Oxazole and isoxazole-containing pharmaceuticals: targets, pharmacological activities, and their SAR studies

Abstract

Oxazole, a five-membered aromatic heterocycle featuring a nitrogen and an oxygen atom separated by a carbon atom, and its isomer isoxazole, with directly attached oxygen and nitrogen atoms, have been pivotal in medicinal chemistry. Over the past few decades, the U.S. Food and Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis and Oxaprozin. Due to their unique physicochemical properties, these drugs often exhibit superior pharmacokinetic profiles and pharmacological effects compared to those with similar heterocycles. This review provides a comprehensive overview of all FDA-approved drugs containing oxazole and isoxazole nuclei, focusing on their pharmacological activities and structure–activity relationships.

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1. Introduction

Oxazole and isoxazole are prominent structural motifs in pharmaceutical chemistry and organic synthesis due to their versatile chemical properties.¹ The distinct structural characteristics of these heterocycles enable their derivatives to engage in a variety of non-covalent interactions, including hydrogen bonding, π–π stacking, hydrophobic effects, and van der Waals forces. As a result, oxazole- and isoxazole-based compounds have found widespread applications in medicinal chemistry, agriculture, chemical synthesis, supramolecular chemistry, and materials science.^2–20 These heterocycles are also integral to the structure of numerous pharmaceuticals, exhibiting a broad spectrum of biological activities, such as antiviral, antifungal, antibacterial, antiproliferative, anticancer, analgesic, and enzyme inhibitory effects.^7,21–43 Currently, approximately 20 synthetic drugs containing oxazole or isoxazole moieties are commercially available, with isoxazole derivatives being more prevalent (Fig. 1).

Fig. 1 The number of oxazole and isoxazole-containing drugs approved by FDA.

Trend analysis over recent years indicates a growing interest in drugs containing oxazole and isoxazole rings, underscoring their significance in addressing various clinical conditions. The increasing number of FDA approvals for such drugs reflects a shift toward the development of more targeted and effective therapies. For instance, the approval of tafamidis represents a breakthrough in the management of a rare and previously untreatable disease, highlighting the progress in understanding and addressing the molecular mechanisms of amyloidosis.

These marketed drugs target a wide range of clinical disorders, including neurological disorders, immune system diseases, cardiovascular diseases, infection, gastrointestinal diseases and others.

Oxazole exhibits chemical properties intermediate between those of furan and pyridine. Like pyridine, oxazole acts as a weak base and can form salts with acidic compounds. Under specific conditions, it undergoes acid hydrolysis, leading to ring-opening. Notably, furan undergoes ring-opening more readily under acidic conditions compared to pyridine, which is highly resistant to such processes.⁴⁴

The structures and bond lengths of oxazole and isoxazole are shown in the diagram below^45–47 (Fig. 2).

Fig. 2 The structure of oxazole and isoxazole.

The aromaticity of oxazole is generally considered to be weaker compared to other well-studied aromatic heterocycles, such as furan^48–51 (Fig. 3). Conflicting reports exist regarding the aromaticity of isoxazole: some studies suggest that it exhibits slightly greater aromaticity than both oxazole and furan, while others propose that its aromaticity is marginally lower.^52,53

Fig. 3 The aromaticity rank of oxazole, isoxazole and furan.

This review provides a comprehensive overview of currently marketed drugs that contain either oxazole or isoxazole scaffolds. These drugs are discussed in terms of their biological targets, pharmacologic activities and structure–activity relationships (SAR). The review aims to serve as a valuable reference for medicinal and organic chemists engaged in drug design and development.

2. General drug design strategies for introducing the oxazole skeleton

Oxazole compounds, which serve as bioisostere of thiazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles, have garnered significant attention.^54–59 Recently, researchers have increasingly focused on oxazole derivatives as potential medicinal agents, aiming to discover novel chemical scaffolds with broad-spectrum activity, high bioactivity, low toxicity, and excellent pharmacokinetic properties.^2,3,60

Bioisosterism plays a significant role in the design of novel pharmaceuticals. As a valuable tool in medicinal chemistry, bioisosterism enables the rational modification of lead compounds to enhance their pharmacological properties. This approach involves the strategic substitution of one functional group or moiety with another that is structurally distinct but pharmacologically analogous. This approach can lead to improved potency, selectivity, and drug-like properties, such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles.

For instance, the oxazole ring, owing to its intermediate chemical properties between furan and pyridine, can function as a bioisostere in drug design. This characteristic has been utilized in the development of pharmaceuticals, where the oxazole moiety facilitates interactions with orexin receptors, contributing to sedative-hypnotic effects.

For example, in the discovery of suvorexant (Fig. 4), Coleman et al.⁶¹ recognized the compelling evidence that orexin signaling plays a central role in maintaining wakefulness. As part of a broader effort in developing therapeutic agents for treating wake/sleep dysregulation, they initiated a program aimed at discovering potent orexin antagonists with clinical utility. They conducted a high-throughput screening (HTS) campaign of sample collection to identify novel chemotypes that could function as antagonists of both orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R). The screening campaign was productive, identifying multiple, diverse chemical series with promising attributes dual orexin antagonists (DORAs).

Fig. 4 Discovery of suvorexant.

One hit, diazepane amide 1, exhibited good affinity for both OX1R and OX2R and blocked orexin-A signaling in cell-based assays. However, despite its potency, compound 1 displayed poor drug-like properties, including low solubility, high clog P, and rapid hepatic metabolism. Subsequent efforts focused on optimizing lipophilicity and metabolic stability, leading to the discovery of compound 2. This derivative maintained strong receptor potency and brain penetration while exhibiting reduced lipophilicity.⁶²In vivo studies confirmed that compound 2 reduced spontaneous locomotor activity and promoted sleep in rats.

Although compound 2 exhibited several favorable attributes, it displayed a poor pharmacokinetic profile, characterized by low oral bioavailability (F < 5%) and high clearance in rats and dogs. Significant reductions in plasma clearance were achieved through further modifications to the diazepane structure and heteroaryl substitution, resulting in analogs such as compound 3.⁶³ Detailed metabolic studies on orexin antagonist 3 revealed a strong tendency for this molecule to generate electrophilic, reactive metabolites upon metabolic activation. Specifically, they hypothesized that oxidative metabolism at methylene sites on the diazepane ring or on the heteroaryl moieties could generate reactive species that would be trapped by glutathione (GSH).

3. Oxazole-containing drugs

Oxaprozin (compound 5), approved by the FDA in 1992, is a non-steroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis and rheumatoid arthritis. In the inflammatory process, cyclooxygenase plays a key role in the biosynthesis of prostanoids⁶⁴ (Fig. 5a). The pharmacological effects of oxaprozin stem from its inhibition of cyclooxygenase-I (COX-1) in human platelets, leading to reduced prostaglandin synthesis.⁶⁵ Additionally, oxaprozin, which reverses the survival of monocytes induced by immune complex without affecting apoptosis of resting cells also exerts anti-inflammatory effects via the inhibition of Akt/IKK/NF-kB pathway. Oxaprozin may also act on the hypothalamus to produce antipyretic effects, resulting in increased peripheral blood flow, vasodilation, and heat dissipation.⁶⁶ The study by Li et al.⁶⁷ revealed that oxaprozin can bind with the macrodomain 3 of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).

Fig. 5 (a) The structure of oxaprozin; (b) the key target interactions.

It can inhibit the binding of oligonucleotides and the formation of guanine-quadruplexes, which are essential for the activity of the virus replication-transcription complex. In the crystal structure, the carboxylic group forms a salt bridge with K592, and the oxazole ring forms a hydrogen bond with water, which in turn is bound to E595 (Fig. 5b).

Dalfopristin (compound 6), approved by the FDA in 1999, is used to treat severe vancomycin-resistant Enterococcus faecium (VREF) infections and skin infections caused by methicillin-resistant Staphylococcus aureus or Streptococcus pyogenes⁶⁸ (Fig. 6a). As a member of the streptogramin group, dalfopristin and its counterpart, quinupristin, act synergistically to inhibit protein synthesis at the ribosomal level. Dalfopristin inhibits the early stages of protein synthesis, while quinupristin targets the late stages. Harms et al.⁶⁹ elucidated the antimicrobial mechanism of dalfopristin by studying its binding to the ribosomal 50S subunit. Quinupristin binds within the ribosomal exit tunnel, blocking the path of newly formed polypeptide chains, whereas dalfopristin binds directly to the peptidyl transferase center (PTC), interfering with tRNA occupation at both the A- and P-sites. Dalfopristin is located in a tight pocket within the PTC, bound together by a network of hydrophobic interactions throughout the macrocycle. The macrocycle forms hydrogen bonds with G2505 and G2061, and the hydroxyl group of dalfopristin forms an additional hydrogen bond with G2505 (Fig. 6b).

Fig. 6 (a) The structure of dalfopristin; (b) the key target interactions.

The current clinical treatments for insomnia include benzodiazepine receptor agonists (BZRAs), melatonin receptor agonists, appetite hormone receptor antagonists, and antidepressants with hypnotic effects. Among them, suvorexant (compound 7) is the first orexin receptor antagonist to be marketed worldwide (Fig. 7a). In 1998, Lecea et al.⁷⁰ and Sakurai et al.⁷¹ independently discovered the orexin system, which significantly modulates wakefulness and appetite. The system consists of two G protein-coupled receptors—the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R)—and two neurotransmitter peptide agonists: orexin-A (OX-A) and orexin-B (OX-B). Both OX-A and OX-B are produced in the hypothalamus and activate OX2R receptors, with a clear link established between OX2R dysfunction and narcolepsy. In 2014, the first antagonist OX2R, suvorexant, obtained regulatory approval as an insomnia medication in the US. The following year, the crystal structure of suvorexant in complex with OX2R was published.⁷² It revealed that suvorexant binds in a “horseshoe shape”, consistent with earlier NMR studies indicating that suvorexant could adopt such a conformation in solution.⁷³ The OX2R receptor was confirmed to be a typical GPCR with seven transmembrane helices. Crystallographic data demonstrated that suvorexant primarily interacts with the receptor through hydrophobic interactions, with only two polar interactions: a direct hydrogen bond to Asn3246.55 and a water-mediated hydrogen bond with His3507.39 (ref. 72) (Fig. 7b).

Fig. 7 (a) The structure of suvorexant; (b) the key target interactions.

Tafamidis (compound 8) was approved by the FDA in 2019 as a selective inhibitor of transthyretin amyloidosis (Fig. 8a). Amyloidosis is a group of disorders characterized by the deposition of amyloid fibrils in various organs, leading to progressive organ dysfunction.⁷⁴ Amyloid, a fibrous substance formed by misfolded proteins, consists of twisted beta-folded chains of multiple peptide aggregates. Transthyretin amyloidosis (ATTR) is a rare and fatal disease caused by the aggregation of transthyretin (TTR), primarily affecting elderly patients. Transthyrotropin is a tetrameric protein consisting of four identical subunits that is present in plasma and can act as a transporter for thyroxine and the vitamin A-retinol-binding protein complex or as a minor transporter for thyroxine.⁷⁵ The tetramer can undergo dissociation and misfolding of the monomer to form an amyloid, with dissociation of the tetramer being the decisive step. Tafamidis selectively binds to the two unoccupied thyroxine (T4) binding sites of the tetramer, stabilizing TTR. The two chlorine atoms of the benzene ring occupy the two halogen-binding pockets (HBPs) located in the inner binding cavity. The benzoxazole ring is in the hydrophobic environment of HBP2 and 2′, HBP1 and -1′. The carboxylic acid moiety forms hydrogen bonds with Lys15/15′ and Glu54/54′ residues at the edge of the T4 binding site⁷⁶ (Fig. 8b). These interactions act as bridges connecting adjacent dimers, making the TTR tetramer more stable and thus increasing its dissociation energy barrier.

Fig. 8 (a) The structure of tafamidis; (b) the key target interactions.

4. Isoxazole-containing drugs

4.1. Antibiotic drugs

Sulfamethoxazole (compound 9) is a widely used prophylactic agent, typically administered in combination with trimethoprim, with sulfamethoxazole as the active ingredient⁷⁷ (Fig. 9a). It is used to treat various bacterial infections, including urinary tract infections, respiratory system infections, and gastrointestinal tract infections. On the other aspect, folic acid plays an important role in the synthesis of proteins and nucleic acids and in the metabolism of various amino acids.⁷⁸ Besides, dihydropteroate synthase (DHPS) is a key enzyme in the folate pathway in bacteria and other organisms. It catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPP) with p-aminobenzoic acid (PABA) to form 7,8-dihydropteroate, the active intermediate of folate (Fig. 9b). Sulfamethoxazole exerts its therapeutic effect by inhibiting the function of dihydropteroate synthase. Structurally similar to PABA, Sulfamethoxazole competes with PABA in the PABA-binding pocket, thereby inhibiting the synthesis of the active intermediate of folic acid^79,80 (Fig. 9c).

Fig. 9 (a) The structure of sulfamethoxazole; (b) condensation mechanism; (c) the key target interactions.

It is also effective against other bacterial infections, including meningococcal meningitis, acute otitis media, trachoma, inclusion conjunctivitis, nocardiosis, chancroid, toxoplasmosis, and malaria. It can competitively inhibit dihydropteroate synthase by acting on its substrate: para-aminobenzoic acid (PABA). Furthermore, it can also prevent the condensation of pteridine with PABA, thus inhibiting the synthesis of dihydrofolic acid in bacteria.⁸¹

Sulfisozole (compound 10) is commonly used as a prophylactic antimicrobial agent to reduce the possibility of urinary tract infections in renal transplant recipients during postoperative recovery⁸² (Fig. 10a).

Fig. 10 (a) The structure of sulfisozole; (b) the IC₅₀ values.

The half-maximal inhibitory concentrations (IC₅₀) of oxazole-containing compounds are listed in the Table above (Fig. 10b). Compared to other groups, such as pyrimidinyl and pyridinyl, sulfamethoxazole is one of the most potent inhibitors, with an IC₅₀ of 23 nM. It (40 nM) has an IC₅₀ similar to that of sulfamethoxazole. In addition, the R² substituent appears to have no effect. The IC₅₀ values for sulfamethoxazole, Ro 72844 and Ro 52928 were almost identical despite changing the R² substituent.⁸³

Dicloxacillin (compound 11), oxacillin (compound 12), flucloxacillin (compound 13), cloxacillin (compound 14) are penicillin beta-lactam antibiotic used in the treatment of bacterial infections. These drugs are particularly effective against Gram-positive organisms in skin and soft tissue infections, except those caused by methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 11a). Their antibacterial activity stems from the inhibition of cell wall synthesis through binding to penicillin-binding proteins (PBPs). PBP contains two enzymatic activities: glycosyltransferase and transpeptidase. In PBP transpeptidases, the serine in the active site attacks the carbonyl group of D-Ala–D-Ala to form a transpeptidase–D-Ala adduct and release cross-linked peptidoglycan. Due to their structural similarity, PBPs mistake β-lactam for D-Ala–D-Ala and bind to it (Fig. 11b). The resulting acyl–enzyme complex is highly stable and irreversibly inactivates PBPs.⁸⁴ Drugs and proteins can covalently bind, resulting in the formation of drug–protein adducts, which is thought to be a necessary step in triggering immune response and can have adverse effects on the human body. Flucloxacillin covalently binds to lysine residues on human serum albumin by opening the β-lactam ring. Antibodies specific to drug molecular structure can be used for the detection of drug–protein adducts (Fig. 11c).

Fig. 11 (a) The structure of dicloxacillin, oxacillin, flucloxacillin, cloxacillin; (b) β-lactam binding cleft; (c) drug–protein adducts.

Benzylpenicillin antibodies can recognize the thiazolidinyl ring but do not cross-react with flucloxacillin, oxacillin, cloxacillin, or dicloxacillin. This is because the thiazolidinyl ring in these molecules is sterically hindered by the isoxazole moiety, preventing antibody recognition.⁸⁵ Consequently, since piperacillin–albumin adducts can stimulate T cells, the presence of flucloxacillin competes with piperacillin for lysine residues on albumin. This competition saturates the albumin drug-binding site, blocking piperacillin binding and resulting in an adduct that fails to stimulate T cells. As a result, the specific T cell response induced by piperacillin is inhibited.⁸⁶

4.2. Antipsychotic drugs

Risperidone (compound 15), approved by the FDA in 2006, is a second-generation antipsychotic (SGA) medication used to treat schizophrenia and various mood disorders associated with excessive dopaminergic D2 and serotonergic 5-HT2A activity (Fig. 12a). Dopamine regulates its pathway by activating D1-like (D1R and D5R) and D2-like (D2R, D3R and D4R) dopamine receptors. Among these receptors, the D3R subtype has been identified as a potential therapeutic target for the treatment of neurological disorders such as schizophrenia, mood disorders and neurocognitive disorders. Structural analyses reveal that risperidone forms hydrogen bonds with serine residues in two distinct orientations. In orientation 1, risperidone is attracted to serine 193, whereas in orientation 2, it binds to serine 366. In addition, in orientation 1, Thr369 forms a hydrogen bond with the N28 atom. In orientation 1, a π–cation interaction between Phe106 and the N16 atom in risperidone occurs. In orientation 2, the side chain of Val86 forms a π–σ interaction with the oxazole ring of risperidone.⁸⁷ Given the high sequence homology between 5-HT2A and 5-HT2B receptors, risperidone's binding mode to the 5-HT2B receptor has been elucidated. The carbonyl group forms hydrogen bonds with Y370 and S131. The piperidine nitrogen atom forms a hydrogen bond with D155. S159 forms a split hydrogen bond with the nitrogen and oxygen atoms on the benzisoxazole ring. The fluorinated benzene ring is in a hydrophobic pocket consisting of V156, I206 and G238 (ref. 88) (Fig. 12b).

Fig. 12 (a) The structure of risperidone; (b) the key target interactions.

Paliperidone (compound 16), approved by the FDA in 2006 for the treatment of schizoaffective disorder, is the primary active metabolite of risperidone and shares a similar mechanism of action⁸⁹ (Fig. 13a). It is the primary active metabolite of risperidone and can bind with D2-like (D2R, D3R and D4R) dopamine receptors. The benzene ring forms a π–π interaction with PHE390 and the isoxazole ring forms an aliphatic–aliphatic interaction with VAL115 (ref. 90) (Fig. 13b).

Fig. 13 (a) The structure of paliperidone; (b) the key target interactions.

Iloperidone (compound 17), an antipsychotic agent approved by the FDA in 2009, is used for the treatment of schizophrenia (Fig. 14a).

Fig. 14 (a) The structure of iloperidone; (b) the key target interactions.

It has a remarkable tolerability profile because it has a very low possibility of causing antipsychotic-induced motor paralysis or antipsychotic-induced extrapyramidal symptoms (EPS).⁹¹ Its main mechanism of action is the combined antagonism of D2/5HT2A receptors. Iloperidone works by binding with the D2 receptor. The oxygen atoms of the isoxazole ring and carbonyl group form hydrogen bonds with SER197 and SER409, respectively. In addition, it can also bind with D3 and D4 receptors through van der Waals interaction with VAL86 and hydrogen bonding with HIS414. Iloperidone also improves cognitive performance, which is derived from its high affinity for alpha adrenergic receptors⁹⁰ (Fig. 14b).

4.3. Others

Isocarboxazid (compound 18), a non-selective monoamine oxidase (MAO) inhibitor, was approved by the FDA in 1959 for the treatment of persistent and debilitating depressive symptoms (Fig. 15). Inactivation of monoamine neurotransmitters requires catalytic oxidative deamination by MAO, which is a prevalent target for many neurodegenerative diseases and depression.⁹² MAO has two isoforms, MAO-A and MAO-B. The key catalytic amino acid residues in the MAO-A structure are Lys305, Trp397, Tyr407, and Tyr444; those in MAO-B are Lys296, Trp388, Tyr398, and Tyr435.⁹³

Fig. 15 The structure of isocarboxazid.

Danazol (compound 19), a derivative of testosterone, was approved by the FDA in 1996 and has been used for the treatment of endometriosis, precocious puberty, and various breast disorders⁹⁴ (Fig. 16). It may also correct thrombocytopenia in some cases. Danazol is a weak antigonadotropin and androgen; it is also a potent inhibitor of several steroidogenic enzymes.⁹⁵ It can interact with both androgen and estrogen receptors. Danazol inhibits the pituitary–ovarian axis by suppressing pituitary secretion of gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby inhibiting estrogen production and ovulation.⁹⁶

Fig. 16 The structure of danazol.

Leflunomide (compound 20), approved by the FDA in 1999, is classified as disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis. Additionally, it has been used as an orphan drug to prevent acute and chronic rejection of solid organ transplants. Rheumatoid arthritis, an autoimmune disease caused by high T-cell activity, ranks among the top 10 major chronic diseases in Western countries⁹⁷ For its immunomodulatory effects, leflunomide targets the human enzyme dihydroorotate dehydrogenase (DHODH). Within the mitochondrial matrix, DHODH catalyzes the conversion of dihydroorotate (DHO) to orotate (ORO), a rate-determining step in de novo pyrimidine biosynthesis.⁹⁸ Activated T cells use the following pathway instead of salvage pathway for the synthesis of pyrimidine. Inhibition of DHODH by leflunomide leads to decreased ribonucleotide uridine monophosphate synthesis, thus inability of T cells to generate enough pyrimidine precursors for expansion. As a result, autoimmune T-cell proliferation is inhibited. It is worth noting that leflunomide is a prodrug which is rapidly converted into the active metabolite A77 1726 to perform the immunosuppressive and disease-modifying effects after oral administration within hours (Fig. 17a).

Fig. 17 (a) The structure of leflunomide and A77 1726; (b) the key target interactions.

Additionally, A77 1726 binds to human DHODH with high affinity. Within the hydrophobic channel, the carbonyl group of the amide forms a water-bridged hydrogen bond with Arg136, while the hydroxyl group forms a direct hydrogen bond with Tyr356. The trifluoromethyl group and benzene ring form hydrophobic interactions with Phe98, Pro364 and Ala59 residues in the pocket⁹⁹ (Fig. 17b).

Valdecoxib (compound 22) was approved by the FDA in 2001 and is a selective cyclooxygenase-2 (COX-2) inhibitor that can be used as a non-steroidal anti-inflammatory drug for the treatment of chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstrual symptoms¹⁰⁰ (Fig. 18).

Fig. 18 The structure of parecoxib, valdecoxib and celecoxib.

It can block the formation of prostaglandins (PGs) produced from arachidonic acid by the COX-2 enzyme. Parecoxib (compound 21) is a water-soluble prodrug of valdecoxib which was not approved by the FDA in 2005. Valdecoxib performs a potency (ED₅₀ = 0.032 ± 0.002 mg kg⁻¹ per day) in chronic antiinflammatory activity exceeding that obtained with the most potent NSAID-celecoxib (ED₅₀ = 0.373 ± 0.163 mg kg⁻¹ per day) using rat adjuvant arthritis model.¹⁰¹ However, valdecoxib was withdrawn from the Canadian, U.S., and EU markets in 2005 due to its potential to increase the risk of heart attack and stroke.

Micafungin (compound 24) is an antifungal agent approved by the FDA in 2005 for the treatment of candida infections and invasive aspergillosis, used as primary or salvage therapy in combination with other antifungal agents successfully. The fungal cell wall is mainly composed of 1,3-β glucan, 1,6-β glucan, chitin and mannoproteins. 1,3-Beta-D-glucan synthase (GS) utilizes uridine diphosphate-activated glucose (UDP-Glc) as a sugar donor to catalyze the formation of β(1→3) glycosidic bonds in 1,3-β-glucan. It also transports glucan through the cell membrane. Micafungin is a derivative of natural lipopeptides WF11899A (FR901379)¹⁰² (Fig. 19). It is an inhibitor of GS, which is crucial for the synthesis of the fungal cell wall.¹⁰³ In other aspects, it appears to be a mild inhibitor of cyclosporine metabolism which may be due to a mild inhibition of CYP 3A metabolism.¹⁰⁴

Fig. 19 The structure of WF11899A and micafungin.

Zonisamide (compound 25), a sulfonamide anticonvulsant, received FDA approval in 2000 for the treatment of partial seizures in adults (Fig. 20).

Fig. 20 The structure of zonisamide.

Epilepsy, a chronic neurological disorder, is primarily managed with anti-seizure medications. Zonisamide demonstrates efficacy in inhibiting the propagation of epileptic discharges, thereby limiting the spread of focal seizures and preventing their propagation from the cortex to subcortical structures.^105,106 The antiepileptic properties of zonisamide may be attributed to its modulation of sodium and calcium channels. Specifically, zonisamide blocks repetitive firing of voltage-gated sodium channels, reduces voltage-dependent transient inward currents, and decreases voltage-sensitive T-type calcium currents without affecting L-type calcium currents. This results in the stabilization of neuronal membranes and the suppression of neuronal over-synchronisation.^105,107,108 Additionally, zonisamide enhances γ-aminobutyric acid (GABA) by increasing presynaptic GABA release and inhibiting interstitial GABA reuptake to potentiate GABA-mediated inhibition. Furthermore, it reduces glutamate-induced excitability and acts as a weak inhibitor of carbonic anhydrase. Although the clinical relevance of these mechanisms to antiepileptic effects remains unclear, the multiple actions of zonisamide contribute to its effectiveness against both focal and generalized seizures.¹⁰⁹

Tivozanib (compound 26) was approved by the FDA in 2021 and is used to treat recurrent or refractory advanced renal cell carcinoma of adult patients (Fig. 21a). It is an inhibitor of vascular endothelial growth factor receptors (VEGFR) which are transmembrane tyrosine kinases. Its three main classes, VEGFR-1, VEGFR-2, and VEGFR-3, are essential for hematopoietic cell development, vascular endothelial cell development, and lymphatic endothelial cell development, respectively.¹¹⁰ Tivozanib works by occupying the ATP site and the regulatory domain pocket (RDP) of VEGFR2. Specifically, the nitrogen atom of the quinoline ring forms a hydrogen bond with Cys919, while the urea moiety forms two hydrogen bonds with Glu885 and one hydrogen bond with Asp1046 (ref. 111) (Fig. 21b).

Fig. 21 (a) The structure of tivozanib; (b) the key target interactions.

Conclusions

In conclusion, the higher number of drugs containing isoxazole rings compared to oxazole rings among those annually approved by the FDA suggests that isoxazole rings may confer more favorable pharmacological properties. In recent years, a number of bioactive molecules containing oxazole molecules have been studied. For example, the benzoxazole honokiol derivatives synthesized by Guo¹¹² demonstrated significant antimicrobial activity and hemolytic activity, which are expected to be novel anti-MRSA drug candidates. 5-(3′-Indolyl)oxazole moiety has also shown a range of biological activities such as anticancer, antibacterial, antiviral, and anti-inflammatory.¹¹³ We expect more oxazole-containing drugs to be used in the clinic in the future. In addition to this, oxazole derivatives such as oxazolones and isoxazolones are also used in drug modification. For example, oxazolones can selectively inhibit COX-1/2 and tyrosinase activity.¹¹⁴ Isoxazolone-modified hydnocarpin can induce apoptosis in human lung cancer cells and melanoma cancer cells.¹¹⁵ Incorporating oxazole or isoxazole rings into drug molecules is a common strategy in rational drug design to enhance activity and reduce IC₅₀. However, some drugs have been withdrawn from the market due to adverse side effects. It is crucial for medicinal and synthetic chemists to consider these occurrences in future drug design efforts, aiming to balance efficacy with safety.

Data availability

This is to certify that this is a review manuscript and thus there is no original data supporting this article. All the data described in the manuscript text was from the literature reports and the corresponding citations have been provided.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Y. D. acknowledges the National Natural Science Foundation of China (No. 22071175) for financial support.

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