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Chapter 10
An Overview on Biological Activities
of Oxazole, Isoxazoles
and 1,2,4-Oxadiazoles Derivatives
Raghuram Gujjarappa, Sattu Sravani, Arup K. Kabi, Aakriti Garg,
Nagaraju Vodnala, Ujjawal Tyagi, Dhananjaya Kaldhi, Virender Singh,
Sreya Gupta, and Chandi C. Malakar
Abbreviations
SRS-A Slow-Reacting Substance of Anaphylaxis
HIV Human Immunodeficiency Virus
TTR Transthyretin
DNA Deoxyribonucleic Acid
NDM-1 New Delhi metallo-ß-lactamase-1
CYP Cytochrome P
COX Cyclooxygenase
CNS Central Nervous System
ADP Adenosine di-phosphate
OGTT Oral Glucose Tolerance Test
PARP Poly(ADP-ribose)polymerase
RNA Ribonucleic Acid
SAR Structure-Activity Relationship
DMT2 Diabetes Mellitus Type 2
PPAR Peroxisome proliferator-activated receptor
MRSA Methicillin-resistant Staphylococcus aureus
FATP Fatty Acid Transport Protein
R. Gujjarappa ·A. K. Kabi ·N. Vodnala ·U. Tyagi ·D. Kaldhi ·C. C. Malakar (B
)
Department of Chemistry, National Institute of Technology Manipur, Langol, Manipur, Imphal
795004, India
e-mail: cmalakar@nitmanipur.ac.in
S. Sravani ·A. Garg ·S. Gupta (B
)
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata 700054, India
V. Singh
Department of Chemistry, Central University of Punjab, Punjab, Bathinda 151001, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
B. P. Swain (ed.), Nanostructured Biomaterials, Materials Horizons: From Nature
to Nanomaterials, https://doi.org/10.1007/978-981-16-8399-2_10
379
380 R. Gujjarappa et al.
P-GP P-glycoprotein
SAC Spindle Assembly Checkpoint
1 Introduction
Oxazole is a heterocycle of the five-membered ring which is composed of oxygen and
nitrogen atoms at first and third positions, respectively, whereas for isoxazole oxygen
and nitrogen atoms are at 1 and 2 positions. In the last few years, reports of biolog-
ically active compounds containing heterocyclic rings have drawn great attention
from medicinal chemists. Oxazole is one of the major biologically active scaffolds
found so far [1]. Surprisingly, a wide range of biological actions is associated with
oxazole containing compounds, including anticancer, antibacterial, anticonvulsant,
anti-allergic, anthelmintic, antiviral, antidepressant, analgesic and antioxidant prop-
erties [2]. Synthetic derivatives of oxazoles are imperative in the drug research port-
folio as a result of good anti-inflammation potential [3], TRPV1 antagonist activity
[4], antitubercular [5] and anti-HIV [6] activities. Additionally, oxazoles are also
found to be used as fluorescent dyes, agrochemicals, corrosion inhibitors [7,8]in
polymer industries [9–11] and photography [12]. This chapter highlights the modern
advancements in the progress of oxazole-based biologically active compounds.
Isoxazoles are also an essential class of heterocycles, which are generally active in
the area of therapeutics and pharmaceuticals such as anticancer, insecticidal, antibac-
terial, antituberculosis, antifungal, antibiotic, antitumour and ulcerogenic. Moreover,
marketed anti-inflammatory drugs as well as COX-2 inhibitors contain molecular
scaffolds of Isoxazole. Isoxazole derivatives such as oxacillin, sulfamethoxazole,
acivicin, cycloserine and sulfisoxazole have been in commercial use for the previous
40 years. In another, Cycloserine is a well-known antibiotic drug that has antibac-
terial, antitubercular activities, and also in medication of leprosy. Acivicin is an
anti-leishmanial, antitumour drug, whilst isoxaflutole is used as an herbicidal drug
[13].
Oxadiazole (known as furadiazoles) is one of the important scaffolds having
aN-heterocyclic five-membered ring consists of two nitrogen and one oxygen
atom. Oxadiazoles could arise in four distinct isomeric forms: 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole; depends on the position of
nitrogen atoms. Amongst the isomers, 1,2,4-oxadiazole, one of the important five-
membered N-heterocycles, received significant attention due to its excellent bioisos-
teric properties and the broad spectrum of biological and pharmaceutical applications.
The fused and pendant 1,2,4-oxadiazole scaffolds have been traced in several well
recognized, commercially accessible drugs. After a few decades since the chem-
istry of 1,2,4-oxadiazole was invented, the unique potential involved researchers
around the globe, giving rise to the recognition of currently available drugs possessing
1,2,4-oxadiazole scaffolds. Nevertheless, the attention in the biological application
of 1,2,4-oxadiazoles and their derivatives have been enlarged in the past twenty years
[14].
10 An Overview on Biological Activities of Oxazole … 381
1.1 Biologically Active Oxazole Related Pharmaceutical
Drugs
Oxazole compounds [15–17] as the bioisostere of imidazoles [18,19], thiazoles
[18,19], triazoles [20,21], benzimidazoles [20,21] as well as tetrazoles [22], have
fascinated progressive consideration. Moreover, several scientists and researchers
over the globe have been affording oxazole-based compounds as pharmacophore
and conceivably discover novel scaffolds with excellent pharmacokinetic property,
low toxicity and a wide spectrum of bioactivity (Fig. 1)[23–25].
Several oxazole-embellished natural products are known to be isolated from
numerous microorganisms and marine invertebrates [26–28], which assist as core
structural motifs for several pharmaceuticals that exhibit various biological activities
such as antifungal, antibacterial, antiproliferative [29–33], analgesic, antileukemic,
antiviral, anticancer and enzyme inhibitory activities [34–43]. The phenomenal
Fig. 1 Biologically active oxazole related pharmaceutical drugs [15–25]
382 R. Gujjarappa et al.
biological functions and ubiquity of oxazoles in synthetic drugs and natural prod-
ucts have generated remarkable attention in the synthesis and biological evolution
of functionalized cyclic oxazole scaffold.
Few of the FDA-approved oxazole containing drugs are listed in Table 1[43].
Tabl e 1 FDA-approved oxazole-containing drugs [43]
Structure of the drug name of the
drug (Drug bank id)
Category/Indication Mechanism of action
Chlorzoxazone
It is recommended for the
reliever of pain related to
acute painful musculoskeletal
conditions
Inhibits degranulation of
mast cells, eventually
suppressing the liberation
of histamine and
anaphylaxis (SRS-A), a
slow reacting substance,
acts as type-I allergic
reactions regulator
Oxaprozin
Recommended for edoema,
inflammation, joint
discomfort and stiffness
which arises from
osteoarthritis and rheumatoid
arthritis
Anti-inflammatory
activities of oxaprozin
referred to the suppression
of cyclooxygenase within
the platelets which results
towards the hindrance in
the synthesis of
prostaglandin. Shows
antipyretic activities which
is associated to the
reactivity on the
hypothalamus, leading
towards enhanced
peripheral blood flow,
vasodilation, as well as
consequent heat dissipation
Benoxaprofen
Withdrawn application Withdrawn application
(continued)
10 An Overview on Biological Activities of Oxazole … 383
Tabl e 1 (continued)
Structure of the drug name of the
drug (Drug bank id)
Category/Indication Mechanism of action
Tafamidis
STreatment for stage-1
symptomatic polyneuropathy,
which may result to postpone
peripheral neurologic
impairment in Europe and
cardiomyopathy in wild type
or hereditary
transthyretin-mediated
amyloidosis
the specific stabilizer of
TTR, and its inhibition of
TTR tetramer dissociation
forms the rationale for its
use as a treatment to slow -
but not cure - the disease
progression of TTR-FAP
Dalfopristin
For the treatment of bacterial
infections (usually in
combination with
quinupristin)
Inhibits the early phase of
protein synthesis
Suvorexantore
Approved for the treatment of
insomnia
A dual antagonist of orexin
receptors OX1R and OX2R
that indorses sleep by
dipping wakefulness and
arousal
1.2 SAR (Structure–Activity Relationship)
of 1,2,4-Oxadiazole Compounds
The 1,2,4-oxadiazoles showcased various essential pharmacokinetic characteristics
and share decent activity in murine models of Methicillin-resistant Staphylococcus
aureus (MRSA) infection (Fig. 2)[44,45]. They are usually embrace of four cyclic
ring system, assigned as A, B, C and D. The subsequent structure–activity relationship
(SAR) recognized some significant explanations:
•The H-bond donor of the ring A is important, whereas for antibacterial activity,
H-bond acceptors at ring A are unfavoured.
•Structural distinctions on ring C are recognized for the biological activity.
384 R. Gujjarappa et al.
Fig. 2 SAR studies of oxadiazole compounds [44,45]
•When other moieties are present, substitution of an oxygen atom by a sulphur atom
at the connecting moiety between rings C and D can ordinarily be reinforced; but,
when other moieties are present, it is unfavourable.
•Ring C and D fusions with phenol are permitted.
The structural differences on the ring C can exhibit bioactivity but, whilst the A
ring is either indole or pyrazole, and the activity would be overturned (Fig. 2).
2 Antibacterial Activity of Oxazole Derivatives
The appearance of carbapenemase forming bacteria, particularly New Delhi Metallo-
β-lactamase known as NDM-1 and its alternates, has elevated a major worry to the
human health. NDM-1 and its variants hydrolyze a broad variety of β-lactam antibi-
otics, as well as carbapenemase. In this context, methyl oxazole amide, compound 1
was a comparatively potent inhibitor against NDM-1 [46–52]. The amide and thiol-
groups are also essential for correlating to the active site of the NDM-1 protein [47].
In addition, Benzamide-based oxazole moieties 2(a–d) displayed decent activity
against Staphylococcus aureus ATCC (Fig. 3).
Moreover, compound 2c was more potent than clinical Linezolid or Vancomycin.
Additionally, Coumarin-based isoxazole 3, isoxazole moiety bearing -Cl substitu-
tion at -oand -ppositions of aromatic ring showed higher activity against Pseu-
domonas aeruginosa and Bacillus cereus. It is might specify that coumarin scaf-
fold with isoxazoles is obviously important for the medicinal implication [48]. In
10 An Overview on Biological Activities of Oxazole … 385
Fig. 3 Oxazole and Isoxazole as antibacterial compounds [46–52]
continuation, bisbenzyl substituted oxazoles 4(a-c) were studied for antibacterial
activity and compound 4c displayed supreme antibacterial activity against P. aerug-
inosa as well as compounds 4a and 4c displayed comparable inhibition against
E. coli [49]. In addition, the carbonyl group of curcumin, attached with isoxazole
sulfonamide which provided compound 5and displayed robust antibacterial activity.
Again, when both carbonyl groups were involved with two isoxazole sulfonamide
molecules, the activity would decline faintly [50]. In another, Enterococci are the
significant pathogens for resistance, and mainly Enterococcus faecium, associated
with the group of “ESKAPE” pathogens which presently originate from nosocomial
infections. In continuation, D-aspartate ligase from E. faecium (Aslfm) as a promi-
nent object for advancement of narrow-spectrum antibacterial agents which is active
against multi-drug-resistant E. faecium. In addition, amino oxazole 6resulting from
the bacterial biotin-dependent carboxylase inhibitors exhibited little micro molar
activity, and specifically, compound 8prevents Aslfm with good activity [51]. In
addition, isoxazole 7bearing tosyloxy phenyl group was screened by the agar cup
plate process for antibacterial activity, utilizing Ampicillin as a classic drug, the
compound shown potential anti-P. Aeruginosa activity [52].
The 2-amino oxazole/4-substituted-phenyl oxazole was synthesized and assessed
for antibacterial and antifungal potency. Some of the molecules have shown greater
activity, i.e. zone of inhibition of 18 mm to 22 mm in Gram-positive bacteria, 16 mm
to 18 mm in Gram-negative bacteria, and 16 mm to 19 mm in Fungi. It indicates that
the oxazole moieties exhibit a strong antibacterial and antifungal activity [53].
Various substituted oxazoles were synthesized and assessed for antibacterial
activity for various strains like S. aureus, E. coli, P. vulgaris, K. pneumonia and
386 R. Gujjarappa et al.
compared with the various standards like Ampicillin and Ciprofloxacin. Some of the
compounds have shown more potent activity than Ampicillin. The zone of inhibition
of the new compounds was found to be 25 mm, whereas Ampicillin is 20 mm in S.
aureus. One compound exhibited a 21 mm inhibition zone, whereas Ampicillin was
22 mm in E. coli which indicates comparable activity. The third compound exhib-
ited an inhibition zone of 22 mm, whereas Ampicillin was 20 mm in P. vulgaris
and others exhibited 23 mm, whereas Ampicillin was 21 mm in K. pneumonia.But
all the newly synthesized compounds have not exhibited comparable activity with
Ampicillin. They exhibited good to moderate antibacterial activity [54].
3 Oxazoles and Their Clinical Drugs
Plenty of medicinal drugs containing oxazole-containing scaffolds have been widely
used in the clinic, for example; Sulfisoxazole 9, Furazolidone 10, Toloxatone 11 and
Linezolid 13 (Fig. 4)[55].
4 Antifungal Activity of Oxazole Derivatives
The installation of the oxazole motif into the indole frame, compound 15,
exhibited good activity against Alternaria brassicicola. Nevertheless, compound
14 comprising the oxadiazolyl group comparatively gave faint inhibitory action [56].
Streptochlorin 18 was originally synthesized from lipophilic extracts of Streptomyces
sp. mycelium and a series of improved streptochlorin analogues such as 16,17,19
and 21 were tested for potency against seven phytopathogenic fungi. All of the
compounds, on the other hand, demonstrated reasonable activity [57]. Additionally,
2-(4-ethyl-2-pyridyl)-1H-imidazole based 1,3,4-oxadiazole scaffolds (compounds
21,22,23, and 24) were verified against several fungal strains and compounds 22,23
Fig. 4 Clinical oxazole drugs [55]
10 An Overview on Biological Activities of Oxazole … 387
Fig. 5 Oxazole related antifungal agents [56-58]
and 24 showcased respectable antifungal activity in contrast with fluconazole (Fig. 5)
[58].
The suppressors of the dual-specificity protein phosphatase CDC25C were discov-
ered to be benzo[d]oxazsole-4,7-diones. Antifungal action of these moieties must
be evaluated. Presence of arylamino, arylthio, or halogen groups will improve the
antifungal activity. So, 5-arylamin-6-bromo-2-ethylbenzo[d]oxazole-4,7-diones and
other compounds by several substituent were considered and evaluated for the anti-
fungal activity. Two compounds were found to be more effective when associated
with the standard drug, 5-Fluorocytosine. The MIC of two compounds was found to
be 1.6 μg/ml and 0.8 μg/ml in Candida albicans Berkhout KCCM 50,235, 3.2 μg/ml
and 3.2 μg/ml in Candida tropicalis Berkout KCCM 50,662, 3.2 μg/ml and 3.2 μg/ml
in Candida krusei Berkhout KCCM 11,655, 1.6 μg/ml and1.6 μg/ml in Crypto-
coccus neoformans KCCM 50,564, 1.6 μg/ml and 0.8 μg/ml in Aspergillus niger
KCTC 1231, 3.2 μg/ml and 1.6 μg/ml in Aspergillus flavus KCCM 11,899, whereas
5-Fluorocytosine was found to be 3.2 μg/ml, 3.2 μg/ml, 3.2 μg/ml, 3.2 μg/ml,
1.6 μg/ml and 1.6 μg/ml, respectively. This indicates that the Benzoxazole derivatives
are highly potent antifungal agents [59].
Phenyl thiazole moiety is an insecticide. It contains phenyl thiazole in its structure.
Replacement of this with its biosphere like oxazole/thiazole ring enhances the activity
of the drug transforming the insecticide into fungicide. This indicates the role of
oxazole in the antifungal activity exhibiting compounds [60].
388 R. Gujjarappa et al.
5 Anticancer Activity of Oxazole Derivatives
Cytochrome P-450 enzymes (CYPs) were the major catalysts for the development of
target-selective suppressor due to the wide homology range of common heme–iron
scaffolds. Moreover, adrenal and intra tumoural androgen biosynthesis was found to
be reduced by the orally active CYP17A1 inhibitor abiraterone acetate. Thus, it is
found to be an active molecule for the treatment of prostate cancer. In continuation,
oxazole 255 well-found satisfactory lyase effectiveness in inhibiting Rat CYP17
lyase activity and showed adequate inhibitory activity against human CYP3A4 [61].
In addition, several 2,4-diphenyloxazole derivatives (compounds 26,27 and 28)were
appraised for their anticancer affectivity and as the results displayed that compounds
26 and 27 exhibited auspicious activity on the HepG2 cell line. Whereas compound 28
showed noteworthy growth inhibition on HeLa cells. Researchers found that substi-
tuted phenyl ring at the second position was positive for the anticancer potency of
scaffold [62]. Compounds 29,30 and 32 which replaced the phenolic hydroxyl group
with naphthalene, pyridine, or quinoline moieties, demonstrated strong inhibitory
effect against three cell lines: A549 (Human lung carcinoma), MCF-7 (Human
breast carcinoma) and Hela (Human cervical carcinoma). Compound 29 exhibited
exceptional inhibitory movement over MCF-7 (Human breast carcinoma) cell lines.
Furthermore, structure–activity relationships (SAR) revealed that the C-5 position of
the oxazole ring is linked to naphthalen-2-yl and quinolin-3-yl, which is important for
5-aryl-2-methyloxazole potency and selectivity [63]. In another, mono-substituted
oxazole 33 afforded reduced activity in contrast with furan derivatives of transcription
in transfected PC-3 cells, whereas 3,5-bis(trifluoromethyl)benzoyl aniline substituted
compound 34 showed better activity (Fig. 6)[64].
In addition, MPS1 (protein kinase monopolar spindle 1) is a critical component
of the spindle assembly checkpoint (SAC) signal, which is improperly expressed in
a variety of human malignancies. Moreover, MPS1 is the topmost 25 genes which
are over-expressed in tumours with chromosomal uncertainty. PTEN-deficient breast
tumour cells are mainly reliant on MPS1 for survival, which makes it the remark-
able target in oncology. In addition, the 1H-pyrrolo[3, 2-c]-pyridine moiety-based
oxazoles (compounds 35 and 36) verified potent as well as ligand-efficient binding to
MPS1. The crystal structures of MPS1 with oxazoles 35 and 36 further revealed that
the oxazole scaffold maintained connection with the active site Lys553 side chain
[65]. In addition, a new 2,5-disubstituted oxazole 37 was isolated from Aspongopus
chinensis (an insect from the Pentatomidae family) and exhibited noteworthy activity
against various tumour cell lines. Multidrug resistance (MDR) is a complicated
abnormality caused by the overexpression of transmembrane proteins from the ATP
binding holder transporter family. P-glycoprotein (P-GP), one of these transporters,
is frequently intertwined with MDR. In another, substituted naphthalenyl oxazole
derivatives (compounds 31,38,39,40 and 41) were measured as P-glycoprotein
(P-GP) substrate as it encouraged ATP cell reduction. The SAR studies has shown
that existence of F, H or OH substituents were encouraging for bioactivity, whereas
Br was found to be contrary in the ATPase assay (Fig. 6)[66].
10 An Overview on Biological Activities of Oxazole … 389
Fig. 6 Mono and bis-substituted oxazoles as anticancer agents [61–64]
Combrestatin A-4 (CA-4) exhibits an effective antitumour activity but the solu-
bility issues limited its use in anticancer therapy. These drawbacks were resolved by
the addition of imidazole and oxazole rings. In various cell lines, including human
518A2 melanoma, human HT-29 colon carcinoma and EA. HY926 endothelial hybrid
cells, the substitution of a halogen atom on the oxazole ring improved anticancer
activity [67]. Oxazole ring plays prominent role in anticancer activity.
Pongamol, a chalcone derivative isolated from Derris indica, has many pharma-
cological activities. One of the activities exhibited by it is the antitumour activity.
There is no documented evidence of this traditional medicine. The oxazole ring addi-
tion to this natural drug enhances its antitumour activity. So pongamol derivatives
of Oxazole and Pyrazole were synthesized and antitumour activity was estimated
over three different human cancer cell lines, HeLa, IMR-32 and Jurkat. The oxazole
derivative and the pyrazole derivative have shown increased activity compared to the
natural drug Pongamol [68].
6 Antitubercular Activity of Oxazole Derivatives
Through the establishment of strains of drug-resistant of Mycobacterium tuber-
culosis, several attempts were made for the improvement of antitubercular agents
possessing higher potency, less adverse effects/toxicity and less multi-drug resis-
tances [69,70]. Fascinated by the aminothiazole compounds showing excellent
therapeutic index and dominant activity, amino oxazole compound 42 (Fig. 7)was
390 R. Gujjarappa et al.
Fig. 7 Oxazoles, isoxazoles and oxadiazoles as antitubercular agents [71–73]
screened for biological evolution and found that compound 42 exhibited reasonable
potency against Mycobacterium tuberculosis H37Rv. The replacement of oxazole
scaffold through oxadiazole might lead into a 2-to-fourfold recovery in strength
comparative to oxazole 42 [71]. In addition, the tri-substituted oxazole 43 with
a thiazole ring was used, and equivalent action against inert Mycobacterium TB
H37Ra and Mycobacterium bovis BCG strains was observed when compared to the
conventional antibiotic Rifampicin. Additionally, Isoxazole 44 containing pyridine
and thiazole rings was initiate to own high-inhibitory potency against vulnerable
strains of M. tuberculosis. In another, Phenylisoxazoles (compounds 45,46,47,48,
49 and 50) bearing pyrrole rings were screened. The antitubercular action of these
moieties displayed that compound 47 with electron-rich isopropyl group exhibited
the notable potency for M. tuberculosis H37Rv strain, whereas moieties containing
methyl & methoxy (compounds 46 &48) provided comparatively abridged activity.
Nevertheless, unsubstituted compound 45 and electron-poor group substituted ones
49 and 50 displayed minimum bioactivity. Precisely, the most potent compound 47
exhibited a good safety profile against the A549 cell line [72].
2-Pyridinyl functionalized thiazolyl-5-aryl-1,3,4-oxadiazoles (compounds 51-
57) were evaluated in the search for more safe and effective anti-tubercular medicines.
In addition, 2-phenyl substituted compounds 52,54,55 and 57 showed auspicious
activity against Mycobacterium bovis BCG, and additionally, these compounds also
exhibited little cytotoxicity over four human cancer cell lines (THP-1, HeLa, PANC-
1, HCT116). Nevertheless, compound 51 with no substitution and other position
substituted compounds 53 and 56 gave extremely reduced antitubercular activity
[73].
Mycobacterial infections are the most common infectious disease globally.
Furthermore, tuberculosis (TB) is witnessed amongst the top ten reasons of death
10 An Overview on Biological Activities of Oxazole … 391
worldwide. This is also the dominating fact of death from a single-infectious agent.
The emergence of drug-resistant mycobacterial strains, which need the use of more
toxic and less effective medications as well as therapy prolonging, is a source of
particular concern. However, 4-methyl-2-aryl-5-(2-aryl/benzyl thiazol-4-yl) oxazole
was synthesized and antitubercular activity was evaluated against various strains
of M. tuberculosis HA37Ra (MTB, ATCC 25,177) and M. bovi s BCG (BCG,
ATCC 35,743) in liquid medium using Rifampicin as a standard drug. In these
series of compounds, five active compounds were found. It has been found that
3-Cl and 4-F substituted benzyl rings increased the antitubercular potency and some
compounds exhibited comparable activity with Rifampicin. One of the molecules
possess excellent antibacterial activity [69].
Oxazoles with carboxylic group substituents exhibit antitumour activity against
Mycobacterium tuberculosis with low toxicity. One of the compounds exhibited anti-
TB activity showing MIC of 0.07 & 0.14 mM against Mycobacterium tuberculosis
and multi-drug-resistant Mycobacterium tuberculosis [74].
7 Anti-inflammatory and Analgesic Activity of Oxazole
Derivatives
There is growing interest in the progress of specific inhibitors for FAAH (fatty acid
amide hydrolase) that point to the cytosolic port Cys269 in medication for inflamma-
tory, pain, or sleep disorders, due to the therapeutic potency of specific inhibitors for
FAAH (fatty acid amide hydrolase) that point to the cytosolic port Cys269 in medica-
tion for inflammatory, pain, or sleep disorders. Oxazole bromide 58 (Fig. 8)showed
noteworthy potency in inhibition of FAAH, whereas the compound 59 having nitrile
gave slightly weak activity [75–83]. The irretrievable inhibitors of FAAH exhib-
ited that predictable compassion to the position of the electrophile starter, but those
were successfully showed amazing drifts in specious sensitivity towards Cys269
that would not be simply projected [76]. In continuation, tri-substituted oxazole
compound 60 displayed excellent efficiency in frequent preclinical models together
with the spinal nerve ligation (SNL) pain models and complete Freund’s adjuvant
(CFA). Moreover, no insightful properties were detected for this brain penetrant
FAAH inhibitor, and compound 60 is found to be potent, specific reversible non-
covalent modifying FAAH inhibitor [77]. In addition, Mofezolac 63 bearing isoxa-
zole scaffold was an effective and selective COX-1 inhibitor and was broadly active in
medication. Several considerations were focussed on its analogues to explore novel
COX-1 inhibitors to overthrown its side effects [78]. In further, indole containing
isoxazole 62 showed similar or more Secretory phospholipase A2 (sPLA2) inhibitory
activity when compared to positive control Ursolic Acid. Additionally, this compound
can bind the proximity of active site amino acid residues; HIS-47, TYR-21, GLY-22,
PHE-5, GLY-29, CYS-44, CYS-28, PHE-98, ASP-48 and TYR-51. Furthermore,
compound 62 is significant for correlations and binding capabilities with sPLA2
392 R. Gujjarappa et al.
could be liable for its sPLA2-inhibitory effect [79]. In addition, in animal models
of nonspecific inflammatory responses or Th1-type immune responses, isoxazole
compound 61 proved an efficient anti-inflammatory drug. The use of compound 61 in
the form of ointment is the added value in the management of skin inflammation [80].
On the other hand, compound 64, 4,5-Diaryl-isoxazole-3-carboxylic acid, inhibits
leukotriene biosynthesis and acts as an effective anti-inflammatory agent [81]. Tri-
substituted indole derivative of isoxazole 65 [82], and 3,5-disubstituted isoxazole
furfuryl derivative 66 [83], have also exhibited significant effect as anti-inflammatory
agent.
Oxazole derivatives were synthesized, their anti-inflammatory effect was tested,
and they were compared to the standard medicine nimesulide using the HRBC
membrane stabilization technique. The percentage protection of the newly synthe-
sized compound was in the values of 55.1, 50, 59 and 60%, and the nimesulide protec-
tion percentage was found to be 61% at 50 μg/ml. These compounds have exhibited
comparable activity with the standard drug, nimesulide. But these compounds don’t
exhibit any increased anti-inflammatory or analgesic activity upon increasing the
concentration to 100 μg/ml [84].
Quinolyl oxazoles with various substitutions were synthesized, and they are
highly effective inhibitors of phosphodiesterase 4 (PDE4). Some of the compounds
Fig. 8 Anti-inflammatory and analgesic compounds [75–83]
10 An Overview on Biological Activities of Oxazole … 393
were considered to be more potent against PDE4 IC50 values of 1 to 1.4 nm. N-
benzylcarboxamide has shown the highest selectivity against phosphodiesterase 4.
Further optimization led to highly selective PDE4 inhibitors with picomolar potency
with the values of 0.05, 0.03, 0.06 and 0.04 nm. This data shows that the oxazole
ring containing compounds exhibit good anti-inflammatory activity [67].
8 Antidiabetic Activity of Oxazole Derivatives
The G-protein coupled receptor 40 (GPR40) is broadly populated in pancreatic
βcells and recognizes endogenous fatty acids, leading in an increase in insulin
output when glucose levels are high [85–87]. Furthermore, compound 67 consisting
of Isoxazole (Fig. 9) showed better impact as GPR40 agonist, exceptional pharma-
cokinetic possessions across species, and minimum central nervous system (CNS)
dispersion. OGTT study in human GPR40 knock-in mice showed this compound
decreases the plasma glucose levels [88]. In continuation, bis-substituted isoxazole
68 containing thiophene moiety increases the assembly of mRNAs encrypting a
select group of βcell proteins vital for glucose detecting and insulin gene tran-
scription [89]. In addition, the tri-substituted oxazole compound 69 was displayed
noteworthy activity on the GPR40 receptor. In continuation, arylsulfonyl 3-(pyridin-
2-yloxy) aniline compound 70 consisting 1,2,4-oxadiazole scaffold showed exciting
activity as GPR119 agonist [90].
PPARs (peroxisome proliferator-activated receptors) are also important thera-
peutic targets for Type 2 Diabetes Mellitus therapy (DMT2). Furthermore, most
existing PPAR ligands comprise a thiazolidinedione (TZD) structure or a carboxylic
acid (CA) that is crucial for activity. Furthermore, the 1,2,4-Oxadiazole compound
71 might bind to Peroxisome proliferator-activated receptors (PPARαand PPARδ)
via an acetamide scaffold and an adjacent methyl group. In addition, skeletal muscle
Fig. 9 Antidiabetic compounds of oxazoles [88–90]
394 R. Gujjarappa et al.
significantly interesting target tissues are extensively working for the treatment of
insulin resistance. It is worth mentioning that one of the most imperative protein
targets for insulin resistance is fatty acid transport protein 1 (FATP1), a member of
Acyl-CoA synthetase. FATP1 is a transmembrane protein and highly over-expressed
in skeletal muscle. Thus, inhibition of FATP1 could lead to the interruption of free
fatty acid transport in insulin resistant cells. Fascinatingly, compound 71 contains
benzoxazole scaffold has shown significant FATP1 inhibition in mouse and human
thus reflected as a potential candidate for free fatty acid regulator in insulin resistant
condition [91]. In continuation, oxadiazole compounds 74a,74b and 74c were found
to be more active with antidiabetic activity in contrast with the typical drug Acarbose
[92]. Furthermore, suppression of the intracellular enzyme 11-beta-hydroxysteroid
dehydrogenase type 1 (11βHSD1) has been proposed as a therapeutic strategy for
the treatment of DMT2. The compound 73 comprising 5-oxazole with piperidyl
ring at fourth position was found to express stimulating inhibitory action against the
11β-HSD1 enzyme [93].
The 1,3-dioxane carboxylic acid derivatives were synthesized and they act as dual
agonists for PPAR α/U. As a lipophilic heterocyclic tail, substituted oxazole must be
incorporated. These compounds were produced and tested in animal models for their
agonistic activity on the PPAR receptor, as well as hypoglycaemic and hypolipidemic
effectiveness. One of the compounds of this series exhibited potent hypoglycaemic,
hypolipidemic and insulin-sensitizing effects [94].
9 Summary/Conclusion
Oxazole-based scaffold and its analogues are well-accepted as promising moieties in
the development and progress of novel drugs revealing immense biological and phar-
maceutical activities. It has been acknowledged from the foregoing deliberations that
various oxazole-embedded molecules can have appreciable attention in the synthesis
and evaluation of new agents effectively employable for the treatment of insomnia,
cancer, Alzheimer’s disease, inflammation, etc. Some of the molecules defined in
this chapter are applicable for medicinal studies, and their appraisal is continuing,
grasping great potential for the identifications of innovative pharmaceutical drugs.
This chapter established the fact that oxazole-based scaffolds as useful templates
for further derivatization or modification to design more effective medicinally active
compounds.
References
1. Zhang HZ, Gan LL, Wang H, Zhou CH (2017) New progress in azole compounds as
antimicrobial agents. Mini-Rev Med Chem 17:122–166
10 An Overview on Biological Activities of Oxazole … 395
2. Peng XM, Cai GX, Zhou CH (2013) Recent developments in azole compounds as antibacterial
and antifungal agents. Curr Top Med Chem 13:1963–2010
3. Kean WF (2004) Oxaprozin: kinetic and dynamic profile in the treatment of pain. Curr Med
Res Opin 20:1275–1277
4. Perner RJ, Koenig JR, Didomenico S, Gomtsyan A, Schmidt RG, Lee CH, Hsu M, McDonald
HA, Gauvin DM, Joshi S, Turner TM, Reilly RM, Kym PR, Kort ME (2010) Synthesis
and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1
antagonists. Bioorg Med Chem 18:4821–4829
5. Dominguez XA, de la Fuente G, Gonzalez AG, Reina M, Timon I (1988) Two new oxazoles
from amyris texana p wilson. Heterocycles 27:35–38
6. Bell FW,Cantrell AS, Hoegberg M, Jaskunas SR, Johansson NG, Jordan CL, Kinnick MD, Lind
P, Morin J, Noreen JR, Oberg B, Palkowitz JA, Parrish CA, Pranc P, Sahlberg C, Ternansky
RJ, Vasileff RT, Vrang L, West SJ, Zhang H, Zhou XX (1995) Phenethylthiazolethiourea
(PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors 1 synthesis and basic
structure-activity relationship studies of PETT analogs. J Med Chem 38:4929–4936
7. Ibrahimi BE, Guo L (2020) Azole-based compounds as corrosion inhibitors for metallic
materials. IntechOpen. https://doi.org/10.5772/intechopen.93040
8. Tang JS, Verkade JG (1996) Chiral auxiliary-bearing isocyanides as synthons: synthesis
of strongly fluorescent (+)-5-(3,4-dimethoxyphenyl)-4-[[N- [(4S)-2-oxo-4-(phenylmethyl)-2-
oxazolidinyl]]carbonyl]oxazole and its enantiomer. J Org Chem 61:8750–8754
9. Zhao Q, Liu S, Li Y, Wang QJ (2009) Design, synthesis, and biological activities of novel
2-cyanoacrylates containing oxazole, oxadiazole, or quinoline moieties. J Agric Food Chem
57:2849–2855
10. Min J, Lee JW, Ahn Y-H, Chang Y-T (2007) Combinatorial dapoxyl dye library and its
application to site selective probe for human serum albumin. J Comb Chem 9:1079–1083
11. Grotkopp O, Ahmad A, Frank W, Muller TJ (2011) Blue-luminescent 5-(3-indolyl)oxazoles via
microwave-assisted three-component coupling-cycloisomerization-Fischer indole synthesis.
Org Biomol Chem 9:8130–8140
12. Turchi IJ, Dewar MJS (1975) Chemistry of oxazoles. Chem Rev 75:389–437
13. Zhu J, Mo J, Lin H-Z, Chen Y, Sun H-P (2018) The recent progress of isoxazole in medicinal
chemistry. Bioorg Med Chem 26:3065–3075
14. Biernacki K, Da´sko M, Ciupak O, Kubi´nski K, Rachon J, Demkowicz S (2020) Novel 1,2,4-
oxadiazole derivatives in drug discovery. Pharmaceuticals 13:111–155
15. Bai Y, Chen W, Chen H, Huang H, Xiaoa F, Deng G-J (2015) Copper-catalyzed oxidative
cyclization of arylamides and β-diketones: new synthesis of 2,4,5-trisubstituted oxazoles. RSC
Adv 5:8002–8005
16. Glöckner S, Tran DN, Ingham RJ, Fenner S, Wilson ZE, Battilocchio C, Ley SV (2014)
The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow
condition. Org Biomol Chem 13:207–214
17. Ibrar A, Khan I, Abbas N, Farooq U, Khan A (2016) Transition-metal-free synthesis of oxazoles:
valuable structural fragments in drug discovery. RSC Adv 6:93016–93047
18. Srivastava BK, Soni R, Joharapurkar A, Sairam KV, Patel JZ, Goswami A, Shedage
SA, Kar SS, Salunke RP, Gugale SB, Dhawas A, Kadam P, Mishra B, Sadhwani N,
Unadkat VB, Mitra P, Jain MR, Patel PR (2008) Bioisosteric replacement of dihydropy-
razole of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N’-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-
dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imida-
zole and oxazole. Bioorg Med Chem Lett 18:963–968
19. Kaspadya M, Narayanaswamy VK, Raju M, Rao GK (2009) Synthesis, antibacterial activity
of 2,4-disubstituted oxazoles and thiazoles as bioisosteres. Lett Drug Des Discovery 6:21–28
20. Zhou CH, Wang Y (2012) Recent researches in triazole compounds as medicinal drugs. Curr
Med Chem 19:239–280
21. Meanwell NA (2013) The influence of bioisosteres in drug design: tactical applications to
address developability problems. In: Meanwell N (eds) Tactics in contemporary drug design.
Topics in Medicinal Chemistry, vol 9. Springer, Berlin, Heidelberg
396 R. Gujjarappa et al.
22. Dai LL, Cui SF, Damu GLV, Zhou CH (2013) Recent advances in the synthesis and application
of tetrazoles. Chin J Org Chem 33:224–244
23. Mayer JCP, Sauer AC, Iglesias BA, Acunha TV, Back DF, Rodrigues OED, Dornelles L (2017)
Ferrocenylethenyl-substituted 1,3,4-oxadiazolyl-1,2,4-oxadiazoles: synthesis, characterization
and DNA-binding assays. J Organomet Chem 841:1–11
24. Sysak A, Obmi´nska-Mrukowicz B (2017) Isoxazole ring as a useful scaffold in a search for
new therapeutic agents. Eur J Med Chem 137:292–309
25. Demmer DS, Bunch L (2015) Benzoxazoles and oxazolopyridines in medicinal chemistry
studies. Eur J Med Chem 97:778–785
26. Lindquist N, Fenical W, Van Duyne GD, Clardy J (1991) Isolation and structure determination
of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona
chinensis. J Am Chem Soc 113:2303–2304
27. Cruz-Monserrate HC, Vervoort RL, Bai D, Newman SB, Howell G, Los JT, Mullaney MD,
Williams GR, Fenical PW, Hamel E (2003) Mol Pharmacol 63:1273–1280
28. Kobayashi J, Tsuda M, Fuse H, Sasaki T, Mikami Y (1997) Halishigamides A-D, New cytotoxic
oxazole-containing metabolites from okinawan sponge Halichondria sp. J Nat Prod 60:150–
154
29. Azman AM, Mullins RJ (2013) Heterocyclic chemistry in drug discovery. In: Li JJ (ed) New
York, Wiley, 231p
30. Cocito C (1979) Antibiotics of the virginiamycin family, inhibitors which contain synergistic
components. Microbiol Rev 43:145–192
31. Moura KCG, Carneiro PF, Pinto MC, da Silva JA, Malta VR, de Simone CA, Dias GG,
Jardim GA, Cantos J, Coelho TS, da Silva PE, da Silva Jr EN (2012) 1,3-Azoles from ortho-
naphthoquinones: synthesis of aryl substituted imidazoles and oxazoles and their potent activity
against Mycobacterium tuberculosis. Bioorg Med Chem 20:6482–6488
32. Antonio J, Molinski TF (1993) Screening of marine invertebrates for the presence of ergosterol-
sensitive antifungal compounds. J Nat Prod 56:54–61
33. Ryu CK, Lee RY, Kim NY, Kim YH, Song AL (2009) Synthesis and antifungal activity of
benzo[d]oxazole-4,7-diones. Bioorg Med Chem Lett 19:5924–5926
34. Desroy N, Moreau F, Briet S, Le Fralliec G, Floquet S, Durant L, Vongsouthi V, Gerusz V,
Denis A, Escaich S (2009) Towards Gram-negative antivirulence drugs: new inhibitors of HldE
kinase. Bioorg Med Chem 17:1276–1289
35. Heng S, Gryncel KR, Kantrowitz ER (2009) A library of novel allosteric inhibitors against
fructose 1,6-bisphosphatase. Bioorg Med Chem 17:3916–3922
36. Copp BR (2003) Antimycobacterial natural products. Nat Prod Rep 20:535–557
37. Lack NA, Axerio-Cilies P, Tavassoli P, Han FQ, Chan KH, Feau C, LeBlanc E, Guns ET, Guy
RK, Rennie PS, Cherkasov A (2011) Targeting the binding function 3 (BF3) site of the human
androgen receptor through virtual screening. J Med Chem 54:8563–8573
38. Hashimoto H, Imamura K, Haruta J, Wakitani K (2002) 4-(4-cycloalkyl/aryl-oxazol-5-
yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selec-
tivity by introduction of a fluorine atom and identification of a potent, highly selective, and
orally active COX-2 inhibitor JTE-522(1). J Med Chem 45:1511–1517
39. Momose Y, Maekawa T, Yamano T, Kawada M, Odaka H, Ikeda H, Sohda T (2002) Novel
5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers
with antidiabetic activities. J Med Chem 45:1518–1534
40. Brown P, Davies DT, O’Hanlon PJ, Wilson JM (1996) The chemistry of Pseudomonic acid. 15.
Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted
oxazoles. J Med Chem 39:446–457
41. Yang WS, Shimada K, Delva D, Patel M, Ode E, Skouta R, Stockwell BR (2012) Identification
of simple compounds with microtubule-binding activity that inhibit cancer cell growth with
high potency. ACS Med Chem Lett 3:35–38
42. Shaw AY, Henderson MC, Flynn G, Samulitis B, Han H, Stratton SP, Chow HH, Hurley LH,
Dorr RT (2009) Characterization of novel diaryl oxazole-based compounds as potential agents
to treat pancreatic cancer. J Pharmacol Exp Ther 331:636–647
10 An Overview on Biological Activities of Oxazole … 397
43. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C,
Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L,
Cummings R, Le D, Pon A, Knox C, Wilson M (2018) DrugBank 5.0: a major update to the
DrugBank database for 2018. Nucleic Acids Res 46:D1074–D1082
44. Janardhanan J, Chang M, Mobashery S (2016) The oxadiazole antibacterials. Curr Opin
Microbiol 33:13–17
45. Ding D, Boudreau MA, Leemans E, Spink E, Yamaguchi T, Testero SA, O’Daniel PA,
Lastochkin E, Chang M, Mobashery S (2015) Exploration of the structure–activity relationship
of 1,2,4-oxadiazole antibiotics. Bioorg Med Chem Lett 25:4854–4857
46. Stokes NR, Baker N, Bennett JM, Chauhan PK, Collins I, Davies DT, Gavade M, Kumar
D, Lancett P, Macdonald R, MacLeod L, Mahajan A, Mitchell JP, Nayal N, Nayal YN, Pitt
GRW, Singh M, Yadav A, Srivastava A, Czaplewski LG, Haydon DJ (2014) Design, synthesis
and structure–activity relationships of substituted oxazole-benzamide antibacterial inhibitors
of FtsZ. Bioorg Med Chem Lett 24:353–359
47. Li N, Xu Y, Xia Q, Bai C, Wang T, Wang L, He D, Xie N, Li L, Wang J, Zhou HG, Xu F,
Yang C, Zhang Q, Yin Z, Guo Y, Chen Y (2014) Simplified captopril analogues as NDM-1
inhibitors. Bioorg Med Chem Lett 24:386–389
48. Patel D, Kumari P, Patel NB (2017) Synthesis and biological evaluation of coumarin based
isoxazoles, pyrimidinthiones and pyrimidin-2-ones. Arab J Chem 10:3990–4001
49. Tomi IHR, Tomma JH, Al-Daraji AHR, Al-Dujaili AH (2015) Synthesis, characterization and
comparative study the microbial activity of some heterocyclic compounds containing oxazole
and benzothiazole moieties. J Saudi Chem Soc 19:392–398
50. Lal J, Gupta SK, Thavaselvam D, Agarwal DD (2013) Biological activity, design, synthesis and
structure activity relationship of some novel derivatives of curcumin containing sulphonamides.
Eur J Med Chem 64:579–588
51. Škedelj V, Perdih A, Brvar M, Krofliˇc A, Dubbée V, Savage V, O’Neill AJ, Solmajer T, Bešter-
Rogaˇc M, Blanot D, Hugonnet JE, Magnet S, Arthur M, Mainardi JL, Stojan J, Zega A (2013)
Discovery of the first inhibitors of bacterial enzyme D-aspartate ligase from Enterococcus
faecium (Aslfm). Eur J Med Chem 67:208–220
52. Kendre BV, Landge MG, Bhusare SR (2015) Synthesis and biological evaluation of some
novel pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives
bearing an aryl sulfonate moiety as antimicrobial and anti-inflammatory agents. Arab J Chem
12:2091–2097
53. Rawat BS, Shukla SK (2016) Synthesis and evaluationof some new thiazole/oxazole derivatives
for their biological activities. World J Pharm Pharm Sci 5:1473–1482
54. Kakkar S, Narasimhan B (2019) A comprehensive review on biological activities of oxazole
derivatives. BMC Chem 13:16
55. Zhang HZ, GanL L, Wang H, Zhou CH (2017) New progress in azole compounds as
antimicrobial agents. Mini-Rev Med Chem 17:122–166
56. Pedras MSC, Abdoli A (2013) Metabolism of the phytoalexins camalexins, their bioisosteres
and analogues in the plant pathogenic fungus Alternaria brassicicola. Bioorg Med Chem
21:4541–4549
57. Zhang MZ, Chen Q, Xie CH, Mulholland N, Turner S, Irwin D, Gu YC, Yang GF, Clough J
(2015) Synthesis and antifungal activity of novel streptochlorin analogues. Eur J Med Chem
92:776–783
58. Wani MY, Ahmad A, Shiekh RA, Al-Ghamdi KJ, Sobral AJFN (2015) Imidazole clubbed
1,3,4-oxadiazole derivatives as potential antifungal agents. Bioorg Med Chem 23:4172–4180
59. Ryu C, Lee R, Kim NY, Kim YH, Song AL (2009) Synthesis and antifungal activity of
benzo[d]oxazole-4,7-diones. Bioorg Med Chem Lett 19:5924–5926
60. Yan Z, Liu A, Huang M, Liu M, Pei H, Huang L, Yi H, Liu W, Hu A (2018) Design, synthesis,
DFT study and antifungal activity of the derivatives of pyrazolecarboxamide containing thiazole
or oxazole ring. Eur J Med Chem 149:170–181
61. Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ (2014) Highly-selective 4-
(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. Bioorg Med Chem Lett 24:2444–2447
398 R. Gujjarappa et al.
62. Mathew JE, Divya G, Vachala SD, Mathew JA, Jeyaprakash RS (2013) Synthesis and charac-
terization of novel 2,4-diphenyloxazole derivatives and evaluation of their in vitro antioxidant
and anticancer activity. J Pharm Res 6:210–213
63. Wu C, Liang ZW, Xu YY, He WM, Xiang JN (2013) Gold-catalyzed oxazoles synthesis and
their relevant antiproliferative activities. Chin Chem Lett 24:1064–1066
64. Bell JL, Haak AJ, Wade SM, Kirchhoff PD, Neubig RR, Larsen SD (2013) Optimization
of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as
potential anti-metastasis agents. Bioorg Med Chem Lett 23:3826–3832
65. Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KMJ, Liu M,
Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, Brandon AH,
Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI,
Linardopoulos S, Montfort RLM, Blagg J (2013) Structure-based design of orally bioavailable
1H-Pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1). J Med
Chem 56:10045–10065
66. Colabufo NA, Contino M, Cantore M, Capparelli E, Perrone MG, Cassano G, Gasparre
G, Leopoldo M, Berardi F, Perrone R (2013) Naphthalenyl derivatives for hitting P-
gp/MRP1/BCRP transporters. Bioorg Med Chem 21:1324–1332
67. Romagnoli R, Baraldi PG, Prencipe F, Oliva P, Baraldi S, Salvador MK, Lopez-Cara LS,
Brancale A, Ferla S, Hamel E, Ronca R, Bortolozzi R, Mariotto E, Porcù E, Basso G, Viola G
(2017) Synthesis and biological evaluation of 2-methyl-4,5-disubstituted oxazoles as a novel
class of highly potent antitubulin agents. Sci Rep 7:46356
68. Rao PR, Chaturvedi V, Babu KS, Reddy PP, Rao VRS, Sreekanth P, Sreedhar AS, Rao JM
(2012) Synthesis and anticancer effects of pongamol derivatives on mitogen signaling and cell
cycle kinases. Med Chem Res 21:634–641
69. Abhale YK, Sasane AV, Chavan AP, Shekh SH, Deshmukh KK, Bhansali S, Nawale L, Sarkar
D, Mhaske PC (2017) Synthesis and antimycobacterial screening of new thiazolyl-oxazole
derivatives. Eur J Med Chem 132:333–340
70. Azzali E, Machado D, Kaushik A, Vacondio F, Flisi S, Cabassi CS, Lamichhane G,
Viveiros M, Costantino G, Pieroni M (2017) Substituted N-phenyl-5-(2-(phenylamino)thiazol-
4-yl)isoxazole-3-carboxamides are valuable antitubercular candidates that evade innate efflux
machinery. J Med Chem 60:7108–7122
71. Meissner A, Boshoff HI, Vasan M, Duckworth BP, Barry CE, Aldrich CC (2013) Structure-
activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis.
Bioorg Med Chem 21:6385–6397
72. Joshi SD, Dixit SR, Kirankumar MN, Aminabhavi TM, Raju KVSN, Narayan R, Lherbet C,
Yang KS (2013) Synthesis, antimycobacterial screening and ligand-based molecular docking
studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties.
Bioorg Med Chem 21:6385–6397
73. Dhumal ST, Deshmukh AR, Bhosle MR, Khedkar VM, NawaleLU, Sarkar D, Mane R A (2016)
Synthesis and antitubercular activity of new 1,3,4-oxadiazoles bearing pyridyl and thiazolyl
scaffolds. Bioorg Med Chem Lett 26:3646–3651
74. Asif M (2016) A brief overview on recent advances in the development of anti-tubercular
compounds containing different heterocyclic ring systems. Appl Micro Open Access 2
75. Otrubova K, Brown M, McCormick MS, Han GW, O’Neal ST, Cravatt BF, Stevens RC,
Lichtman AH, Boger DL (2013) Rational design of fatty acid amide hydrolase inhibitors that
act by covalently bonding to two active site residues. J Am Chem Soc 135:6289–6299
76. Otrubova K, Cravatt BF, Boger DL (2014) Design, synthesis, and characterization of α-
ketoheterocycles that additionally target the cytosolicport Cys269 of fatty acid amide hydrolase.
J Med Chem 57:1079–1089
77. Chobanian HR, Guo Y, Liu P, Chioda MD, Fung S, Lanza TJ, Chang L, Bakshi RK, Dellureficio
JP, Hong Q, McLaughlin M, Belyk KM, Krska SW, Makarewicz AK, Martel EJ, Leone JF,
Frey L, Karanam B, Madeira M, Alvaro R, Shuman J, Salituro G, Terebetski JL, Jochnowitz N,
Mistry S, McGowan E, Hajdu R, Rosenbach M, Abbadie C, Alexander JP, Shiao LL, Sullivan
KM, Nargund RP, Wyvratt MJ, Lin LS, DeVita RJ (2014) Discovery of MK-4409, a novel
10 An Overview on Biological Activities of Oxazole … 399
oxazole FAAH inhibitor for the treatment of inflammatory and neuropathic pain. ACS Med
Chem Lett 5:717–721
78. Perrone M. G., Vitale P., Panella A., Fortuna C. G., and Scilimati A. (2015) General role of the
amino and methylsulfamoyl groups in selective cyclooxygenase (COX)-1 inhibition by 1,4-
diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model. Eur J Med
Chem 94:252–264
79. Pedada SR, Yarla NS, Tambade PJ, Dhananjaya BL, Bishayee A, Arunasree KM, Philip GH,
Dharmapuri G, Aliev G, Putta S, Rangaiah G (2016) Synthesis of new secretory phospholi-
pase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer
agents. Eur J Med Chem 112:289–297
80. M˛aczy´nski M, Artym J, Koci˛eba M, Kochanowska I, Ryng S, Zimecki M (2016) Anti-
inflammatory properties of an isoxazole derivative-MZO-2. Pharmacol Rep 68:894–902
81. Banoglu E, Çeliko˘glu E, Völker S, Olgaç A, Gerstmeier J, Garscha U, Çalı¸skan B, Schubert US,
Carotti A, Macchiarulo A, Werz O (2016) 4,5-Diarylisoxazol-3-carboxylic acids: A new class
of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein
(FLAP). Eur J Med Chem 113:1–10
82. Alonso JA, Andrés M, Bravo M, Buil MA, Calbet M, Castro J, Eastwood PR, Esteve C, Ferrer
M, Forns P, Gómez E, González J, Lozoya E, Mir M, Moreno I, Petit S, Roberts RS, Sevilla
S, Vidal B, Vidal L, Vilaseca P (2014) Structure–activity relationships (SAR) and structure–
kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2antagonists
III: The role of a hydrogen-bond acceptor in long receptor residence times. Bioorg Med Chem
Lett 24:5127–5133
83. Chouaïb K, Romdhane A, Delemasure S, Dutartre P, Elie N, Touboul D, Ben jannet H, Hamza
MA (2016) Regiospecific synthesis, anti-inflammatory and anticancer evaluation of novel 3,5-
disubstituted isoxazoles from the natural maslinic and oleanolic acids. Ind Crop Prod 85:287–
299
84. Patil VC, Bhusari KP, Khedekar PB (2014) Synthesis and anti-inlfammatory activity of some
3-substituted thiazolyl and oxazolyl indole derivatives. World J Pharm Pharm Sci 3:1292–1306
85. Zahanich I, Kondratov I, Naumchyk V, Kheylik Y, Platonov M, Zozulya S, Krasavin M (2015)
Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free
fatty acid receptor 1 (GPR40). Bioorg Med Chem Lett 25:3105–3111
86. Taha M, Ismail NH, Imran S, Wadood A, Rahim F, Saad SM, Khan KM, Nasir A (2016)
Synthesis, molecular docking and a-glucosidase inhibition of 5-aryl-2-(6¢-nitrobenzofuran-
2¢-yl)-1,3,4-oxadiazoles. Bioorg Chem 66:117–123
87. Shioi R, Okazaki S, Noguchi-Yachide T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi
T (2017) Switching subtype-selectivity: Fragment replacement strategy affords novel class of
peroxisome proliferator-activated receptor a/d (PPARa/d) dual agonists. Bioorg Med Chem
Lett 27:3131–3134
88. Liu J, Wang Y, Ma Z, Schmitt M, Zhu L, Brown SP, Dransfield PJ, Sun Y, Sharma R, Guo Q,
Zhuang R, Zhang J, Luo J, Tonn GR, Wong S, Swaminath G, Medina JC, Lin DCH, Houze JB
(2014) Optimization of GPR40 agonists for type 2 diabetes. ACS Med Chem Lett 5:517–521
89. Kalwat MA, Huang Z, Wichaidit C, McGlynn K, Earnest S, Savoia C, Dioum EM, Schneider
JW, Hutchison MR, Cobb MH (2016) Isoxazole alters metabolites and gene expression,
decreasing proliferation and promoting a neuroendocrine phenotype in β-cells. ACS Chem
Biol 11:1128–1136
90. Zhang J, Li AR, Yu M, Wang Y, Zhu J, Kayser F, Medina JC, Siegler K, Conn M, Shan B,
Grillo MP, Eksterowicz J, Coward P, Liu J (2013) Discovery and optimization of arylsulfonyl
3-(pyridin-2-yloxy)anilines as novel GPR119 agonists. Bioorg Med Chem Lett 23:3609–3613
91. Matsufuji T, Ikeda M, Naito A, Hirouchi M, Kanda S, Izumi M, Harada J, Shinozuka T (2013)
Arylpiperazines as fatty acid transport protein 1 (FATP1) inhibitors with improved potency and
pharmacokinetic properties. Bioorg Med Chem Lett 23:2560–2565
92. Taha M, Rahim F, Imran S, Ismail NH, Ullah H, Selvaraj M, Javid MT, Salar U, Ali M,
Khan KM (2017) Synthesis, α-glucosidase inhibitory activity and in silico study of tris-indole
hybrid scaffold with oxadiazole ring: As potential leads for the management of type-II diabetes
mellitus. Bioorg Chem 74:30–40
400 R. Gujjarappa et al.
93. Yoon DS, Wu SC, Seethala R, Golla R, Nayeem A, Everlof JG, Gordon DA, Hamann LG,
Robl JA (2014) Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type
1(11β-HSD1) inhibitors for the treatment of metabolic disorders. Bioorg Med Chem Lett
24:5045–5049
94. Pingali H, Jain M, Shah S, Makadia P, Zaware P, Goel A, Patel M, Giri S, Patel H, Patel P (2008)
Design and synthesis of novel oxazole containing 1,3-Dioxane-2-carboxylic acid derivatives
as PPAR a/c dual agonists. Bioorg Med Chem 16:7117–7127
