by The Institute of Cancer Research/Vernalis, while later licensed to Novartis. It was advanced into Phase I/II clinical trials from 2011 to 2014 across multiple cancer indications, such as relapsed/refractory multiple myeloma, nonsmall cell lung cancer (NSCLC), breast cancer, and other solid tumors. The largest of these trials evaluated the dose-escalation, combination therapy with bortezomib, as well as safety or tolerability endpoints (e.g., MTD, adverse events).[34] [35] Furthermore, rhizoxin is a macrocyclic lactone antibiotic containing an oxazole ring, which was originally isolated from Rhizopus species. Mechanistically, it disrupts microtubule polymerization, which makes it an antimitotic agent. It proceeded through both Phase I as well as multiple Phase II oncology trials, including studies in advanced solid tumors, squamous cell head and neck cancer, breast cancer, melanoma, and NSCLC. Phase I investigations used a 72-hour continuous intravenous infusion, whereas Phase II trials administered 1.5 to 2.0 mg/m² every 3 weeks. Hereby, the main toxicities were leukopenia, stomatitis, neutropenia, and occasional phlebitis.[36] [37] Moreover, GNF6702 is a 2,4-dimethyl-1,3-oxazole-5-carboxamide derivative, which was discovered by the Genomics Institute of the Novartis Research Foundation. It acts as an allosteric proteasome inhibitor and selectively targets kinetoplastid parasites (e.g., Leishmania, Trypanosoma). In preclinical mouse models for visceral leishmaniasis, Chagas disease, and sleeping sickness, GNF6702 demonstrated complete parasite clearance, favorable safety, and high selectivity, as compared with mammalian cells. However, it remains in preclinical development with no current human clinical trials registered.[38] [39]

Fig. 2 Structures of oxazole-based clinical trial candidates.

Advancements in the Biological Activities of Oxazole Derivatives

Oxazole-containing derivatives have a large number of pharmacological implications, which have drawn their attention toward both medicinal and industrial applications. In terms of biological activity, oxazole derivatives display a range of therapeutic effects.[40] They are known to inhibit key enzymes such as COX and tyrosinase, contributing to their anti-inflammatory and anticancer properties.[41] They also exhibit antibacterial,[42] antifungal,[43] and antioxidant activities,[44] as well as antitubercular[45] [46] effects. Other notable biological activities include anticonvulsant[47] and antihyperglycemic[48] properties.

Beyond their pharmaceutical uses, oxazole derivatives serve as functional materials with different applications. They are utilized in the production of homopolymers, peptides, and condensation reagents, and as active ingredients in herbicides, pesticides, and fungicides.[49] [50] Additionally, oxazole compounds are employed as profitable luminophores in plastic materials, laser dyes, and polymer systems.[51] [52] They are also used as chiral ligands in asymmetric synthesis[53] and employed as intermediates in the synthesis of agrochemicals.[54] Furthermore, oxazole derivatives play a role in polymerization reactions, further expanding their industrial and commercial utility.[55] This broad range of applications highlights the versatility and importance of oxazole derivatives in both biological and industrial contexts.

Advancements in the Antibacterial Activity of Oxazole Analogues

A growing global concern is the increasing resistance of pathogenic bacteria to existing antibiotics and antifungal agents, which has become a significant challenge in health care.[56] To address this issue, it is crucial to discover and develop novel classes of drugs that can effectively combat the rising threat of resistant microbes.[56] [57] This has emerged as one of the most important areas of antibacterial research. Among the promising candidates, heterocyclic compounds such as oxazole derivatives have gained attention due to their broad spectrum of biological effects, especially antimicrobial properties.[58]

In 2022, Singagari and Sundararajan designed and synthesized a series of 4,5-dihydro-1H-pyrazol-3-yl substituted 4-benzylidene-2-methyloxazol-5(4H)-one derivatives (1a-o, [Fig. 3]) and evaluated their antimicrobial activities.[59] Among the synthesized series, 1h exhibited the highest antibacterial activity, having a minimum inhibitory concentration (MIC) value of 1.56 µg/mL against Bacillus subtilis, Staphylococcus albus, and Proteus vulgaris, i.e., equivalent to the standard drug ciprofloxacin (MIC = 1.56 µg/mL). Results of antitubercular assays indicated that compounds 1j and 1l exhibited the strongest inhibitory profile with a MIC value of 3.13 µg/mL against Mycobacterium tuberculosis H37Rv, as compared with isoniazid (MIC = 0.05 µg/mL). Further, molecular docking studies demonstrated that 1l showed the best binding score of −9.94 kcal/mol against MtKasA (PDB: 2WGE), whereas 1j was found to be most potent with a binding score of −8.91 kcal/mol against MtpKnB (PDB: 2FUM) by surpassing even the reference agent mitoxantrone. These results suggested that oxazole derivatives bearing unsubstitution, meta-OH and meta-CH₃ groups at the R position on the phenyl linked to the pyrazoline ring exhibited superior antibacterial potency.

Fig. 3 Structures of oxazole derivatives (1-8) as potent antibacterial agents.

Keivanloo et al reported a novel series of 1,3-oxazole-quinoxaline amine hybrids (2a-l, [Fig. 3]) and evaluated their antibacterial activity.[60] Among them, compounds 2b, 2c, 2g, and 2j displayed the most potent inhibitory effect against Micrococcus luteus and Pseudomonas aeruginosa with MIC values of 62.5 and 31.25 µg/mL, respectively, which were almost equipotent to the standard drug tetracycline. Next, the molecular docking analysis highlighted that compound 2j is the most potent with the best docking score of −8.49 kcal/mol toward Yersinia pestis DHPS (PDB ID: 5JQ9).[60] Structure–activity relationship (SAR) data suggested that phenyl and 4-Cl as R group on oxazole nucleus, while aliphatic or aryl substituted aliphatic 2° amines as the R¹ group were the favorable substituents for encouraging antibacterial activity.

Seelam et al developed a series of thiadiazole-tethered oxazole hybrids (3a–j, [Supplementary Table S1], available in the online version). The introduction of electron-withdrawing groups (-4-Cl, 4-Br, 4-NO₂, 2-Cl, 3-NO₂) at phenyl on the isoxazole ring is essential for suitable antibacterial activity. Among these compounds, 3a, 3b, 3c, 3e, and 3j demonstrated excellent antibacterial potential compared with streptomycin against B. subtilis and Bacillus thuringiensis, possessing MIC values of approximately 3.125 µg/mL, as compared with streptomycin (MIC values 6.25 and 12.5 µg/mL, respectively). Due to the variability inherent in the disc diffusion assay, the activity of these derivatives at lower concentrations was further investigated using the broth dilution method. The bacterial strains B. thuringiensis, P. aeruginosa, B. subtilis, and Escherichia coli were tested, and the outcomes of their antimicrobial potential.[61]

Mohanty et al synthesized a series of oxazole 2,4-diamine compounds (4, [Fig. 3]) and evaluated their antibacterial potential against both Gram-positive and Gram-negative bacterial strains. Electron-withdrawing groups (EWGs), like as fluoro- or choro-substitution on the phenyl ring, are essential to deliver potent antibacterial activity. All the synthesized derivatives demonstrated significant antibacterial activity. Ciprofloxacin (50 µg/mL) was used as the standard drug. Among the newly synthesized compounds, 4b and 4c showed the highest antibacterial activity.[62]

Chilumula et al have prepared a series of novel benzoxazole-5-carboxylate derivatives (5a-i, [Fig. 3]) and evaluated their antibacterial activity using the cup plate assay. The compounds demonstrated excellent antibacterial potency toward Staphylococcus aureus and B. subtilis (Gram-positive bacteria), as well as E. coli and Salmonella typhi (Gram-negative strains). Electron-donating groups (EDGs) favor antibacterial potency. Disubstitution of the Ar group at the meta and para positions (2-OH-4-OCH₃-C₆H₃) synergizes the antibacterial efficacy. Among all the molecules tested, compound 5g exhibited superior antimicrobial results against both tested strains, with zone of inhibition values ranging between 20 and 24 mm, which was more potent than standard antibiotic ampicillin (zone of inhibition = 17–22 mm).[63]

In the same year, Dabholkar et al synthesized novel compounds containing the oxazole ring (6a–e, [Fig. 3]) and tested their antifungal and antibacterial activities by utilizing the disc diffusion assay technique. Ampicillin trihydrate was taken as the reference antibacterial agent. Results of in vitro antibacterial studies indicated that compound 6c was the most effective molecule against S. aureus (zone of inhibition = 11 mm), 6b, and 6e showed the topmost antibacterial efficacy toward Corynebacterium diphtheriae, with zone of inhibition values of 11 mm. Also, 6b experienced the most promising antibacterial potency for P. aeruginosa (zone of inhibition = 12 mm), whereas compounds 6a, 6c displayed remarkable antibacterial activity against E. coli with zone of inhibition values of 12 mm, as compared to standard antibiotic ampicillin trihydrate (zone of inhibition = 21–28 mm).[64] SAR findings suggested that attachment of EDGs like methyl and methoxy groups at R and R¹ positions, respectively, whereas the unsubstituted or OH-substituted-R4 position showed the most promising antibacterial results.

Reddy et al synthesized new oxazole derivatives (7a-l, [Supplementary Table S3], available in the online version) and tested their antimicrobial activities against different bacterial strains.[65] These compounds exhibited significant inhibitory effects at concentrations ranging from 258 to 564 µg/mL in 20% water in dimethyl sulfoxide. The favorable substituents were para-halo-substituted (4-Cl or 4-Br) phenyl at the R position. Among the synthesized compounds, 7b, 7f, 7e, and 7g showed pronounced antibacterial activities ([Fig. 3]), with the following order of increasing potency: 7g > 7f > 7e > 7b. Specifically, compounds 7c, 7d, 7h, and 7k presented significant antibacterial potency toward E. coli, while 7i and 7j were more effective against B. subtilis, and 7m and 7l showed better activity against Klebsiella pneumoniae. Ampicillin was selected as the reference drug for comparison of antimicrobial efficacy.

Kamble et al synthesized piperidinyl-substituted oxazole-containing derivatives (8a–b, [Fig. 3]) with unsubstituted phenyl or p-nitrophenyl at Ar. They evaluated the antibacterial potency of the compounds toward S. aureus and E. coli bacterial strains.[66] The results are presented in [Supplementary Table S4] (available in the online version).

Advancements in Antifungal Activity of Oxazole Analogues

The development of antifungal agents has been taken after antibacterial agents. Bacteria are prokaryotic, and hence, they have a large number and metabolic sites, which are distinct from the possession of a hominid host.[67] Fungus is eukaryotic in nature and the utmost poison to the host cell. By virtue of this fungus commonly spreads slowly and generally in a multicellular system. There are numerous new antifungal agents that particularly discharge fungal pathogens from a hominid host, along with lesser toxicity, and are hence called antimycotic drugs.[68] [69] [70]

Bąchor and colleagues reported a new series of isoxazole-based α-acyloxyamide derivatives (9, [Fig. 4]) and evaluated their antifungal activity against Candida albicans. Sulfur-rich heterocycles (thiazole or thiophene) at Ar, whereas a benzyl group at Ar' enhanced the antifungal activity. Among all, compounds 9a and 9b demonstrated the most prominent anti-fungal activity against C. albicans biofilm (MIC ≥ 10 μg/mL; % minimum biofilm eradication concentration (MBEC) reduction = 54.9% and 24.6%, respectively) without adverse interference to beneficial Lactobacillus spp., which was a major advantage over conventional antifungals like clotrimazole or octenidine dihydrochloride. Further, compounds 9a and 9b also exhibited lower cytotoxicity against Henrietta Lacks (HeLa) cells.[71]

Fig. 4 Structures of oxazole derivatives (9-14) as potent antifungal agents.

In the same year, Tlapale-Lara et al assessed pyrazole and oxazoline (10a–j and 11a–j, [Fig. 4]) derivatives as potent antifungal agents. The in silico evaluation indicated that all molecules adhere to Lipinski's rules with low toxicity and suggesting good drug-like behavior. Further, Homology modeling of CYP51 was conducted based on available Candida species to generate validated 3D models for in silico interactions analysis. The models confirmed that these compounds fit well within the enzyme's active site. In addition, Molecular docking revealed that these compounds exhibit better binding energies, and compound 11d exhibited the highest binding energy (–14.23 Kcal/mol) against C. albicans, as compared with fluconazole (−7.29 Kcal/mol). In vitro antifungal testing across several Candida species demonstrated that compounds 10a–j and 11a–j showed significant MIC₉₀ values ranging between 0.11–14.4 and 0.05–42.3 μg/mL, respectively, as compared with fluconazole (MIC₉₀ = 1.4– > 57.6 μg/mL).[72] Pharmacophore hybridization in pyrazolyl oxazoles (11a–j) exerted synergistic advantages in antifungal action, and a Bulkier halogen at R (e.g., Br) showed promising activity.

In 2009, Ryu et al prepared novel benzoxazole derivatives (12a–b, [Fig. 4]) and investigated their antimycotic potential against various fungal strains. The control drug, 5-fluorocytosine, was used for comparison of antifungal activity. Results of this study presented the antifungal effect of synthesized molecules either superior to or comparable with that of the reference drug, as presented in [Supplementary Table S5] (available in the online version).[73] para-Bromophenyl substitution on the core scaffold was found to be more beneficial for the antifungal profile in contrast to the unsubstituted counterpart.

Rawat and Shukla synthesized a new series of oxazole derivatives (13, [Fig. 4]) with antifungal potency. The antimycotic potential was evaluated using the cup plate assay method, where ketoconazole (100 µg/mL) was selected as the reference antifungal agent. The result suggested that the -p-NO₂ group at R displayed the most favorable antifungal profile, as compared with other EDGs (OH, OCH₃) or EWGs (halogens) substitutions. The oxazole imine compound 13e exhibited the maximum inhibition against both C. albicans and Aspergillus niger, having zone of inhibition values of 17 and 16 mm, respectively, as compared with the standard antifungal drug ketoconazole (zone of inhibition = 20 mm; C. albicans and 18 mm; A. niger). Also, its analogues 13a, 13b, 13c, 13d, and 13f showed moderate activity against both fungal strains, with zone of inhibition values ranging from 9 to 14 mm against the tested fungal species.[74]

Kakkar et al synthesized new compounds containing the oxazole ring (14, [Fig. 4]) and evaluated their antimycotic potential. The introduction of the Cl group contributed to C. albicans inhibition, and the phenoxy group to A. niger inhibition. Compound 14a exhibited the most potent activity against A. niger, whereas derivatives 14b and 14c showed moderately antifungal activity against A. niger. In contrast, compounds 14b and 14c were found to be highly active toward C. albicans, as compared with Fluconazole ([Supplementary Table S6], available in the online version).[22]

Advancements in Antitubercular Activity of Oxazole Analogues

Tuberculosis (TB) is a virulent disorder that primarily affects the lungs. In contrast to another disease, which is induced by a particular virulent agent, TB is the second massive common killer all over the world. The World Health Organization estimates that near about 9 million persons in a year diagnosed with TB, along with 3 million of them forgotten by the health system.[75] A series of bicyclic nitroimidazole oxazole has been mainly searched as radiosensitizers in cancer chemotherapy, but it is also found useful against the culture replication of airborne pathogen M. tuberculosis.[76] [77]

Thakare et al focused on the design, synthesis, and evaluation of novel benzoxazole derivatives (15a–i, [Supplementary Fig. S5], available in the online version) with potential antibacterial and antitubercular activities.[78] In this work, these derivatives were characterized by IR, NMR, and MS to confirm their structures and purity. Furthermore, the antibacterial activity was assessed via serial dilution methods against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (E. coli). Here, methoxy and halogen (Br > I > I) groups at R and X positions, respectively, were found to be necessary for anti-TB activity. Whereas propyl ester exerted the most promising inhibitory effect against M. tuberculosis. Among the compounds, 15a, 15c, 15f, and 15i showed significant inhibition at concentrations of 50 and 100 μg/mL. Similarly, the anti-tubercular efficacy was evaluated using the Alamar blue assay against M. tuberculosis H-37RV strain and compounds 15c and 15i, demonstrating noteworthy anti-TB activity at similar concentrations.[78]

Shinde et al reported the synthesis of novel oxazole-based hybrid molecules (16 and 17, [Fig. 5]) to develop potent anti-tubercular agents. Here, these molecules were biologically evaluated against M. tuberculosis H₃₇Rv, including drug-resistant strains like MDR and XDR, using a colorimetric microplate assay. SAR data revealed that 4-nitrophenyl at the second position of the oxazole nucleus enhanced the biological activity. Among all these compounds, only 16a exhibited significant anti-TB activity with a MIC value of 6.25 μg/mL, in comparison to Isoniazid (MIC = 3.125 μg/mL). Further, molecular docking was performed for compound 16a against bacterial enzyme deoxyribonucleic acid gyrase (PDB ID: 4B6C). The docking results revealed van der Waals interactions with VAL 77 and various pi-cation or pi-alkyl interactions with amino acids ARG 82, ILE 84, and PRO 85 that likely contribute to its efficacy.[79]

Fig. 5 Structures of oxazole derivatives (15-19) as potent antitubercular agents.

Moraski and their group synthesized various derivatives (18a–i, [Supplementary Table S7], available in the online version) using the Suzuki coupling reaction and evaluated their antitubercular activity. The MICs were determined against M. tuberculosis H37Rv. Rifampicin and clinical candidate PA-824 were chosen as reference anti-TB agents. The results revealed that, except for compound 18h (>128 μmol/L), the derivatives were generally less effective against verda reno (means green kidney) cells. The 4-benzyloxy phenyl ring at R showed the most promising antitubercular activity as compared with single aromatic ring substitutions. Among all the tested molecules, compound 18h was found to be most effective against M. tuberculosis H37Rv with a MIC value of 0.60 μmol/L, as compared with rifampicin (MIC = 0.06 μmol/L). The results are presented in [Supplementary Table S7] (available in the online version).[80]

Prior to Moraski's work, Zwawiak et al synthesized and investigated novel 2,3-dihydroimidazo [2,1-b]oxazoles (19, [Fig. 5]) as potential antitubercular agents. The in vitro antitubercular assay of synthesized molecules was performed by taking isoniazid (INH) as the standard antitubercular drug. Tiny alkyl groups are advantageous for the anti-TB profile (ethyl > methyl). Compounds 19a and 19b were tested against M. tuberculosis, Mycobacterium avium, and Mycobactrium bacillus Calmette–Guérin, whereas two wild species were collected from TB patients. Among these strains, 1676 showed resistance to INH, and the 456 strain exhibited resistance to both reference agents. Further, the antitubercular potential of these derivatives was assessed, and MIC values of the synthesized compounds are presented in [Supplementary Table S8] (available in the online version).[81]

Advancements in Anticancer Activity of Oxazole Analogues

Malignancy is one of the serious diseases, where anomalous cells arise and might develop in existing cells at each one phase of mortal life.[82] Here, nearly a hundred types of tumors have been involved, such as blood tumor, skin tumor, brain tumor, breast tumor, prostate tumor, lung tumor, colon tumor, etc.[83] There are different therapies for tumors, inclusive of chemotherapy, radiation, and surgery. After the existence of these therapies, tumors have into the biggest challenge with the health complications globally. However, a large number of anticancer drugs were tested a few years ago due to the existence of distinct cell lines and the use of various techniques.[84] [85] [86]

Khowdiary et al discussed the synthesis and evaluation of a new series of oxazole derivatives tethered with an oxadiazole moiety (20, [Fig. 6]) as potent antileukemic agents. In their work, the synthesized compounds were tested for their in vitro inhibitory effect against HL-60 and PLB-985 enzymes, in comparison to Etoposide. It was noticed that the 4-trifluoromethyl group was the most favorable substitution to elicit anticancer effect (4-CF₃ > 2,5-di-F > 3,5-di-OH). Compound 20b exhibited the most potent dual inhibitory profile with IC₅₀ values of 8.50 and 12.56 µg/mL, respectively, as compared with etoposide (IC₅₀ = 10.50 and 15.20 µg/mL, respectively). Further, molecular docking revealed strong binding affinities within the active site, and 20a, 20b, and 20c have the highest binding energy. Likewise, ADMET analysis showed that potent molecules do not violate the Lipinski rule of 5 and have a good therapeutic profile.[87]

Fig. 6 Structures of oxazole hybrid derivatives (20-28) as potent anticancer agents.

Quite recently, Komirishetti and Mittapelli reported the synthesis and biological evaluation of a novel series of imidazole clubbed pyrimidinyl oxazole hybrids (21a–j, [Supplementary Fig. S6], available in the online version) as potent anticancer agents. Further, all the compounds were investigated for anticancer assessment against four human cancer cell lines, viz. MCF-7, Colo-205, A549, and A2780 cells were tested with the help of the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, whereas etoposide was used as a standard treatment. Trimethoxy substitution (3,4,5-trimethoxy) at R showed an advantageous anticancer influence than mono-/di-substituted methoxy groups. Among all the compounds tested, compound 21a emerged as the most potent cytotoxic agent, having an IC₅₀ value of 0.06 ± 0.0072 µmol/L against MCF-7, which was more active than Etoposide (IC₅₀ = 2.19 ± 1.87 µmol/L).[88]

Premakumari et al synthesized a novel amido-sulfomido methane-associated bis-oxazole compound (22, [Fig. 6]).[89] SAR outcomes concluded that the EWGs substituted (4-Cl-phenyl) was more beneficial than the unsubstituted or 4-CH₃ substituted counterparts. The antitumor potential of 22c against various cancer cell lines is described in [Supplementary Table S9] (available in the online version).

Mathew et al synthesized 23a–c ([Fig. 6]), which were found to be less potent than sulindac sulfide amide. Among these, 23b, which was substituted with dimethyl derivatives of sulindac, showed modest activity against all the described cell lines in vitro, as presented in [Supplementary Table S10] (available in the online version). Further, 24b, shows notable activity as a carboxylate and demonstrates moderate potency compared with sulindac, as detailed in [Supplementary Table S10] (available in the online version).[90] The results suggested that favorable substituents for compounds 23, 24, 25 were a 3,4,5-trimethoxyphenyl ring attached to the indole ring via an alkene linkage. The results suggested that favorable substituents for compounds 23, 24, and 25 were a 3,4,5-trimethoxyphenyl ring attached to the indole ring via alkene linkage.

Kachaeva et al synthesized several derivatives of oxazole (26a–f, [Fig. 6]) and investigated their antitumor potential. Derivatives 26a, 26b, 26c, and 26e, which contain amino, sulfanyl, or sulfonyl groups at position 5 of the 1,3-oxazole ring, exhibited modest antitumor activity. Results revealed that all tested oxazole analogues possessed significant anticancer potential against selected cancerous cells, having GI₅₀ values in the range of 0.2 to 0.6 μmol/L. Compound 26e exhibited the topmost anticancer activity against the tested NCI-60 cancer cell lines with GI₅₀ values ranging between 0.15 and 6.4 μmol/L.[91]

In the work by Romagnoli et al, a library of antitubulin agents (27a–c, [Fig. 6]) was synthesized and investigated for their antitumor potential against various cancer cell lines, while Combretastatin A-4 (CA-4) was taken as the reference drug. Further, compounds 27b and 27c showed the best anticancer profile among the derivatives, outperforming CA-4 in several cases. Compound 27b showed comparable potency to CA-4 toward SEM as well as Jurkat cells, while it was found to be many-fold more potent against other tumor cell lines ([Supplementary Table S11], available in the online version).[92]

Ranjith and their team synthesized a series of benzoxazole derivatives (28, [Fig. 6]). All the compounds were tested for antitumor potential using the MTT assay against the MCF-7 cancer cells. The results showed that a single EWG (bromo/nitro) substituted phenyl ring showed a potent anticancer effect, with 28a and 28b exhibiting the highest potency, with % growth inhibition values of 45.568 and 42.236, respectively.[93]

Advancements in Antioxidant Activity of Oxazole Analogues

Free radicals like superoxide anion radicals (O₂ ^•−), hydroxyl radicals (OH^•), peroxy radicals (RO₂ ^•), nitric oxide (NO), and (O) atoms are important for many physicochemical systems. The drugs that are most correlated to antioxidant activity can metabolize the free radicals and their intermediary products diffusively into nontoxic compounds.[94] Increment in cancers, cardiovascular system diseases, and aging occurred due to oxidative cellular damage. Antioxidants are substances that mitigate oxidative stress in cells.[95]

Rao et al designed and synthesized a series of oxazole clubbed 1,2,4-triazolothiadiazole hybrids (29, [Fig. 7]) as potent antimicrobial agents. Herein, antimicrobial efficacy was tested against six Gram-positive and Gram-negative strains by using ofloxacin as the standard drug. The substituents at the meta position of phenyl ring linked to the oxazole ring were preferred to exhibit biological activity (isopropyl > 4-methoxyphenyl > allyl).

Fig. 7 Structure of oxazole derivatives (29-31) for antioxidant activity.

Among these, compounds 29a and 29b exhibited the most potent antibacterial activity with zone of inhibition values ranging from 18–36 and 16–32 mm against all tested bacterial strains. Additionally, the antioxidant activity revealed that compounds 29c and 29b emerged as the most potent in 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and H₂O₂ radical scavenging assay with half-maximal inhibitory concentration (IC₅₀) values of 24.39 and 18.76 µg/mL, respectively, as compared with ascorbic acid (IC₅₀ = 20.20 and 21.76 µg/mL). Molecular docking study against E. coli with PDB ID:4CKL revealed that 29b elicited the highest binding energy −5.67 kcal/mol.[96]

In this context, Sagud et al synthesized naphthoxazole derivatives with a methoxy group at the naphthoxazole ring system (30a–b, [Fig. 7]) and evaluated their antioxidant potential with the help of DPPH radical scavenging and Ferric reducing ability of plasma assay methods.[97] The half-maximal DPPH radical scavenging concentration (IC₅₀) of derivative 30a was determined to be 0.4 µmol/L. The results were presented in [Supplementary Table S12] (available in the online version).

Canan et al synthesized a series of derivatives of oxazole-5(4H)-one (31a–j, [Fig. 7]) and tested their antioxidant activity using male albino Wistar rats.[98] NADPH-dependent lipid peroxidation was determined spectrophotometrically using the formation of thiobarbituric acid-reactive substances technique. The result showed that mono-substitution of tiny EDG, like CH₃ at R, whereas di-substitution of EWG (fluoro) at the X position, is preferred. Compound 31c exhibited the highest reactivity in terms of microsomal ethoxyresorufin O-deethylase (EROD) activity of 4.47 ± 0.04 pmol/mg/min, as compared with standard caffeine (EROD = 6.41 ± 0.99 pmol/mg/min). Substitution with a biphenyl group decreased the EROD activity but had no effect on lipid peroxidation levels, demonstrating moderate antioxidant activity.

Advancements in Antiviral Activity of Oxazole Analogues

In 2024, Severin et al synthesized a novel series of 1,3-oxazole-4-carbonitriles and 4-sulfonylamide-5-phenyl-1,3-thiazoles (32, [Fig. 8]) as a potent marker of human papillomavirus.[99] A QSAR model employing artificial neural networks was developed to predict their anti-human papillomavirus (HPV) activity. Further, these compounds were evaluated for in vitro activity against HPV types 11, 16, and 18 using C33-A cell lines to determine antiviral efficacy measured through EC₉₀, half-maximal cytotoxic concentration (CC₅₀), and selectivity indices SI₉₀. It was revealed that 32a exhibited the highest antiviral activity against HPV11 with EC₅₀, CC₉₀, and SI₉₀ values of 20.44, 88.10, and 4 µmol/L, respectively, whereas standard drug 9-[2-phosphono-methoxy)ethyl]guanine had EC₅₀, CC₉₀, and SI₉₀ values of 82.94, ≥150, and ≥2 µmol/L, respectively. The result showed that the phenyl ring at R, whereas the sulfonyl phenyl linked to sulfonyl piperazine at R¹ presented promising antiviral action.

Fig. 8 Structure of oxazole derivatives (32-34) for antiviral activity.

Kachaeva et al synthesized a range of 1,3-oxazole analogs (33a–b, [Fig. 8]) and evaluated the prevalence of HPV infection. 33a and 33b showed EC₅₀ values of ≥50 and 2.43 µmol/L against HPV-18 and HEK-293 cells, respectively, in comparison to the cidofovir showing EC₅₀ values of 148 µmol/L against both cells, suggesting that sulfonyl piperidine is more efficacious than the N-unsubstituted sulfonamide group counterpart. In this work, regression analysis was used to evaluate the antiviral activity of the compounds. The results of EC₅₀ and CC₅₀ values of these analyses were presented in [Supplementary Table S13] (available in the online version).[100]

Makarov et al developed a library of isooxazole analogs (34a–c, [Fig. 8]) and evaluated their antiviral activity. HeLa cells were used for plaque reduction assays to isolate CVB3 97-927 and for Carrageenan paw edema test (cytopathic effect) inhibition assays with CVB3 Nancy, HRV-14, and HRV-2. The activities of the R substituents are as follows: - 4-F > 3-F > 3-NO₂. The range of CC₅₀ values for the derivatives was found to be 4.6 to >50 µg/mL, as shown in [Supplementary Table S14] (available in the online version).[101]

Advancements in Anticonvulsant Activity of Oxazole Analogs

Epilepsy is a life-threatening and serious disease for humans. Epilepsy refers to a neurodegenerative disorder in which disruption of nerve cell activity occurs in the brain. More than 1 million cases per year were considered in India. To eradicate epilepsy, the discovery of potent antiepileptic drugs is too important.[102] [103]

Srilakshmi et al designed a series of thiazole-oxazolone derivatives (35a–m, [Fig. 9]) and evaluated their anticonvulsant activity. In their research, in silico molecular docking revealed significant binding affinities of these derivatives toward targets like carbonic anhydrase (PDB ID: 1HOW) and GABAAT (PDB ID: 3F86). Molecular docking study against carbonic anhydrase enzyme revealed that 35b showed the highest docking score of −9.97 kcal/mol in comparison to Phenytoin (binding energy = − 6.65 kcal/mol). In addition, 35f showed the topmost binding energy of −7.37 kcal/mol against the GABAAT receptor in comparison to Phenytoin (binding energy = − 3.78 kcal/mol). Furthermore, the biological evaluation through the maximal electroshock test (MES) and scPTZ seizure models demonstrated that compounds 35a, 35c, and 35e exhibited notable anticonvulsant activity at various doses, with 35c emerging as the most potent.[104] The results showed that halo-substitution on the meta position (m-Cl, m-Br) of the phenyl ring tethered via Schiff base linkage increased the activity of the compounds.

Fig. 9 Structure of oxazole and triazole thione derivatives (35-37) for anticonvulsant activity.

Song et al developed a series of triazole-containing benzo[d]oxazole derivatives (36a–d, [Fig. 9]) and tested them for anticonvulsant activity using the scPTZ (subcutaneous pentylenetetrazol) and MES models.[105] The newly developed compounds were administered to mice at different time intervals (0.5 and 4 hours). Compounds 36a–d showed the highest activity at a drug concentration of 30 mg/kg after 0.5 hours in the MES screening. Compound 36d demonstrated significant activity at 30 mg/kg after 4 hours, whereas compounds 36a–c required a higher dose of 100 mg/kg to show comparable activity at the same time interval. 36d showed an ED₅₀ value of 12.7 and 29.5 mg/kg via the intraperitoneal route in MES and scPTZ models, respectively, compared with carbamazepine, demonstrating ED₅₀ values of 9.8 and >100 mg/kg, respectively. The results showed that 4-F-benzyl substitution at the benzoxazole core elicited more promising anti-convulsant action than 2-F- or 3-F-benzyl counterparts. The data are presented in [Supplementary Table S15] (available in the online version).[106]

Singh et al prepared novel derivatives of triazole thione semicarbazones (37a–e, [Fig. 9]) and investigated their antiepileptic potential as GABA agonists. In this study, Albino mice of either sex, weighing 20 to 25 g, were used for testing the anticonvulsant activity with diazepam as the reference drug for comparison. The anticonvulsant potential of the synthesized molecules is depicted in [Supplementary Table S16] (available in the online version).[107] 37d, 37e, and 37c showed maximum activity, whereas compounds 37a and 37b exhibited moderate activity. So, these are the lead molecules for another therapeutic potential.

Advancements in Anti-Inflammatory and Analgesic Activity of Oxazole Analogs

Nonsteroidal anti-inflammatory agents/analgesics are a class of analgesics (pain-relieving) that reduce pain, fever, and inflammation without loss of consciousness. Besides therapeutic uses, side effects like gastric bleeding, ulceration also occurred by administering these drugs. So, it becomes the biggest challenge to overcome these side effects and provide much better and safer drugs in the market. With this, the discovery of new drugs became more important.[105] [108] [109]

Garg et al discovered a series of oxazole derivatives (38, [Fig. 10]).[110] After synthesis, spectroscopic methods such as FT-IR and ¹H NMR were used to validate the chemical structures of the synthesized analogs. Among the compound, derivative 38b, with a p-amino benzaldehyde linked to the amino group of phenyl oxazole amine was the most effective anti-inflammatory candidate with 28.67% inflammatory inhibition (Paw edema volume = 1.28 ± 0.03) in the third hour in the carrageenan-induced rat hind paw edema method, as compared with indomethacin (% inhibition = 45.86%; Paw edema volume = 1.44 ± 0.02).

Fig. 10 Structure of oxazole derivatives (38-41) for anti-inflammatory and analgesic activity.

Meenakshi et al investigated the dual functionality of 2,4,5-trisubstituted oxazole derivatives (39, [Fig. 10]) as aquaporin-4 (AQP4) inhibitors as well as anti-inflammatory agents in human lung cells. In this research work, molecular docking was conducted against the AQP4 receptor (PDB ID: 3GD8), which revealed that compound 39a, with methyl, a tiny EDG at R while an unsubstituted phenyl ring at the Ar position, respectively, exhibited the strongest binding affinity of −7.3 kcal/mol via interacting primarily with GLY144, GLY146, and VAL147 amino acid residues. Moreover, the ADME study showed that these compounds followed Lipinski's rule of five. In vitro studies on NCI-H460 lung cells demonstrated that compound 39a effectively inhibited LPS-induced upregulation of the AQP4 gene and suppressed the transcription of proinflammatory cytokines. In addition, hemolysis assays confirmed its excellent biocompatibility with less than 1.6% hemolytic potential even at drug concentrations up to 600 µmol/L.[111]

Shakya et al discovered oxazole ring-containing derivatives (40a–b, [Fig. 10]) and investigated their anti-inflammatory potential.[112] Albino rats were used for preclinical trials. The newly developed compounds were given at a dose of 20 mg/kg body mass via the oral route, and paw volume was measured plethysmographically. An equal amount of normal saline was used as the control group, and ibuprofen (20 mg/kg body weight) was used as the reference drug. Compounds 40a and 40b exhibited significant anti-inflammatory potential, surpassing the reference drug, as shown in [Supplementary Table S17] (available in the online version).[112]

Sarkate and Shinde developed oxazole-based compounds (41, [Fig. 10]) and assessed their anti-inflammatory, analgesic, and nitric oxide-releasing properties.[113] Among all synthesized compounds, compounds 41a and 41b were found to be the most potent anti-inflammatory analogues with 69.26 and 68.78% inflammatory inhibition, respectively, at 3 hours. Results of 41a were equipotent to celecoxib (standard COX-2 inhibitor) at 3 hours. The biological evaluation results are presented in [Supplementary Table S18] (available in the online version).

Advancements in Antidiabetic Activity of Oxazole Analogs

DM, a metabolic disease that induces an elevated blood glucose level due to impairment of the insulin hormone. Untreated high blood sugar leads to hyperglycemia and long-term complications, including angiopathy, neuropathy, and retinopathy. So, it is very necessary to treat this disease to prevent its complications.[114] [115] [116]

Husain et al targeted the PPARγ receptor and designed a series of oxazole derivatives as potential antidiabetic agents. In this work, a series of distinctive oxazole compounds (42-43, [Fig. 11]) was structurally modeled using ChemDraw 3D and optimized for physicochemical properties. The favorable substituents were the Schiff base of benzamide and cyclopentadiene clubbed with o-hydroxy benzaldehyde at the second position of the oxazole core. Among the compounds, 43a and 43b have the topmost drug scores (0.91 and 0.86) than Rosiglitazone (0.80). Next, all compounds were docked using PyRx software into the PPARγ receptor (PDB ID: 1PRG), which revealed that 42a and 42b displayed better binding energies, i.e., −11.1 and −10.1 kcal/mol, respectively, than rosiglitazone (binding energy = − 9.1 kcal/mol). The binding interactions included hydrogen bonds, pi-cation, and pi–pi interactions, which contributed to their stability and specificity.[117]

Fig. 11 Structure of oxazole derivatives (42-44) for antidiabetic activity.

Mariappan et al established a series of oxazolone derivatives and investigated their oral hypoglycemic potential (44a–c, [Fig. 11]) using the streptozotocin-induced diabetes model in rats. Rosiglitazone was used as the reference drug, demonstrating 69% blood glucose-decreasing potential at a dose of 100 mg/kg orally. It was revealed that compound 44b showed the maximum potential amongst all compounds compared with the control drug, as shown in [Supplementary Table S19] (available in the online version).[48]

Conclusion and Future Outlook

The data presented in this review underscore the broad spectrum of therapeutic activities exhibited by oxazole and its derivatives, including antimicrobial, anticancer, antitubercular, antidiabetic, anti-inflammatory, analgesic, anticonvulsant, and antiviral properties. A thorough literature survey reveals that compounds containing an oxazole nucleus have gained significant attention from researchers and biochemists due to their promising biological activities. This has driven efforts to explore and develop novel strategies for synthesizing oxazole-based drugs. This review emphasizes that oxazole derivatives hold considerable potential to generate potent bioactive compounds, making them a valuable focus for the discovery of new therapeutic agents. Future directions should emphasize artificial intelligence tools to identify target sites for therapeutic heterocycles, followed by evaluation of available binding residues that may help to design new potent molecules. Further, hybridization of therapeutically beneficial heterocyclic scaffolds can become a synergistic therapeutic strategy against a wide range of disorders. Also, advancements in multitarget inhibitors, along with associated novel drug delivery systems, can afford medicinal advantages. In addition, adaptive SAR modeling on the basis of resistance data and their pharmacokinetic assessment is essential for clinical translation. In contrast, interdisciplinary efforts will be decisive to accelerate the development of next-generation heterocyclic therapeutics.

Conflict of Interest

None declared.

Supporting Information

The chemical structures of 1a–o, 2a–i, 5a–i, 6a–e, 15a–i, 21a–j ([Supplementary Figs. S1]–[S6]), available in the online version; 3a–j ([Supplementary Table S1], available in the online version), 7a–l ([Supplementary Table S3], available in the online version), 18a–i ([Supplementary Table S7], available in the online version), and the in vitro activity data of compounds mentioned in the text ([Supplementary Tables S1]–[S19], available in the online version) can be found in the “Supporting Information” section of this article's webpage.

^# These authors contributed equally to this work.

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Publication History

Received: 16 May 2025

Accepted: 22 October 2025

Article published online:
21 November 2025