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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 online version).[48]
