Oxazolone: From Chemical Structure to Biological Function – A Review

Abstract

Oxazolone is a versatile heterocyclic compound with significant applications in organic synthesis, pharmaceuticals, and immunology. This review provides a comprehensive analysis of its chemical properties, synthesis strategies, and biological activities. Oxazolone derivatives have been widely explored for their roles as intermediates in peptide coupling, drug design, and materials science. Additionally, oxazolone is a well-established hapten used in immunological studies, particularly in models of allergic contact dermatitis and colitis. Recent advancements in the functionalization and application of oxazolone derivatives have expanded their utility in medicinal chemistry and materials research. This article highlights key developments in oxazolone chemistry, its role in disease models, and emerging trends in its biomedical applications. In recent years, the structural flexibility and synthetic accessibility of oxazolone have made it a key scaffold for designing multifunctional molecules. Its compatibility with various functional groups allows for diverse modifications, enhancing its relevance in developing targeted therapeutic agents. Furthermore, its reactivity has been exploited in generating libraries of bioactive molecules for high-throughput screening. The increasing interest in oxazolone-based systems reflects their potential to address complex challenges in drug development and biomolecular engineering. Continued exploration of these compounds is expected to open new directions in both academic and industrial research, underscoring their enduring scientific and practical value.

Keywords

Introduction

Compounds that contain atoms of at least two different elements (S, N, O) and exist in ring structure are called heterocyclic compounds¹. Azlactones also known as oxazolone are 5-membered heterocycles which contain 2 oxygen atoms with 1 nitrogen^2-5. The structural framework of azlactones was first identified and designated by Erlenmeyer¹. Azlactones exist in five different isomeric forms, which vary based on the location of the carbonyl group (C=O) and the position of the double bond (C=C) within the molecule, most commonly – studied being the Oxazol-5position of the carbonyl group & the double (4H)-ones and classified into unsaturated and saturated oxazolones⁶. In organic synthesis, Oxazolones are considered versatile building units because of the presence of various electrophilic and pro-nucleophilic reactive sites⁴. These are multifunctional compounds which take part in several reactions like cycloadditions, replacement reactions, dimerization reaction, forming a variety of intermediates and chemicals like peptides⁸, amino acids⁷, 5 and 6 membered polyfunctional compounds along with some heterocyclic precursors⁹ and photosensitive devices for proteins¹⁰ and coupling as well. Oxazolones exhibit a broad spectrum of pharmaceutical properties, including anti-diabetic, anti-cancer^20,21, Anti-bacterial activity, Urease inhibition activity, Fungicidal activity, Tyrosinase inhibitory activity¹⁸, Cardioprotective activity^4,22, Contact allergen, Immunomodulatory activity, Anti-inflammatory activity, Analgesic activity, Anti-angiogenic activity, Sedative, Anti-depressant, Anti-HIV, Anti-proliferative, Anti-tubercular, Anti-convulsant, Anti-microbial^14-16. They possess activities such as photochemical^4,11,12 and photophysical^23-26 and often act as pH sensors¹³. In recent years, the azlactone core has been widely used in various organic reactions, gaining considerable attention from the organic synthesis community²⁸. Additionally, over the last ten years, material sciences have seen significant advancement and recently numerous studies have begun exploring the reactivity of the Azlactone ring^29-31. For instance, this heterocycle has been employed to produce various types of polymers and nano-particles^32-36. In recent decades, numerous research papers have focused on the Erlenmeyer synthesis, employing various methods and catalysts. These catalysts include aluminum oxide (Al?O?)³⁷, organic bases, supported heteropoly acids³⁸, ytterbium triflate (Yb(OTf)?)⁴³, calcium acetate (Ca(OAc)?)⁴², bismuth acetate (Bi(OAc)?)³⁹, and phosphotungstic acid (H?PW??O??)^41,42.

 

 

CHEMISTRY

Oxazolone is a derivative of the oxazole nucleus. Erlenmeyer azlactone synthesis is the general method of synthesis of oxazolone (Other methods such as The Bergmann synthesis, DCC Method (Di cyclo hexyl carbodiimide, Miscellaneous methods, etc.). The functional groups substituted at the 4 and 2 positions play a key role in the activity of oxazolone. Research indicates that a total of seventeen azlactones or oxazolones were primarily synthesized using commercially available glycine with benzoyl chloride or acetic anhydride, in the presence of anhydrous sodium acetate, under Erlenmeyer conditions along with the required aldehyde, yielding very high product amounts.

UNSATURATED

SATURATED

The activity of oxazolone depends on the functional groups substituted at the C-4 and C-2 positions. The immunosuppressive effect is significantly influenced by the substitution of a p-nitro exocyclic phenyl group at C-4⁴⁴. For tyrosinase inhibition, a cinnamoyl group at C-4 and particular functional groups at both C-4 and C-2 are important. The presence of an aliphatic double bond at C-4 and a phenyl ring at C-2 plays a key role in its medicinal effects⁴⁵. Enhancing the electron-donating properties of the phenyl ring substituent at C-2 slows down the ring-opening reaction of oxazolone⁴⁶. Exocyclic double bonds in oxazolone can function as dienophiles, and N-substituted oxazolones are involved in intermolecular Diels-Alder reactions⁴⁷. Activation of the carbonyl group in unsaturated oxazolone by Lewis’s acids enhances the electrophilicity of the β-carbon⁴⁸. Azlactones derived from chiral α-amino acids are optically active but easily racemize. In 5(4H)-oxazolones, nucleophiles often attack at C-2, this results in the breaking of the carbonyl-oxygen bond, leading to the formation of α-amino acids or their derivatives. These compounds, stabilized by resonance in their anionic form, can react with electrophiles at C-4, or less frequently, at C-2. Moreover, they can function as 1,3-dipoles in cycloaddition reactions.

SYNTHESIS OF OXAZOLONE

Synthesis of 2-phenyl-5(4H)-oxazolones

Synthesis of lambdoid oxazol-5(4H)-one

Synthesis of 4-(4-(3-(butyl amino)-2-hydroxypropylamino) benzylidene)-2-phenyloxazol-5(4H)-one

Synthesis of 4-(4-(3-(methylamino)-2-hydroxypropylamino) benzylidene)-2-phenyloxazol 5(4H)-one

Synthesis of 4-(4-(3-(diethylamino)-2-hydroxypropylamino) benzylidene)-2-phenyloxazol 5(4H)-one

Synthesis of 4-(4-(3-(dimethylamino)-2-hydroxypropylamino) benzylidene)-2-phenyloxazol 5(4H)-one

Synthesis of 4-4(4-(3-(ethylamino)-2-hydroxypropylamino) benzylidine)-2 phenyloxazol 5(4H)-one

Synthesis of 4-(substituted benzylidine)-2-(pyrazin-2-yl) Oxazol-5(4H)-one

Synthesis is 4-methyl-2-phenyl-oxazolone

Synthesis of 2-benzyl-oxazolone

Synthesis of 4-chloro-2-phenyl-oxazolone

Synthesis of 5-Ethoxy-2-phenyl-oxazolone

Synthesis of 4-hydroxy-2-phenyl-oxazolone

Synthesis of 2-(4-methoxyphenyl)-oxazolone

Synthesis of 4-Nitro-2-phenyl-oxazolone

Synthesis of 5-Bromo-2-phenyl-oxazolone

Synthesis of 2-(2,4-Dichlorophenyl)-oxazolone

Synthesis of 2-Phenyl-4-thioxo-oxazolone

Synthesis of 4-Thiomethyl-2-phenyl-oxazolone

Synthesis of 2-Benzyl-4-thioxo-oxazolone

Synthesis of 4-Thiophenyl-2-phenyl-oxazolone

Synthesis of Indole-oxazolone Hybrid

BIOLOGICAL ACTIVITY

ANTIMICROBIAL ACTIVITY

Oxazolone derivatives exhibit broad-spectrum antimicrobial properties against bacteria and fungi due to their ability to interfere with cellular processes essential for pathogen survival.

1.Antibacterial Activity

Mechanism of Action involves, Oxazolone derivatives act against bacterial pathogens through several pathways. One key mechanism involves blocking the activity of DNA gyrase and topoisomerase IV, two crucial enzymes required for bacterial DNA replication, leading to the prevention of bacterial proliferation. This mechanism is particularly effective against Escherichia coli and Staphylococcus aureus. Another key mechanism involves the inhibition of peptidoglycan biosynthesis, where the compounds interfere with enzymes responsible for crosslinking the bacterial cell wall, making bacteria more susceptible to lysis. Additionally, certain derivatives disrupt bacterial membrane integrity, causing ion leakage and loss of essential cellular metabolites, leading to bacterial death. Structure-Activity Relationship (SAR) is the presence of electron-withdrawing groups such as nitro (-NO?) or halogens (-Cl, -Br) significantly enhances the lipophilicity of the molecule, facilitating penetration through bacterial cell membranes. Hydrophobic substitutions at the C-2 or C-4 position improve interactions with bacterial enzymes, thereby increasing potency. Moreover, the incorporation of thioxo (-S) modifications has been found to improve β-lactamase resistance, making these derivatives effective against drug-resistant bacterial strains like MRSA and Klebsiella pneumoniae⁷¹.

2.Antifungal Activity

Mechanism of the antifungal properties of oxazolone derivatives arise from their ability to target ergosterol biosynthesis, a key component of fungal cell membranes. By inhibiting fungal enzymes like lanosterol 14α-demethylase, these derivatives disrupt membrane integrity, leading to increased permeability and cell lysis. Additionally, oxazolone derivatives can interfere with mitochondrial electron transport, this results in the buildup of reactive oxygen species (ROS), causing oxidative damage and triggering apoptosis in fungal cells. Some derivatives also inhibit chitin synthase, preventing the formation of fungal cell walls and thus hindering growth. In the Structure-Activity Relationship (SAR), The introduction of hydroxyl (-OH) and halogen (-Cl, -Br) groups enhances the ability of the molecule to penetrate fungal cell walls. Methoxy (-OCH?) and benzyl groups at the C-2 position improve antifungal selectivity by increasing binding affinity to fungal enzymes. The incorporation of heterocyclic rings further stabilizes the molecule and enhances bioavailability, making it more effective against fungal infections such as Candida albicans and Aspergillus Niger⁷².

ANTIPARASITIC ACTIVITY

Mechanism involves Oxazolone derivatives exhibit antiparasitic effects by inhibiting thiol-dependent proteases, which are crucial for the survival of parasites like Leishmania donovani and Trypanosoma cruzi. These compounds also disrupt mitochondrial oxidative phosphorylation, leading to ATP depletion and energy crisis in the parasite. Another mechanism involves DNA intercalation, where oxazolone derivatives insert themselves into the parasite’s DNA, causing fragmentation and ultimately cell death. Structure-Activity Relationship (SAR)includes the addition of thioxo (-S) groups enhances the inhibition of parasitic proteases, while electron-withdrawing nitro (-NO?) and halogen (-Cl) groups improve oxidative stress induction in parasites. A phenyl or benzyl group at the C-2 position enhances the ability to bind to DNA, enhancing efficacy against protozoan infections.

ANTICANCER ACTIVITY

Oxazolone derivatives exert anticancer effects through multiple mechanisms. One key pathway is caspase-3 and caspase-9 activation, leading to apoptotic cell death. Another mechanism involves microtubule polymerization inhibition, which prevents cancer cells from progressing through mitosis, leading to cell cycle arrest at the G2/M phase. Some derivatives also suppress PI3K/Akt/mTOR signaling, a crucial pathway for tumor survival and proliferation. Additionally, certain oxazolone derivatives act as topoisomerase II inhibitors, preventing DNA repair in rapidly dividing cancer cells, ultimately leading to apoptosis. Indole-oxazolone hybrids significantly improve DNA binding affinity, increasing cytotoxicity against cancer cells. Nitro (-NO?) and bromo (-Br) substitutions enhance oxidative stress within tumor cells, leading to increased ROS production and apoptosis. The presence of hydroxyl (-OH) and methoxy (-OCH?) groups at strategic positions improves selective cytotoxicity, making these derivatives promising anticancer agents⁷³.

ANTI-INFLAMMATORY ACTIVITY

Oxazolone derivatives exert anti-inflammatory effects by targeting the cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) pathways, reducing the synthesis of pro-inflammatory mediators such as prostaglandins and leukotrienes. Another mechanism involves NF-κB inhibition, which prevents the transcription of inflammatory cytokines like TNF-α and IL-6. Additionally, some derivatives reduce nitric oxide (NO) production by blocking the activity of inducible nitric oxide synthase (iNOS), leading to reduced inflammation. The existence of hydroxyl (-OH) and carboxyl (-COOH) functional groups enhances receptor binding and anti-inflammatory potency. Methoxy (-OCH?) substitutions improve selectivity toward COX-2 over COX-1, minimizing gastrointestinal side effects⁷⁴.

ANTIOXIDANT ACTIVITY

Oxazolone derivatives inhibit oxidative damage by trapping reactive oxygen species (ROS) and reactive nitrogen species (RNS). They also enhance glutathione (GSH) levels, protecting against oxidative DNA damage. Additionally, these derivatives inhibit lipid peroxidation, preserving cell membrane integrity. Phenolic (-OH) and amino (-NH?) groups improve radical scavenging efficiency. Thioxo (-S) modifications enhance electron donation capacity, making these derivatives more potent antioxidants⁷⁵.

5-Ethoxy-2-phenyl-oxazolone

ANTIVIRAL ACTIVITY

Oxazolone derivatives inhibit viral polymerases, preventing viral RNA/DNA replication. Some derivatives block viral entry and fusion by binding to spike proteins, while others suppress viral proteases, preventing virion maturation. Halogen (-Cl, -Br) and nitro (-NO?) substitutions improve viral enzyme inhibition. Heterocyclic additions enhance binding affinity to viral proteins, increasing antiviral efficacy⁷⁶.

NEUROMODULATORY AND ANALGESIC ACTIVITY

These derivatives modulate NMDA and GABA receptors, enhancing neurotransmission. They also inhibit neuroinflammation by reducing microglial activation and suppressing cytokine release. Some derivatives activate opioid receptors, reducing pain perception. Methoxy (-OCH?) and hydroxyl (-OH) groups improve receptor interactions. Thioxo (-S) modifications enhance neuroprotective effects, making them suitable for neurodegenerative disorders⁷⁷.

2-(2-chlorophenyl)-4-(methylthio)-5-oxo-2,3-dihydro-1H-oxazolone

ANTI-TUBERCULAR ACTIVITY

Oxazolone derivatives have been investigated for their ability to combat Mycobacterium tuberculosis (M. tuberculosis), especially in drug-resistant strains. Inhibition of enoyl-acyl carrier protein reductase (InhA); Disrupts mycolic acid biosynthesis, impairing bacterial cell wall integrity. Targeting DNA gyrase; Inhibits bacterial DNA replication and transcription. Blocking ATP synthase; Leads to energy depletion and bacterial death. Halogen (-Cl, -Br) substitution at C-2 increases lipophilicity, enhancing bacterial penetration. Electron-donating groups (-OH, -OCH?) improve binding to enzyme active sites⁷².

4-Fluoro-2-phenyl-oxazolone

ANTIDIABETIC ACTIVITY

Oxazolone derivatives exhibit potential in diabetes management by modulating glucose metabolism and insulin signaling. Activation of peroxisome proliferator-activated receptor gamma (PPAR-γ); Improves insulin sensitivity. Inhibition of α-glucosidase and dipeptidyl peptidase-4 (DPP-4); Lowers postprandial glucose levels. Enhancement of GLUT4 translocation: Increases glucose uptake in muscle cells. Carboxyl (-COOH) and hydroxyl (-OH) groups improve receptor binding affinity. Benzyl substitution at C-2 increases selectivity towards PPAR-γ⁷⁶.

2-Phenyl-4-thioxo-oxazolone

CARDIOPROTECTIVE ACTIVITY

Oxazolone derivatives show protective effects against cardiovascular diseases (CVDs) such as hypertension and atherosclerosis. Inhibition of angiotensin-converting enzyme (ACE): Reduces blood pressure. Enhancement of nitric oxide (NO) production: Improves vascular dilation. Suppression of LDL oxidation: Prevents atherosclerotic plaque formation. Hydroxyl (-OH) and methoxy (-OCH?) groups enhance antioxidant capacity. Aromatic substitutions at C-2 improve lipid metabolism regulation⁷².

4-Hydroxy-2-phenyl-oxazolone

ANTI ALZHEIMER’S AND NEUROPROTECTIVE ACTIVITY

Oxazolone derivatives demonstrate potential in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Blocking the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); Enhances cholinergic neurotransmission. Reduction of β-amyloid aggregation; Prevents plaque formation. Mitigation of oxidative stress; Reduces neuroinflammation and neuronal damage. Electron-donating groups (-OH, -NH?, -OCH?) increase AChE inhibition. Fluorinated derivatives improve blood-brain barrier (BBB) permeability⁷⁸.

ANTI-ULCER ACTIVITY

Oxazolone derivatives exhibit gastroprotective effects against peptic ulcer disease (PUD). Inhibition of H?/K?-ATPase (proton pump); Reduces gastric acid secretion. Enhancement of mucus secretion; Protects the gastric mucosa. Suppression of Helicobacter pylori; Reduces ulcer recurrence. Electron-withdrawing groups (-NO?, -Cl) enhance proton pump inhibition. Hydroxyl (-OH) and carboxyl (-COOH) modifications improve gastric mucosal protection.

4-Methoxy-2-phenyl-oxazolone

ANTI-OBESITY ACTIVITY

Oxazolone derivatives play a role in lipid metabolism regulation, making them potential candidates for obesity treatment. Inhibition of pancreatic lipase; Reduces fat absorption. Activation of AMP-activated protein kinase (AMPK); Stimulates the oxidation of fats. Adjustment of leptin and adiponectin levels; Regulates appetite and energy expenditure. Thioxo (-S) derivatives improve AMPK activation. Benzyl modifications increase selectivity for metabolic enzymes.

4-Bromo-2-phenyl-oxazolone

IMMUNOMODULATORY ACTIVITY

Oxazolone derivatives can modulate immune responses, making them useful in autoimmune diseases and organ transplantation. Inhibition of T-cell proliferation; Reduces autoimmune attacks. Suppression of cytokine release (IL-2, IFN-γ); Modulates immune responses. Enhancement of regulatory T-cell activity; Prevents excessive inflammation. Aromatic modifications improve cytokine suppression. Halogen substitutions enhance immune selectivity⁷⁹.

4-Chloro-2-phenyl-oxazolone

ANTI-HIV ACTIVITY

Inhibition of HIV reverse transcriptase (RT); Prevents viral replication. Suppression of viral protease; Blocks protein maturation. Interference with viral fusion; Prevents cell entry. Indole-oxazolone hybrids improve HIV RT inhibition. Hydroxyl and halogen modifications enhance antiviral activity⁸⁰.

4-Methyl-2-phenyl-oxazolone

CONCLUSION

Oxazolone derivatives have demonstrated significant biological activities, making them promising candidates for pharmaceutical development. Structural modifications at key positions (C-2, C-4, and C-5) have shown a direct impact on antimicrobial, anticancer, anti-inflammatory, antioxidant, and anticonvulsant activities. The addition of electron-withdrawing groups (e.g., –Cl, –Br, –NO?) and electron-donating groups (e.g., –OH, –OCH?, –SCH?), as well as heterocyclic and fused ring systems, has led to improved pharmacokinetic and pharmacodynamic properties. Several studies have highlighted the potential of oxazolone-based compounds as inhibitors of bacterial enzymes, apoptosis-inducing agents in cancer cells, and radical scavengers in oxidative stress-related conditions. However, further research is required to optimize their bioavailability, reduce toxicity, and enhance selectivity toward specific targets. The development of oxazolone hybrids with other pharmacophores, such as indole and thiophene, represents a promising strategy for designing more potent and selective therapeutic agents. Future research should focus on (i) in-depth mechanistic studies to elucidate the exact molecular targets of oxazolone derivatives, (ii) computational approaches to guide rational drug design, and (iii) preclinical and clinical evaluations to translate these compounds into viable therapeutic agents. Given their diverse bioactivity profile and structural versatility, Oxazolone derivatives show significant promise for creating new medications to tackle global health issues.

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