key: cord-0004698-1pt4ab8x
authors: Agrawal, Neetu; Mishra, Pradeep
title: The synthetic and therapeutic expedition of isoxazole and its analogs
date: 2018-02-27
journal: Med Chem Res
DOI: 10.1007/s00044-018-2152-6
sha: b4e66f625263c0bc00e9be3a4a18d47bb2ed86c1
doc_id: 4698
cord_uid: 1pt4ab8x

Isoxazole, constituting an important family of five-membered heterocycles with one oxygen atom and one nitrogen atom at adjacent positions is of immense importance because of its wide spectrum of biological activities and therapeutic potential. It is, therefore, of prime importance that the development of new synthetic strategies and designing of new isoxazole derivatives should be based on the most recent knowledge emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of isoxazole derivatives which could provide a low-height flying bird’s eye view of isoxazole derivatives to the medicinal chemists for the development of clinically viable drugs using this information.

Heterocyclic compounds have attracted considerable attention as they act as a bridge between chemical and life sciences. A significant amount of contemporary investigation is currently pursued on these compounds worldwide. The chemistry of isoxazoles ( Fig. 1) has been an interesting field of study for decades because of their prominent potential as analgesic (Karthikeyan et al. 2009 ), anti-inflammatory (Rajanarendar et al. 2015; Banoglu et al. 2016) , anticancer (Kumbhare et al. 2012; Tzanetou et al. 2014) , antimicrobial (Siddiqui et al. 2013; Basha et al. 2015) , antiviral ), anticonvulsant (Frølund et al. 2007 ), antidepressant (Yu et al. 2012; Zhang et al. 2016 ) and immunosuppressant . The literature survey revealed that the substitution of various groups on the isoxazole ring imparts different activity.

Several marketed drugs with isoxazole nucleus belong to different categories with diverse therapeutic activities that have resulted in the development of a plethora of method for the synthesis of this valuable fragment. Such drugs are listed in Table 1 . Inspired by these observations, this review summarizes current propensity in the isoxazole synthetic chemistry and divulges the utility of this potent nucleus as a rich source of new compounds having promising biological activities. Although several reviews have been published earlier on isoxazole (Manna et al. 2014; Hu and Szostak 2015; Chikkula and Raja 2017; Sysak and Obmińska-Mrukowicz 2017) , the focus was either synthetic routes or chemical reactions of the nucleus or the several biological activities of the isoxazole derivatives. Our effort is an exhaustive and systematic compilation of synthetic, as well as therapeutic voyage of isoxazole and its derivatives till now.

Literature survey revealed that several substituted isoxazoles had been prepared from numerous synthetic routes. The first contribution to the chemistry of isoxazoles was made by Claisen in 1903, when he synthesized the first compound of series, isoxazole, by oximation of propargylaldehyde acetal (Claisen 1903) .

A regioselective, experimentally convenient one-pot copper(I)-catalyzed procedure was developed for the rapid synthesis of 3,5-disubstituted isoxazoles (Route a, Fig. 2 ) by reacting in situ generated nitrile oxides and terminal acetylenes (Hansen et al. 2005 ). Reddy et al. synthesized 3,5-disubstituted isoxazoles (Route b, Fig. 2 ) using ptosylalcohol(TSA)-catalyzed reaction between propargylic alcohols and N-protected hydroxylamines followed by tetrabutylammonium fluoride (TBAF) mediated detosylation 5-endo-dig cyclization (Raji . Perez et al. reported an experimentally and environmentally benign one-pot three component process for the regioselective synthesis of 3,5-disubstituted isoxazoles (Route c, Fig. 2 ) from aldehydes and alkynes using choline chloride (ChCl): urea as a biorenewable deep eutectic solvent (DES). DES are an environmentally benign alternative to hazardous (Majewsky et al. 2014) 2 Sulfisoxazole Antibacterial (Genc et al. 2008) 3 Acetyl sulfisoxazole Antibacterial (Cronin et al. 2002) 4 Cycloserine Antitubercular, Antileprotic (Desjardins et al. 2016) 5 Acivicin Antitumour, Antileishmania (Conti et al. 2003) 6 Broxaterol Bronchodilatory agent (Giustina et al. 1995) 7 Oxacillin Antibacterial (Lainson et al. 2017) (Zhao et al. 2017a) 10 Zonisamide Anticonvulsant (Buoli et al. 2017) , Antiobesity (Shin et al. 2014) 11 Risperidone Antpsychotic (Schoretsanitis et al. 2017) 12 Valdecoxib COX-2 inhibitor (Bartzatt 2014) 13 Danazol Androgenic (McKinney et al. 2013) (organic) solvents that can be recycled (Pérez and Ramón 2015) . Jadhav et al. synthesized highly pure 3,5-disubstituted isoxazoles (Route d, Fig. 2 ) by converting aldoximes to nitrile oxides in the presence of Hydroxy (tosyloxy) iodobenzene (HTIB) and then reacting them with alkynes. The reagent HTIB is stable and can be handled without special care (Jadhav et al. 2013) . A highly regioselective method for the one-pot preparation of 3,5-disubstituted isoxazoles (Route e, Fig. 2 ) involves the reaction of terminal alkynes with n-BuLi and then aldehydes followed by the treatment with molecular iodine and subsequently with hydroxylamine (Harigae et al. 2014) . Huang et al. (2014) reported an environmentally benign procedure for the synthesis of 3-alkyl-5-aryl isoxazoles (Route f, Fig. 2 ) under ultrasound radiation without using any catalyst. This method has advantages of easier work-up, mild reaction condition, high yields and shorter reaction time. Trogu et al. (2012) discovered a faster and efficient method for preparation of 3,5-disubstituted isoxazoles (Route g, Fig. 2 ) by base catalyzed condensation reactions of nitroacetic esters with dipolarophiles in the presence of water instead of chloroform.

Mohammed and coworkers synthesized isoxazoles (Route h, Fig. 2 ) using 1, 8-diazabicyclo[5.4 .0]undec-7-ene (DBU) as a reagent which promotes the 1,3-dipolar addition of nitrile oxides with alkynes without the use of metal (Mohammed et al. 2015) . Kesornpun et al. performed cycloaddition of nitrile oxides with alkynes in aqueous solutions under acidic conditions rather than under the conventional basic conditions (Kesornpun et al. 2016) . 5arylisoxazole derivatives (Route i, Fig. 2 ) can be synthesized using an environmentally benign procedure via the reaction of 3-(dimethylamino)-1-arylprop-2-en-1-ones with hydroxylamine hydrochloride in the aqueous medium without using any catalyst (Dou et al. 2013 ). Valizadeh et al. introduced an environment-friendly synthesis for 3,5disubstituted isoxazoles (Route j, Fig. 2 ) using ionic liquids (IL). A typical reaction of β-diketone with hydroxylamine was carried out in the IL, butylmethylimidazolium salts ([BMIM]X) to form isoxazoles in excellent yields (Valizadeh et al. 2009 ). The IL was recovered and recycled successfully.

Various methods have been reported to prepare isoxazoles with a variety of substituents at 3, 4, and 5 positions. Denmark and Kallemeyn (2005) first synthesized isoxazolylsilanols by [3+2] cycloaddition reaction between alkynyldimethylsilyl ethers and aryl and alkyl nitrile oxides (Route a, Fig. 3) . The cross-coupling reaction of these heterocyclic silanols with a variety of aryl iodides leads to the formation of a variety of 3,4,5-trisubstituted isoxazoles. Gayon et al. (2011) synthesized trisubstituted isoxazoles using an uninterrupted four-step sequence method from readily available propargylic alcohols using sequentially iron and palladium catalyzed systems (Route b, Fig. 3 ).

The overall yields of this method were high, and it emerged as a time-saving procedure.

Recently, Li et al. (2017) used syringe pump infusion for the synthesis of polysubstituted isoxazoles (Route c, Fig. 3 Fig. 2 Routes for the synthesis of 3,5-disubstituted isoxazoles using a copper nitrate mediated synthesis from two different alkynes with high chemo-and regioselectivity. Substituted isoxazoles (Route d, Fig. 3 ) can be obtained from the cyclopropyl oximes (Wang et al. 2008 ) via ring-opening and intramolecular nucleophilic vinylic substitution reaction in the presence of POCl 3 /CH 2 Cl 2 . Willy et al. (2008) synthesized 3,4,5-substituted isoxazoles (Route e, Fig. 3 ) by cycloaddition reaction between in situ generated nitrile oxide and alkynones in the presence of triethylamine using dielectric heating for 30 min. The primary activated nitro compounds condensed with alkenes to give isoxazolines and with alkynes to give isoxazoles (Route f, Fig. 3 ) in chloroform in the presence of 1,4-diazabicyclo[2.2.2]octane or other suitable N-bases via 1,3-dipolar cycloaddition (Machetti et al. 2007) .

Different methods have been reported for the synthesis of aminoisoxazoles. Treatment of β-ketonitriles with hydroxylamine in aqueous ethanol (Route a, Fig. 4) gives 3-aminoisoxazoles (Elnagdi et al. 1975) . One-pot three-component coupling of β-oxo dithioesters, amines and hydroxylamine in ethanol at reflux affords 5-substituted 3-aminoisoxazoles (Route b, Fig. 4 ) via an in situ generated β-oxo thioamide intermediate (Samai et al. 2013) . 4-aminoalkylisoxazol-3-ones can be obtained from 3-allyllactams (bielectrophiles) in high yields (Nenajdenko et al. 2005) . During the course of the reaction, closure of one heterocycle is accompanied by the opening of the other (Route c, Fig. 4) .

3-aminocrotononitrile reacts with hydroxylamine hydrochloride (Route d, Fig. 4 ) to give 5-amino-3methylisoxazole (Abushanab et al.. 1973) . The [2+3] cycloaddition reaction of nitrile oxides with captodative olefins or methyl crotonate derivatives is regioselective (Route e, Fig. 4 ) and leads to the formation of the 5substituted amino-isoxazole or the 4-substituted methoxycarbonyl-isoxazole derivatives, respectively (Lasri et al. 2008) . The [4+1] cycloaddition reaction of isocyanides with α-haloketone oxime (Route f, Fig. 4 ) in the presence of Route a

Route c

Route e Route f Fig. 3 Routes for the synthesis of 3,4,5-trisubstituted isoxazoles sodium carbonate yields 5-substituted aminoisoxazoles (Buron et al. 1997) . While treatment of α-chloro oximes with lithiated nitriles, produced a variety of 5-aminoisoxazoles (Route g, Fig. 4) with alkyl functionality at 4-position (Bourbeau and Rider 2006) . Liu et al. (2009) Aryl 1,3-diketoesters reacts hydroxylamine hydrochloride under different pH conditions. Acid conditions gave 3,5-isoxazole esters (Route a, Fig. 5 ) principally whereas reactions under neutral and basic conditions led to different 4,5 and 2,3-dihydro-hydroxy-isoxazoles, respectively (Andrzejak et al. 2010 ). Heating of 2-formyl azirines for 24 h in toluene at 200°C (Route b, Fig. 5 ) affords isoxazole (Brahma and Ray 2008) . 3-substituted isoxazoles-4-carbaldehyde (Route c, Fig. 5 ) can be prepared by condensation reaction of nitroalkanes with 3-oxetanone (Burkhard et al. 2011). Martins et al. (2000) reported the synthesis of 5-carboxyisoxazoles (Route d, Fig. 5 ) from the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones with hydroxylamine in a hydrochloric acid or sulphuric acid medium.

4H-isoxazol-5-ones were synthesized by one-pot threecomponent condensation of aryl aldehydes, hydroxylamine hydrochloride and ketoesters using potassium phthalimide

Route a

Route e Route f Fig. 5 Routes for the synthesis of miscellaneous isoxazoles (Kiyani and Ghorbani 2013d) , sodium ascorbate (Kiyani 2013) , sodium tetraborate (Kiyani and Ghorbani 2013b) , sodium azide (Kiyani and Ghorbani 2013c) , sodium citrate (Kiyani and Ghorbani 2013a) , sodium saccharin (Kiyani and Ghorbani 2013e) , N-bromosuccinimide or boric acid as a catalyst in aqueous medium at room temperature (Route e, Fig.  5 ). Later Chavan et al. (2015) synthesized 4H-isoxazol-5ones efficiently by one-pot uncatalyzed reaction of hydroxylamine hydrochloride, ketoesters and aromatic aldehydes substituted with electron donating group in the aqueous medium. Ji et al. (2006) 

Owing to the diverse and potential pharmacological activities of the isoxazole ring, many researchers across the globe are engaged in the development of pharmacologically Analgesic and anti-inflammatory activity Rajanarendar et al. (2015) synthesized some 6-methyl isoxazolo [5,4-d] isoxazol-3-yl aryl methanones, assessed them for molecular properties prediction, drug-likeness, lipophilicity and solubility parameters, evaluated for in vitro COX inhibitory activity and screened for anti-inflammatory activity using carrageenan induced paw edema method. The compounds with chloro or bromo substitutions on phenyl ring (1; Fig. 7 ) exhibited significant antiinflammatory activity and were more selective towards COX-2 enzyme. Habeeb et al. (2001) reported the synthesis of 4,5-diphenyl-4-isoxazolines possessing a variety of substituents at the para position of one of the phenyl ring and evaluated for analgesic and selective COX-2 antiinflammatory activity. The compounds having C-3 Me substituent on central isoxazoline ring were potent analgesics, as well as selective towards COX-2. 4,5-diphenyl-5-(4-methylsulfonylphenyl)-4-phenyl-4-isoxazoline and screened for anti-inflammatory activity. Among these, the compound 2 (Fig. 7) having a sulfonylmethyl group at the para position of phenyl ring was most potent analgesic, as well as anti-inflammatory agent. Molecular modeling studies on 2 showed that the S atom of sulfonylmethyl and the C-3 Me group was crucial for selective inhibition of COX-2. Perrone et al. (2016) synthesized a new series of isoxazole and evaluated them for their COX inhibitory activity and selectivity. Compound 3 (Fig. 7) was found to be a sub-micromolar selective COX-2 inhibitor (IC 50 0.95 µM).

Some indolyl-isoxazoles (4; Fig. 7 ) were synthesized by Panda et al. and evaluated for acute anti-inflammatory activity using carrageenan-induced rat paw edema method. All the compounds exhibited good anti-inflammatory activity ranging from 36.6 to 73.7% reduction in edema (Panda et al. 2009 ). Another series of indole derivatives bearing isoxazoline moiety were synthesized by Amir et al. (2010) and tested in vivo for their anti-inflammatory activity by carrageenan-induced rat paw edema method. From these studies compound 5 (Fig. 7) showed maximum antiinflammatory activity along with a maximum reduction in ulcerogenic activity and lipid peroxidation. Karthikeyan et al. (2009) reported the synthesis of a series of pyrazolyl isoxazolines 6 and isoxazoles 7 (Fig. 7) using 1,3-dipolar cycloaddition of pyrazole derived nitrile oxides with various dipolarophiles. The synthesized compounds were evaluated for antinociceptive activity. All the compounds displayed efficacy comparable to standard drugs pentazocine and aspirin.

Chemical-cooling agents like menthol induce analgesia by activating TRPM8 channels that act as a Ca 2+ -permeable ligand-gated cation channel. Some aminoisoxazole-based derivatives synthesized by Ostacolo et al. (2013) were able to modulate TRPM8 that can be used for cold-evoked analgesia. The ability of the compounds to act as TRPM8 agonists was studied using [Ca 2+ ]-imaging experiments in sensory neurons in vitro, and an in vivo model of cold allodynia. Some of the compounds were up to 200-fold more potent than menthol, but none of them showed improved efficacy. The compound 8 (Fig. 7) was most promising. TRPV1 channels are Ca 2+ -permeable nonselective cation channel expressed in primary afferent neurons and are the integrator of nociceptive responses to both chemical and noxious stimuli. After the HTS, Palin et al. (2011) synthesized an isoxazole-3-carboxamide series and evaluated them for their ability to modulate TRPV1 channel. Substitution of isoxazole-3-carboxamide with 1S, 3R-3-aminocyclohexanol motif (compounds 9 and 10; Fig.  7 ) aided both potency and solubility. These compounds were further progressed to animal studies, where both the compounds attenuated the acute inflammatory response in the rat complete Freund's adjuvant assay.

A series of 4,5-diaryloisoxazol-3-carboxylic acids was synthesized by Banoglu et al. (2016) as leukotriene biosynthesis inhibitors targeting FLAP. Leukotrienes have important roles in various inflammatory diseases. In the very first step of leukotriene biosynthesis, there is an involvement of FLAP. Compounds 11a and 11b (Fig. 7 ) emerged as potent anti-inflammatory agents possessing potent inhibitory activity against cellular 5-Lipoxygenase product synthesis with IC 50 of 0.24 µM each. Silva et al. (2002) synthesized isoxazole derivatives as nAChR ligands for the development of analgesics. nAChR has gained much attention due to beneficial effects of nicotine in CNS disorders such as Alzheimer's disease, Parkinson's disease, and pain reflexes. Compound 12 (Fig. 7) displayed the best analgesic profile in the series. Peifer et al. (2009) synthesized 3,4-diaryl isoxazoles as a dual inhibitor of p38α MAP kinase and CK1δ. Compounds 13 and 14 ( Fig. 7) were found to be highly potent dual inhibitors of p38α and CK1δ. p38α MAP kinase plays a major role in signal transduction of severe inflammatory diseases like rheumatoid arthritis, asthma and autoimmune disorders (Peifer et al. 2006 ). Laufer et al. (2006) synthesized 3,4 and 4,5-disubstituted and 3,4,5-trisubstituted isoxazoles which were tested in an in vitro ELISA of isolated p38 MAP kinase and for inhibitory potency against cytP450 to develop agents for the treatment of rheumatoid and inflammatory diseases. The pyridinyl isoxazole (15; Fig. 7 ) displayed significant suppression of cytokine release, low affinity towards cytP450 and potent inhibitory activity towards isolated p38 MAP kinase. Antitumor/anticancer activity Vitale et al. (2014) designed and synthesized new isoxazoles taking [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole], a highly selective COX-1 inhibitor (Vitale et al. 2013 ) as a lead. COX-1 inhibition is considered as a promising therapeutic strategy for cancer and neuro-inflammation-derived neurodegenerative diseases. All the compounds were evaluated for their in vitro COX inhibitory activity and selectivity. The substitution of methyl in the lead compound with an amino group (16; Fig. 8 ) improved the COX-1 selectivity and inhibitory activity. Instead low or no activity was observed for its N,N-dialkyl and N,N-diacetyl derivatives. The inhibitory activity of compound 16 (Fig. 8 ) was also assessed in ovarian cancer cell line (OVCAR-3) where it was found to be 20-fold more potent than the lead compound. Shaw et al. (2012) synthesized N-phenyl-5carboxamidyl isoxazoles and screened for their cytotoxic activity against colon 38 and CT-26 mouse colon tumor cells. The most active and solid-tumor compound 17 ( Fig. 8 ) (IC 50 2.5 µg/mL) significantly downregulated the expression of phosphorylated-STAT3, a novel target for chemotherapeutic drugs, in both human and mouse colon cancer cells. Tzanetou et al. (2014) synthesized tetraloneisoxazole fused compounds and evaluated in four different cell lines: two endothelial cell lines (HMEC-1 and MBEC) and two tumor cell lines [human cervical carcinoma (HeLa) and human breast carcinoma (MCF-7) cells. Compound 18 (Fig. 8 ) exhibited promising cytostatic activity, demethylation of which led to 10-fold less active compound.

Over-expression of FLT3 plays a critical role in development and progress of acute myeloid leukemia. Xu et al. (2015) designed and synthesized a series of novel N-(5-(tert-butyl)isoxazol-3-yl)-Nʹ-phenylurea derivatives as FLT 3 inhibitors. Among the synthesized compounds, compound 19 (Fig. 8 ) inhibited the phosphorylation of FLT3 and led to complete tumor regression in the MV4-11 xenograft model. Compound 19 (Fig. 8 ) also displayed acceptable aqueous solubility, desirable pharmacokinetic properties and high cytotoxic selectivity against MV4-11 cells. SAR studies revealed that an electron-rich fused ring (R) at the phenyl was beneficial for the antiproliferative activity. Im et al. (2015) synthesized a series of 4arylamido 3-methylisoxazoles and evaluated them for antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Most of the compounds displayed selective antiproliferative activity toward the U937 cell line, and the activities were better than the reference drug Sorafenib while weak cytotoxic activities against human normal cell line and A375P. The most potent inhibitor 20 (Fig. 8 ) was found to be a potent inhibitor of FMS kinase too with an IC 50 of 9.95 nM. The FMS kinase inhibitors have great potential in the treatment of bone osteolysis and inflammation, as well as cancers promoted by macrophages.

Sambasiva synthesized 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives and screened against four human cancer cell lines (A549, COLO 205, MDA-MB 231 and PC-3). Compound 21 (Fig. 8) showed potent cytotoxicity against all the tested cell lines at IC 50 < 12 µM. The SAR revealed that fluorine or trifluoromethyl group at the fourth position of phenyl in isoxazole ring promotes the cytotoxicity. Ratnakar prepared isoxazole functionalized chromene derivatives (22; Fig. 8 ) and screened against four human cancer cell lines namely A549-Lung Cancer (CCL-185), MCF7-Breast cancer (HTB-22), DU145-Prostate cancer (HTB-81), HeLa-Cervical cancer (CCL-2) using 5-Fluorouracil as a positive control by MTT assay. All the compounds displayed poor to moderate activity.

Shakeel-u-Rehman et al.

(2014) linked 6hydroxycoumarins to isoxazole and screened for their cytotoxic activity against five different human cancer cell lines namely prostate (PC-3), colon , leukemia (HL-60) and lung (A-549). The ortho substituted isoxazole derivatives of 6-hydroxy coumarin (23; Fig. 8 ) emerged as effective cytotoxic agents against PC-3 cancer cell line. Rajanarendar et al. (2015) synthesized a series of novel isoxazolo[5ʹ,4ʹ:5,6]pyrido[2,3-b]indoles and evaluated against three human cancer cell lines Hela, MCF-7 and NCI-H460 (lung cancer) according to MTT assay method using Cisplatin as a reference drug. Compounds 24 and 25 (Fig. 8 ) displayed potent anticancer activity comparable to reference drug towards all the tested cancer cell lines. Rest of the compounds exhibited moderate to good anticancer activity with low selectivity.

Isoxazoles linked 2-phenylbenzothiazole 26 (Fig. 8) , synthesized by Kumbhare et al. (2012) , displayed significant anticancer activity against MCF-7 cells (IC 50 26-43 µM), A549 cells (human lung adenocarcinoma; IC 50 11-24 µM) and Colo-205 cells (human colon cancer; IC 50 11-21 µM) and possessed the ability to cause apoptosis. Özkay et al. (2013) synthesized some isoxazole-(benz)azole derivatives and evaluated them for cytotoxic effects on HT-29 (colon carcinoma) and C-6 (melanoma) cell lines using MTT assay. The compounds which displayed significant cytotoxicity were selected and then analyzed for their inhibitory activity on DNA synthesis of carcinogenic cells. The compounds 27a and 27b (Fig. 8) showed potent cytotoxic activity against both cancer cell lines and displayed significant inhibitory activity on DNA synthesis of carcinogenic cells.

Hsp90 is overexpressed in a number of human cancers that makes it a potential target for cancer treatment. Chen et al. (2014) synthesized a series of small molecules with 4,5-diarylisoxazole scaffold and evaluated them for Hsp90 inhibitory activity. In this series, compound 28 (Fig. 8) showed high affinity for Hsp90 and strongly inhibited it at both molecular and cellular level. Further in vivo studies showed that compound 28 (Fig. 8 ) strongly suppresses the tumor growth of human glioblastoma xenograft model U-87MG and displayed good results in pharmacokinetic and safety experiments. Another series of 4,5-diaryl isoxazoles was synthesized by Zhang et al. (2017) by incorporating diversified amino acid derivatives with various lengths to the 3-amido motif. These compounds were evaluated for Hsp90 inhibitory activity and antiproliferative activity against H3122 human lung cancer and BT-474 breast cancer cells. Compound 29 (Fig. 8) bearing a terminal valine methyl ester and an ethylene glycol-containing linear linker displayed high Hsp90 binding potency (14 nM), as well as antiproliferative activity against the tested cell lines. Bargiotti et al. (2012) synthesized isoxazolo(aza)naphthoquinones and evaluated them for cytotoxic Hsp90 inhibitory activity in a series of human tumor cell lines. Most of the compounds mainly 3-pyridyl derivatives (30; Fig. 9 ) displayed high affinity and potent antiproliferative activity. Baruchello et al. (2014) reported Hsp90 and HDAC6 inhibitory activity of 4,5,6,7-tetrahydro-isoxazolo-[4,5-c] pyridine compounds and evaluated for antiproliferative activity. The N-5 substitution with a 2,4-resorcinol carboxamide appeared to be crucial for activity. Compound 31 (Fig. 9 ) with a long chain hydroxamic residue bound to C-3 amide portion inhibited both Hsp90 and HDAC6. Kamal et al. synthesized a series of 3,5-diaryl isoxazoline/isoxazole linked pyrrolo-benzodiazepine (Kamal et al. 2010 ) and 2,3dihydroquinazolinones (Kamal et al. 2011 ) and evaluated for their anticancer activity. From the former series, compound 32 (Fig. 9 ) exhibited G0/G1 arrest, activation of caspase-3 and finally apoptotic cell death. Compound 33 (Fig. 9 ) from the latter series showed the disruption of microtubules, as well as fragmentation of nuclei and emerged as an efficient cyclin B1 inhibitor, as well as a CDK1 inhibitor and this hybrid compound was effective against 18 human cancer cell lines. Liu et al. (2009) synthesized a series of cis-restricted 3,4diaryl-5-aminoisoxazoles and evaluated against five human cancer cell lines (human myeloid leukemia cells K562, human esophageal carcinoma cells ECA-109, human nonsmall lung cancer cells A549, human hepatocellular carcinoma cells SMMC-7721, and human prostate carcinoma cells PC-3). The tested compounds displayed more potent cytotoxic activity against leukemia cells K562 than other cell lines. However, the compounds 34 (Fig. 9 ) and its N,Ndiacetyl derivative (35; Fig. 9 ) exhibited potent in vitro cytotoxic activities with IC 50 values in the range of 0.04-12.00 µM against all tested cancer lines and inhibited tubulin polymerization similar to that of combretastatin A-4 (36; Fig. 9 ), a potent antitumor agent. Diana et al. (2010) synthesized a series of novel 2,5-bis (3ʹ-indolyl)furans and 3,5-bis(3ʹ-indolyl)isoxazoles and evaluated their antiproliferative activity in vitro against diverse human tumor cell lines. Among the isoxazoles, compound 37 ( Fig. 9 ) was found to be most active and showed high selectivity towards 29 cell lines. Simoni et al. (2001) synthesized retinoic acid receptor ligands with potent apoptotic activity. Retinoids play a major role in regulating the growth and differentiation of a wide variety of normal and malignant cell types. Compound 38 (Fig. 9 ) exhibited good affinity for the retinoid receptors. Moreover, its ability to act on K562 and HL60R cell lines suggested its important implications in the treatment of different leukemias. SIRT1/SIRT2 inhibitors have been found to possess antitumor activity. Mahajan et al. (2014) synthesized pyrazolone and isoxazol-5-one cambinol analogs and reported their sirtuin inhibitory activity with in vitro and in vivo antilymphoma activity. Among them, the isoxazole derivatives have emerged as selective SIRT 2 inhibitor displaying >15.4fold SIRT-2 selectivity. The SIRT-2 selective inhibitor 39 (Fig. 10 ) exhibited potent cytotoxicity in both lymphoma and epithelial cancer cell lines with IC 50 ranging from 3 to 7 µM. Panathur et al. (2015) synthesized a new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole. The molecules were screened for anticancer activity against three human cancer cell lines (MDA-MB-231, MCF-7, and HT-29). Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogs. The SIRT1 inhibition activity of two potent molecules (40a and 40b; Fig. 10 ) was investigated, and the SIRT1 IC 50 values were 35.25 and 37.36 µM, respectively. 3-amino-benzo[d]isoxazole based compounds were synthesized by Jiang et al. (2015) and evaluated for their tyrosine kinase c-Met inhibitory activity. This tyrosine kinase c-Met is a receptor for hepatocyte growth factor. Abnormality in this pathway leads to tumor growth, angiogenesis, and metastasis. Compound 41a and 41b ( Fig. 10 ) displayed most potent c-Met inhibitory activity both at enzymatic (IC 50 1.8 nM) and cellular (IC 50 0.18 nM) levels with high antiproliferative efficacy against EBC-1 (human lung squamous carcinoma) cell line. Chouaïb et al. (2016) synthesized 3,5-disubstituted isoxazoles from natural maslinic acid and oleanolic acids and evaluated them for anti-inflammatory and antiproliferative activity against murine mammary carcinoma cell line EMT-6 and human colorectal adenocarcinoma cell line SW480. Among all the derivatives, the compound 42 (Fig. 10) bearing a furfuryl ring at its isoxazole moiety was found to possess promoting anti-inflammatory and anticancer effects. Najafi et al. (2015) prepared triazole-isoxazole derivative and evaluated for their cytotoxic activity against two human breast cancer cell lines MCF-7 and T-47D. Compounds 43a and 43b (Fig. 10) were found to be effective in vitro anticancer agents. However, no compound showed significant activity against tested cancer cell lines. Pedada et al. (2016) synthesized a series of indolecontaining isoxazoles and evaluated them for sPLA 2 inhibitory activity. sPLA 2 inhibitors are used for the preventive and therapeutic treatment of inflammatory diseases including cancer. All the compounds showed significant in vitro and in vivo sPLA 2 inhibitory activity. It was observed that isoxazoles with an electron withdrawing group like-F, CF 3 on phenyl ring displayed excellent sPLA 2 inhibitory activities. In particular, compound 44 (Fig. 10) showed potent sPLA 2 inhibitory activity comparable to positive control ursolic acid and exhibited in vitro antiproliferative activity against MCF-7 breast and DU145 prostate cancer cell lines. Yang et al. (2017) synthesized pyridinyl-4,5-2H-isoxazole derivatives and evaluated them for their in vitro inhibitory activity against MCF-7 cell line. Only the compounds with hydrophobic groups on phenyl displayed potent biological activities. Compounds 45a and 45b (Fig. 10 ) displayed highest anti-tumor activity and were found to possess potent antiproliferative activity against Human hepatoma cell line (HepG2) and cervical cancer cell line (HeLa) also. Kalirajan et al. (2012) synthesized isoxazole substituted 9-anilinoacridine derivatives and evaluated them for in vitro antioxidant, as well as cytotoxic activity against Hep2 cell line. All the compounds possessed significant antioxidant activity and compound 46 (Fig. 10) displayed potent anticancer activity. Md Tohid et al. (2012) synthesized diarylisoxazoles containing an indole group either at 3position or 5-position of isoxazole core and evaluated for their pro-apoptotic antitumor activity. The indol-5-yl substituted compounds (47; Fig. 10) were the most active, as well as selective when tested for their in vitro growth inhibitory activity against Colo320 (colon) and Calu-3 (lung) human cancer cell lines. These compounds had little or no effect on normal cell line viability suggesting their selective pro-apoptotic antitumor effects.

RamaRao et al. (2011) synthesized 5-(heteroaryl)isoxazoles and evaluated for antibacterial activity against E. coli, S. aureus and P. aeruginosa. The isoxazoles substituted with 2thienyl (48; Fig. 11 ) or 5-bromo-2-thienyl moieties (49; Fig.  11 ) in the 5-position displayed significant activity. Gautam and Singh (2013) synthesized a series of 4,5-dihydro-5-(substitutedphenyl)-3-(thiophene-2-yl)isoxazole and were tested in vitro for their antibacterial activity against S. aureus, B. subtilis, E.coli and P. aeruginosa and their antifungal activity against A. niger and C. albicans using disc diffusion method. The compound 50 (Fig. 11 ) was found to be highly active against E.coli, P. aeruginosa and C. albicans which may be attributed to its increased lipid solubility due to the presence of chloride on the aromatic ring. The rest of the compounds were found to be moderate to highly active. Basha et al. (2015) synthesized some thiazolyl isoxazoles and studied their antibacterial activity against S. aureus, B. subtilis, K. pneumoniae and P. aeruginosa and their antifungal activity against A. niger and P. chrysogenum. Thiazolyl isoxazoles having phenyl ring (51; Fig. 11 ) substituted with chloro and nitro were found to be potential antibacterial agents against S. aureus and A. niger.

In (1,4-phenylene)bis(arylsulfonyl isoxazoles) series synthesized by Lavanya et al. (2014) , the compound substituted with chloro on the aromatic ring (52; Fig. 11 ) exhibited excellent antibacterial activity (38 mm at 100 µg/mL) against B. subtilis, while rest of the compounds inhibited the spore germination against P. chrysogenum and Fig. 11 ) improved the activity against Aspergillus spp., in particular. And the compounds having fluoro substituent at 2-position of aryl moiety displayed remarkable activity against Candida spp., C. neoformans, A. fumigatus and fluconazole resistant C. albicans strain and exhibited weak inhibition profiles for various isoforms of human cytP450 and excellent blood plasma stability.

The 2,3,5-substituted perhydropyrrolo[3,4-d]isoxazole-4,6-diones (54; Fig. 11 ) have been synthesized by Agirbas 2009) synthesized a series of novel 4-(5ʹ-substituted-aryl-4ʹ,5ʹ-dihydro-isoxazole-3ʹ-yl-amino)phenols (55; Fig. 11 ) and screened for in vitro antibacterial activity against S. aureus and S. typhi and antifungal activity against C. albicans and A. niger. Compound bearing 4-Cl phenyl substitution at 5position of isoxazole was found to be most potent antibacterial and antifungal agent of the series. Vaidya et al. (2007) synthesized a series of N-substituted-2-(benzo [d] isoxazol-3-ylmethyl)-1H-benzimidazoles and screened for antibacterial activity against S. typhimurium and S. aureus. Compounds exhibited good activity against S. typhimurium while poor activity against S. aureus except for compound 56 (Fig. 11 ) which was highly active even at 1 µg/mL. In another series, fused ring isoxazolinones displayed a wide range of antimicrobial activity. In particular, derivative 57 ( Fig. 11 ) bearing thiophene ring was most potent against B. subtilis and C. albicans (Mazimba et al. 2014) . Chundawat et al. (2014) synthesized some fluorinecontaining heterocycles incorporating benzofuran with dihydroisoxazoles (58; Fig. 11 ). The compounds were evaluated for their in vitro antibacterial activity against the Gram-positive bacteria S. aureus, B. subtilis, S. pneumoniae, S. pyogenes, the Gram-negative bacteria E. coli, P. aeruginosa, S. typhi and antifungal activity against the fungi C. albicans, A. niger, A. clavatus. All the compounds showed moderate to high activity against all tested bacterial strains and C. albicans. Weidner-Wells et al. (2004) synthesized a series of 5-substituted isoxazol-3-yl linked with oxazolidinone and screened for in vitro antimicrobial activity against susceptible and resistant Gram-positive organisms. Several analogs (59; Fig. 11 ) from this series were comparable to or more potent than linezolid in vitro and also exhibited in vivo activity in a lethal murine infection model but less than linezolid. Padmaja et al. (2009) synthesized some aminoiminoisoxazole derivatives by Michael condensation of 2-(1ʹ,2ʹdiaroylethyl)malononitrile and 2-(1,2-diarylsulfonylethyl) malononitrile with hydroxylamine hydrochloride. All the compounds possessed excellent antimicrobial activity against Gram-positive bacteria and good activity against Gram-negative bacteria with a maximum for the compound 60 ( Fig. 11) having chloro substituent in the aryl moiety. These compounds also exhibited high antioxidant property in both nitric oxide and DPPH methods. Siddiqui et al. (2013) synthesized an isoxazole derivative 61 (Fig. 12) and evaluated for in vitro antibacterial and antifungal activity. It was found to be highly active against P. aeruginosa and A. niger, moderately active against B. subtilis and E. coli and poorly active against S. aureus. Srinivas et al. (2009) synthesized a series of methylene-bis-4,6-diarylbenzo [d] isoxazoles and evaluated them against C. albicans, A. fumigatus, T. rubrum, and T. mentagrophytes. Compounds 62, 63, and 64 (Fig. 12) showed good activity against all the tested fungi that were almost equal to the standard Amphotericin B. The comparison of antifungal activity of dimeric compounds with monomeric compounds revealed that almost all the dimeric compounds showed enhanced activity than their monomeric analogs. Srinivas et al. (2010) synthesized an another series of methylene-bis-tetrahydro[1,3]thiazolo [4,5-c] isoxazole and evaluated for their antifungal activity against C. albicans, A. fumigatus, T. rubrum, and T. mentagrophytes and further for nematicidal activity against D. myceliophagus and C. elegans. The compound 65 (Fig. 12) showed good activity against all the tested fungi, as well as significant nematicidal activity. Liu et al. (2014) synthesized a series of 2-(5-methyl-3-(4-chloro/trifluoromethylphenyl)isoxazol-4yl)-5-arylamino-1,3,4-oxadiazoles and tested for in vitro antifungal activities against B. cinerea and R. cerealis by the mycelium growth rate method. All the compounds displayed moderate to high activities against B. cinerea whereas low activities against R. cerealis. Among them compounds 66a, 66b, and 66c (Fig. 12) showed high activities against B. cinerea with the EC 50 value less than 20 µg/mL. Brahmayya et al. (2013) synthesized some 5-aryl-4-methyl-3-yl-(imidazolidin-1-yl-methyl, 2-ylidene nitroimine) isoxazoles (67; Fig. 12 ) and tested them for fungicidal activity against R. oryzae, C. tropicum and A. niger. The compounds having halogen and methoxy groups emerged as good antifungals. Guo et al. (2015) synthesized 5-isoxazolyl substituted pyrimidine nucleosides and evaluated them for inhibitory activity on the growth of L. donovani. Aryl substituted isoxazole nucleosides (68; Fig. 12 ) showed stronger activity than alkyl substituted isoxazole nucleosides. And for aryl substituted isoxazole nucleosides, methyl and fluoro substituent at 4-position of the phenyl ring of the isoxazole moiety improved the antileishmanial activity. Mares et al. (2002) synthesized 3methyl-5-aminoisoxazole-4-thiocyanate (69; Fig. 12 ) and studied on the dermatophyte E. floccosum. The compound 69 (Fig. 12) strongly inhibited the growth of the fungus in vitro and altered the ultrastructural morphology of the fungus. Kachhadia et al. (2004) prepared a series of 1-[p-(3ʹ-chloro-2ʹ-benzo(b)thiophenoylamino)-phenyl]-5-aryl-isoxazoles and screened for their antitubercular activity. Compounds 70a, 70b, and 70c (Fig. 13 ) showed significant activity against MTB H 37 Rv. Patel et al. (2014) synthesized coumarin-based isoxazoles and evaluated for their antimycobacterial activity against MTB H 37 Rv using Lownstein-Jensen MIC method. Compound 71 (Fig. 13) bearing methoxy group exhibited good antimycobacterial activity with MIC of 62.5 µg/mL and 99% of inhibition while rest of the compounds showed MIC in the range of 100-1000 µg/mL. Changtam et al. (2010) synthesized isoxazole analogs of curcumin and evaluated for antimycobacterial activity. The presence of p-methoxy and phydroxy groups on aromatic ring enhanced the activity. Compound 72 (Fig. 13) with mono-O-methyl curcumin isoxazole (MIC 0.09 µg/mL) was found to be 1131-fold more active than curcumin and approximately 18 and 2-fold more active than standard drugs kanamycin and isoniazid, respectively. Compound 72 (Fig. 13 ) also displayed high activity against multidrug-resistant MTB clinical isolates .125 µg/mL). Joshi et al. (2016) synthesized pyrrolyl derivatives with isoxazole moiety and evaluated for activity against MTB. Compound 73 (Fig. 13 ) exhibited significant activity against H 37 Rv strain and found to be non-toxic when tested for mammalian cell toxicity using A549 cancer cell line. Naidu et al. (2014) synthesized a series of 3-(4-(substituted sulfonyl)piperazin-1-yl)benzo[d]isoxazole analogs and evaluated for their in vitro antitubercular activity against MTB H 37 Rv strain. All the compounds exhibited MIC between 3.125 and 50 µg/mL. Compound 74 (Fig. 13 ) emerged as the most promising candidate for the series by inhibiting 99% growth of MTB H 37 Rv strain at a concentration of 3.125 µg/mL and a selectivity of >130. Compound 75 (Fig. 13 ) was found to possess excellent activity and specificity against MTB H 37 Rv both intracellularly and extracellularly. The ester bio-isosteres of compound 75 were inactive as antitubercular agent suggesting that the ester may be acting as a prodrug. Yamuna et al. (2012) synthesized isoxazolo cyclohepta [b] indoles and screened for in vitro antimycobacterial against MTB H 37 Rv. The maximum activity was found in compound 76 (Fig. 13) having a chloro substituent in the cyclohepta[b]indole moiety. This compound was found to be non-mutagenic and therefore biologically safe for intake. Rakesh et al. (2009) synthesized 3,5-disubstituted isoxazoline esters and evaluated them for anti-tuberculosis activity. Substitution of isoxazoline C-5 position with piperazyl-urea (77a; Fig. 13 ) and piperazylcarbamate (77b; Fig. 13 ) improved anti-tubercular activity. However, replacement of ester group at C-3 position with bioisosteric groups led to complete loss of activity.

Due to the evolution of significant resistance toward antiviral drugs, the development of new drugs possessing potent antiviral activity is critical. Lee et al. (2009) synthesized some 5-isoxazol-5-yl-2ʹ-deoxyuridines (78; Fig.  14) and evaluated their activity against 12 different viruses, namely HSV-1, HSV-2, HIV-1, HIV-2, Encephalomyocarditis virus, Coxsackie B3, vesicular stomatitis, three different influenza viruses (Taiwan, Seoul and Panama) and two corona viruses. All the compounds (78; Fig. 14) exhibited antiviral activities against all the tested virus except HIV, influenza and corona viruses. While some compounds were more active than the reference drugs but they were less selective. Deng et al. (2009) synthesized a series of alkenyldiarylmethanes with a benzo[d]isoxazole ring in place of metabolically unstable methyl ester moiety and screened for anti-HIV activity. All the compounds were found to inhibit HIV-1 Reverse Transcriptase but the compound 79 (Fig. 14) was most promising and a good alternative to hydrolytically unstable methyl esters.

Patil and Bari (2013) synthesized isoxazolines incorporating indole and evaluated them for antidepressant activity by forced swim test in mice, and their locomotor activity was assessed using actophotometer. All the compounds showed significant antidepressant activity with no significant change in locomotor activity. Compounds 80a and 80b (Fig. 15 ) emerged as potent antidepressants from this series when compared with reference drugs imipramine and fluoxetine indicating that introduction of an appropriate heterocyclic ring can lead to potent antidepressants. Andrés et al. (2003) reported the synthesis of enantiomeric pairs of 7-amino-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole derivatives. Compound 81 (Fig. 15 ) proved to be the most potent α 2 -adrenoceptor blocker with potent serotonin (5-HT) reuptake inhibiting activity and thus acting as antidepressant agents. A further study (Andrés et al. 2007) showed that the compound 81 (Fig. 15 ) was more potent as 5-HT reuptake inhibitor than as α 2 -adrenoceptor blocker both after subcutaneous and oral administration.

The α4β2 nicotinic acetylcholine receptors (nAChRs) are an attractive target for the development of novel antidepressants. Liu et al. (2011) synthesized several isoxazole analogs of Sazetidine-A (82; Fig. 15 ) by replacing the metabolically unstable acetylene of Sazetidine-A with metabolically stable isoxazole ring. Sazetidine-A interacts with α4β2-nAChRs as a partial agonist and possesses favorable antidepressant profiles. The compound 83 (Fig.  15 ) displayed selectivity, as well as excellent antidepressant behavioral activity measured by the mouse forced-swim test. Zhang et al. (2016) synthesized some hybrid compounds by combining substituted isoxazolyl side chains with N-pyridyldiamines as selective partial agonists for α4β2-nAChRs. Compound 84 (Fig. 15 ) displayed high binding selectivity towards α4β2 over α3β4-nAChRs and significant antidepressant activity in the forced swim test. Yu et al. (2012) synthesized a series of 5-alkoxy isoxazole as nAChRs ligands. Most of the compounds displayed selectivity for rat α4β2 over α3β4-nAChRs. Among them, compound 85 (Fig. 15 ) was highly selective and displayed potent antidepressant-like activity. Olesen et al. (1998) synthesized a series of 3-((5-alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridine (86; Fig.  15 ) and evaluated for their affinity and selectivity for central nicotinic receptors. It was found that only the monoalkyl amino-substituted compounds had high affinity and selectivity for the central nicotinic receptors. The affinity increased with increasing the alkyl side chain length up to propyl. Evaluation of these compounds in cell lines expressing nicotinic receptor subtypes showed that the compounds had up to 10-fold higher affinity for α4β2 receptor than α3β2 receptor subtype. Kumar et al. (2017) synthesized a series of 3,4,5-trisubstituted isoxazoles incorporating furan and piperazine moiety and evaluated for their antidepressant activity by Porsolt's forced swimming test on albino mice and antianxiety activity by plus maze method. Compounds 87a and 87b (Fig. 15 ) displayed significant antidepressant, as well as anti-anxiety activity. The molecular modeling studies showed good binding interactions of these compounds with the MAO-A (Fig. 16) .

Enhancement of GABA transmission by inhibiting GABA uptake has been proved to be an effective treatment for convulsions. Falch et al. (1999) synthesized some novel 3hydroxy-4-amino-4,5,6,7-tetrahydro-1,3-benzisoxazole derivatives and screened for GABA inhibitory and anticonvulsant activity. In the series of compounds, (R)-enantiomer of 88 (Fig. 17) in which primary amino group was converted to a secondary amino group, showed potent GABA inhibitory activity and was 12 times more potent as glial GABA uptake inhibitor than of neuronal GABA uptake. However, substitution of N-methyl group with Nethyl group decreased the glial selectivity. Compound 88 potently protected Frings mice against audiogenic seizures when administered intracerebroventricularly. A series of osubstituted, m-substituted and p-substituted 4-phenyl-5-(4piperidyl)-3-isoxazolols was synthesized by Frølund et al. (2007) and evaluated for antagonistic activity against GABA A receptor, a potential target for the treatment of epilepsy, anxiety and sleep disorders. The m-phenyl substituted compounds (89a, 89b) and p-phenoxy (89c) substituted compounds (Fig. 17) displayed high affinity and antagonist potencies in the low nanomolecular range. Clausen et al. (2005) synthesized a series of lipophilic diaromatic derivatives of (R)-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol and evaluated pharmacologically in vitro and in vivo for anticonvulsant activity. The compounds were effective as GABA uptake inhibitors and anticonvulsants showing that these compounds can cross BBB. The compound 90 (Fig. 17 ) appeared to be potent at GABA transporter 1 and 2. synthesized a series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2,5-dione and screened through MES and scPTZ tests to find compounds affording protection against human generalized tonic-clonic seizures and generalized absence tonic-clonic seizures, respectively. Compound 91a and 91b (Fig. 17) were found to be most potent antiepileptogenic agents against MES and scPTZ tests, respectively.

Malik and Khan (2014) synthesized a series of (5-amino-3-substituted-1,2,4-triazin-6-yl)

(2-(6-halo-substituted benzo[d]isoxazol-3-yl)pyrrolidin-1-yl)methanone derivatives and evaluated their anticonvulsant activities by the MES test. Compound 92 (Fig. 17 ) was found to be most potent and had the binding affinity with sodium channels in vitro. Eddington et al. (2002) synthesized a series of enaminones derived isoxazoles 93 (Fig. 17 ) by condensation of 1,3-diketo esters with 3-and 5-amino isoxazoles that led to a series of potent anti-maximal electroshock analogs. Huang et al. (2015) synthesized a series of azacyclic compounds with 5-substituted isoxazoline groups and evaluated their mAChR agonistic potential. A tetrahydropyridine compound 94 (Fig. 18 ) substituted with 5-(2-pyrrolidin-1-yl)isoxazoline at 3-position exhibited potent and selective mAChR agonist activity. The compound 94 (Fig. 18 ) also possessed a disease-modifying role in Alzheimer's disease. Gutiérrez et al. (2013) synthesized some 3,5-disubstituted isoxazole derivatives, tested for their in vitro AChE inhibitory activity and performed their docking study. Compounds 95 and 96 (Fig. 18 ) emerged as potent AChE inhibitors. Anand and Singh (2012) synthesized pyrrolo-isoxazole benzoic acid derivatives as potential AChE for the management of Alzheimer's disease. All the derivatives displayed potent in vitro AChE inhibitory activity. Compound 97 (Fig. 18 ) was found to be most active which also ameliorated the scopolamine-induced amnesia in mice. JNK3 is exclusively found in the brain and play an important role in the brain to mediate neurodegeneration such as beta-amyloid processing and neuronal apoptosis in Alzheimer's disease. Compounds with JNK3 inhibitory activity and selectivity over p38 can be potential therapeutics for neurodegeneration disorders as p38 inhibition leads to serious toxic effects. He et al. (2014) developed isoxazoles (98; Fig. 18 ) with improved JNK3 selectivity over p38 to treat neurodegenerative disorders. Meleddu et al. (2017) synthesized a series of 3,5-diaryl-4,5-dihydroisoxazoles to find MAO-B selective inhibitors to act as neuroprotective agents. None of the compounds inhibited MAO-A and compound 99 (Fig. 18) with a 3,4-dichlorophenyl moiety at position-5 of the dihydroisoxazole ring was the most active on MAO-B.

Insecticidal activity Peng-fei et al. (2012) synthesized some novel phenyl substituted isoxazole carboxamides and evaluated for insecticidal activities against Mythimna separate (oriental armyworm). All the compounds showed moderate insecticidal activity, out of which compounds 100a and 100b (Fig. 19) showed comparatively higher activities. SAR studies revealed that a combination of both aliphatic and aromatic amide moieties could improve the insecticidal activity. Yu et al. (2009) prepared a series of 3-(arylthiomethyl)isoxazole-4,5-carboxamides (101; Fig. 19 ) and evaluated for insecticidal activity using high-throughput screening (HTS) against Spodoptera exigua (beet armyworm) and A. aegypti (yellow fever mosquito). The results confirmed that 3,4,5-trisubstituted isoxazoles present a bioactive scaffold that can be utilized to design novel insecticides. To identify potential selective and resistancebreaking mosquitocides against the African malaria vector Anopheles gambiae, Verma et al. (2015) investigated the AChE inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (102; Fig. 19 ), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (103; Fig. 19 ). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE.

Agonism of S1P 1 , in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. Watterson et al. (2016) synthesized a series of isoxazoles derived from isoxazole-3-carboxylic acids and isoxazole-5-carboxylic acids to develop selective S1P 1 selective agonists. Compound 104 (Fig. 20) was emerged as a lead compound with good efficacy when administered orally in a rat model of arthritis (ED 50 0.05 mg/Kg) and a mouse experimental autoimmune encephalomyelitis model of multiple sclerosis (ED 50 0.05 mg/Kg). EPACs are involved in regulating a wide variety of intracellular physiological and pathophysiological processes like T-cell mediated immunosuppression (Almahariq et al. 2015) . Ye et al. (2015) synthesized a series of 2-(isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide as EPAC antagonists. Compounds 105a and 105b (Fig. 20) have emerged as potential EPAC1 and EPAC2 inhibitors. The SAR studies revealed that further modifications at the 3positions, 4-positions, 5-positions of the phenyl scaffold and the 5-position of the isoxazole moiety might give more potent EPAC antagonists. Wagner et al. (2008) synthesized isoxazolo[4,5-d] pyrimidine and tested for their effects on immune response in the mouse model. Compound 106 (Fig.  20) emerged as a universal inhibitor of immune response while compound 107 (Fig. 20) selectively suppressed the humoral immune response.

Kafle and co-workers (Kafle et al. 2011; Kafle and Cho 2012) synthesized a series of isoxazolones to develop a potent inhibitor of PTP1B as an antiobesity and antihyperglycemic agent. PTP1B inhibition leads to prolongation of tyrosine phosphorylated stats of insulin and leptin receptors resulting in suppression of weight gain and augmentation of insulin sensitivity. Among them, compound 108 ( Fig. 21) was the most potent and selective inhibitor of PTP1B with an IC 50 of 2.3 µM and can be considered as a promising lead compound for the control of obesity and hyperglycemia. Kumar et al. (2009) synthesized 3,5-diaryl isoxazole derivatives and screened them for in vivo antihyperglycemic and lipid-lowering activity. Some of the synthesized compounds 109 (Fig. 21) showed promising antihyperglycemic activity with moderate lipid-lowering activity. These compounds did not show any significant activity in PPAR and DPP-4 assay but exhibited the promising PTP1B inhibitory activity which revealed their mode of action. Jadhav et al. (2012) synthesized a series of compounds containing 3-phenyl isoxazoles and evaluated them for DGAT1 which is a promising target enzyme for obesity due to its involvement in the rate determining step of triglyceride biosynthesis. Compound 110 (Fig. 21) with an in vivo triglyceride reduction of 90% and IC 50 of 64 nM emerged as a promising anti-obesity agent. Mokale et al. (2014) synthesized a series of 2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives and evaluated them for in vivo hypolipidemic activity by triton induced hyperlipidemia in rats. Most of the compounds had the ability to lower the elevated lipid levels, amongst which 111a; 111b, and 111c (Fig. 21) were found to be most active as compared to standard drug Fenofibrate. Further SAR studies revealed that isoxazole ring is important for hypolipidemic activity. FXR has been reported to have profound effects on plasma lipids in the animal model. Genin et al. (2015) discovered piperidinylisoxazole system as selective FXR agonist in vitro which showed robust lipid modulating properties lowering LDL and triglycerides while raising HDL in preclinical species and. The molecule LY2562175 (112; Fig. 21 ) is ultimately advanced to the clinical evaluation in humans due to its excellent lipid modulation profile in rodents, as well as acceptable pharmacokinetic properties. Dopamine transporter inhibitory activity Carroll et al. (2004) synthesized several 3β-(substituted phenyl)-2β-(3-substituted isoxazol-5-yl)tropanes and evaluated for their ability to inhibit radioligand binding at the monoamine (dopamine, serotonin and norepinephrine) transporters for the treatment of cocaine abuse. Most of the analogs were dopamine transporter selective, increase locomotor activity with slow onset and long duration of action. But the high dopamine transporter selective compound 113 (Fig. 22 ) surprisingly did not increase the locomotor activity that could be due to lack of brain penetration. Similarly, Jin et al. (2008) synthesized a series of 2β-[3ʹ-(substituted benzyl)isoxazol-5-yl]-and 2β-[3ʹ-methyl-4ʹ-(substituted phenyl) isoxazol-5-yl]-3β-(substituted phenyl)tropanes. These compounds were evaluated for affinities at monoamine (dopamine, serotonin and norepinephrine) transporters for the treatment of cocaine abuse. All the tested compounds were found to be relatively selective for dopamine transporter. The compounds of former series exhibited 3-fold to 25-fold higher affinities at dopamine transporter. Among them, compound 114 (Fig. 22 ) was most potent and dopamine transporter selective analog. Koufaki et al. (2014) synthesized a series of 3,5-disubstituted isoxazoles and evaluated their cytoprotective and antiageing properties in terms of stress resistance in human primary fibroblasts (in vitro model) and with the extended longevity of the nematode C. elegans (in vivo model).

Compound 115 (Fig. 23 ) bearing a phenolic group and a 6-OH chroman group was revealed to be a potent antioxidant and anti-ageing agent. Padmaja et al. (2011) discover neuroprotective agents with much lower cytotoxicity. The neuroprotective activity was evaluated against oxidative stress-induced death of neuronal H22 cells (mouse hippocampal cell line). The majority of them displayed high in vitro neuroprotective activity with EC 50 below 1 µM and lacked cytotoxicity. Badru et al. (2012) synthesized a series of pyrroloisoxazole derivatives via 1,3-dipolar cycloaddition of azomethine N-oxides with N-(α-naphthyl)maleimide. Compound 120 (Fig. 24 ) exhibited significant anti-stress activity in immobilization stress-induced increase in nonsocial behavior. Maurya et al. (2011) synthesized 3,5-disubstituted isoxazolines and evaluated their anti-stress potential under acute stress condition in relation to peripheral and biochemical changes. Some compounds 121 and 122 (Fig. 24 ) displayed protective effects against acute stress-induced elevation in gastric ulceration, adrenal hypertrophy, hyperglycemia, plasma creatine kinase activity, and corticosterone levels. Dallanoce et al. (2007) synthesized three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohol derivatives 123 (Fig. 25) and evaluated for their binding affinity at human β 1 -ARs, β 2 -ARs, and β 3 -ARs in membranes from Chinese hamster ovary cells stably transfected with the respective receptor subtype. The highest efficacy (70-90%) was observed at β 2 -ARs whereas all compounds behaved as partial agonists (30-60%) at the β 3 -subtype and the lowest (15-35%) was found at β 1 subtype. Shailaja et al. (2011) synthesized a series of 3,5-disubstituted-4,5-dihydroisoxazoles and 3,4,5-trisubstituted isoxazoles and evaluated for their action on isolated frog heart. All the test compounds moderately reduced the heart rate, cardiac output, and force of contraction and compounds 124 and 125 (Fig. 25) showed better inhibition of sodium exchange ion on isolated frog heart studies. Yamamoto et al. (2007) synthesized isoxazole derivatives and evaluated for LPA antagonistic activity to find potent drugs to treat liver fibrosis. Compound 126 (Fig. 25 ) exhibited high inhibitory activity at LPA receptor and was expected to be a potent drug candidate for the treatment of liver fibrosis. Wagner et al. (2004) synthesized 5-alkyl and 5-arylisoxazolo[4,5-d] pyrimidinones structurally similar to hypoxanthine and evaluated for anxiolytic activity. Compounds 127a and 127b (Fig. 25 ) displayed the approximately same anxiolytic activity as that of diazepam at the non-sedative dose. Altug et al. (2017) synthesized a series of sulfonamide based 5-amino isoxazole derivatives (128; Fig. 25 ) and screened for their CA inhibitory properties against four human isoforms: hCA I, hCA II, hCA IV, and hCA VII. All the compounds exhibited excellent inhibitory activity against the cytosolic isoform hCA II, an antiglaucoma drug target. Batra et al. (2002) utilized 3-substituted-phenyl-5isoxazole carboxaldehydes to generate isoxazole-based combinatorial libraries on solid phase through automation. All the compounds were evaluated for their antithrombotic activity in vivo. Compound 129 (Fig. 25 ) was found to be most potent with 90% protection against bleeding time. 

The present review demonstrates the synthesis and structural modifications of isoxazoles. Isoxazole is a versatile building block in many biologically active compounds, and its easy synthesis offers the structure activity studies of various substitutions on this pharmacophore as illustrated in Table 2 . This review is endeavoring to find potential future directions in the development of more potent and specific analogs of isoxazole-based compounds for the biological target. The information of the isoxazole based heterocycles illustrated in this review will not only update medicinal chemists with recent findings of biological activities of isoxazoles but also encourage them to use this promising scaffold for the design of novel molecules to identify many more biologically active isoxazoles for the benefit of humanity.

Synthetic studies in the lsoxazolo[4,5-b] pyrazine system

Synthesis and structure-antibacterial activity relationship investigation of isomeric 2,3,5-substituted perhydropyrrolo

Platinum-catalyzed cyclizations viacarbene intermediates: syntheses of complementary positional isomers of isoxazoles

Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression

Synthesis of isoxazole-containing sulfonamides with potent carbonic anhydrase II and VII inhibitory properties

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent antiinflammatory agents

Synthesis and evaluation of novel 4-[(3H,3aH,6aH)-3-phenyl)-4,6-dioxo-2-phenyldihydro-2H-pyrrolo [3,4-d]isoxazol-5(3H,6H,6aH)-yl]benzoic acid derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents

Tricyclic isoxazolines: Identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and α2-adrenoceptor antagonism

]isoxazoles, displaying combined 5-HT uptake inhibiting and α2-adrenoceptor antagonistic activities: a novel series of potential antidepressants

Synthesis of 2, 3 and 4, 5-Dihydro-hydroxy-isoxazoles and Isoxazoles Under Different pH Conditions

Synthesis and evaluation of hexahydropyrrolo[3,4-d]isoxazole-4,6-diones as anti-stress agents

Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenaseactivating protein (FLAP)

Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors

Drug analogs of COX-2 selective inhibitors lumiracoxib and valdecoxib derived from in silico search and optimization

-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

Synthesis and antimicrobial activity of thiazolyl pyrazoles and isoxazoles

Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents

A convenient synthesis of 4-alkyl-5-aminoisoxazoles

Synthesis of Azirines Containing Aldehyde Functionality and their Utilization as Synthetic Tools for Five Membered Oxazoles and Isoxazoles

Synthesis and fungicidal activity of novel 5-aryl-4-methyl-3yl (imidazolidin-1yl methyl, 2-ylidene nitro imine) isoxazoles

Facile one-pot synthesis of 5-substituted isoxazoles and pyrazoles via microwave-promoted intramolecular cyclization of γ-hydroxyalkynal oximes and hydrazones

The use of zonisamide for the treatment of psychiatric disorders: A Systematic Review

Cascade formation of isoxazoles: Facile base-mediated rearrangement of substituted oxetanes

A new straightforward formation of aminoisoxazoles from isocyanides

Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3β-(substituted phenyl)-2β-(3ʹ-substituted isoxazol-5-yl)tropanes

Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity

An efficient synthesis of 4-arylmethylidene-3-substituted-isoxazol-5(4h)-ones in aqueous medium

Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors

Isoxazole-A potent pharmacophore

Regiospecific synthesis, anti-inflammatory and anticancer evaluation of novel 3,5-disubstituted isoxazoles from the natural maslinic and oleanolic acids

Synthesis and in vitro antimicrobial evaluation of novel fluorine-containing 3-benzofuran-2-yl-5-phenyl-4,5-dihydro-1H-pyrazoles and 3-benzofuran-2-yl-5-phenyl-4,5-dihydro-isoxazoles

Selective inhibitors of GABA uptake: Synthesis and molecular pharmacology of 4-N-methylamino-4

Synthesis and biological evaluation of new amino acids structurally related to the antitumoragent acivicin

Structure-based classification of antibacterial activity

An alkynyliodide cycloaddition strategy for the construction of iodoisoxazoles

Novel chiral isoxazole derivatives: Synthesis and pharmacological characterization at human β-adrenergic receptor subtypes

Synthesis of alkenyldiarylmethanes (ADAMs) containing benzo[d]isoxazole and oxazolidin-2-one rings, a new series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Synthesis of 3,4,5-trisubstituted isoxazoles via sequential [3 + 2] cycloaddition/silicon-based cross-coupling reactions

Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in Dcycloserine resistance

Synthesis and antitumor activity of 2,5-bis(3′-indolyl)-furans and 3,5-bis(3′-indolyl)-isoxazoles, nortopsentin analogues

Clean and efficient synthesis of isoxazole derivatives in aqueous media

Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives

Reaction of 2-Arylhydrazono-3-oxonitriles with Hydroxylamine. Synthesis of 3-Amino-4-arylazoisoxazoles

Selective inhibitors of glial gaba uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues

4-Aryl-5-(4-piperidyl)-3-isoxazolol GABA A antagonists: synthesis, pharmacology, and structure−activity relationships

Synthesis and antimicrobial activity of some isoxazole derivatives of thiophene

Transition-metal-catalyzed uninterrupted four-step sequence to access trisubstituted isoxazoles

An overview on some benzimidazole and sulfonamide derivatives with anti-microbial activity

Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H -indole-3-carboxylic Acid: A Novel FXR Agonist for the treatment of dyslipidemia

Effect of two beta 2-agonist drugs, salbutamol and broxaterol, on the growth hormone response to exercise in adult patients with asthmatic bronchitis

Leflunomide in monotherapy of rheumatoid arthritis: meta-analysis of randomized trials

Synthesis of 5-isoxazol-3-yl-pyrimidine nucleosides as potential antileishmanial agents

Isoxazoles: synthesis, evaluation and bioinformatic design as acetylcholinesterase inhibitors

Design and synthesis of 4,5-diphenyl-4-isoxazolines: Novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity

One-Pot Copper(I)-Catalyzed Synthesis of 3,5-Disubstituted Isoxazoles

Preparation of 3,5-disubstituted pyrazoles and isoxazoles from terminal alkynes, aldehydes, hydrazines, and hydroxylamine

Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

Recent developments in the synthesis and reactivity of isoxazoles: metal catalysis and beyond

Synthesis and biological evaluation of isoxazoline derivatives as potent M1 muscarinic acetylcholine receptor agonists

An efficient synthesis of isoxazoles and pyrazoles under ultrasound irradiation

Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors

Synthesis and biological evaluation of isoxazole, oxazole, and oxadiazole containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

A facile one-pot synthesis of 3,5-disubstituted isoxazole derivatives using hydroxy (tosyloxy) iodobenzene

Direct synthesis of 4-fluoroisoxazoles through gold-catalyzed cascade cyclization-fluorination of 2-alkynone O-methyl oximes

The dipolar route to naphtho [2,1-c] isoxazoles from the Baylis-Hillman adducts of 2-alkynylbenzaldehydes

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

Synthesis and monoamine transporter binding properties of 2beta-[3'-(substituted benzyl)isoxazol-5-yl]-and 2beta-[3'-methyl-4'-(substituted phenyl)isoxazol-5-yl]-3beta-(substituted phenyl)tropanes

Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties

Synthesis of isoxazoles and cyanopyridines bearing benzo (b) thiophene nucleus as potential antitubercular and antimicrobial agents

Isoxazol-5(4H) one derivatives as PTP1B inhibitors showing an anti-obesity effect

Isoxazolone derivatives as potent inhibitors of PTP1B

Docking studies, synthesis, characterization and evaluation of their antioxidant and cytotoxic activities of some novel isoxazole-substituted 9-anilinoacridine derivatives

Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents

Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents

Synthesis and antinociceptive activity of pyrazolyl isoxazolines and pyrazolyl isoxazoles

Corrigendum: water-assisted nitrile oxide cycloadditions: synthesis of isoxazoles and stereoselective syntheses of isoxazolines and 1,2,4-oxadiazoles

Synthesis of 4-arylmethylidene-3-methyl-isoxazol-5 (4H)-ones via a three-component reaction in water catalyzed by sodium ascorbate

Synthesis of arylmethylidene-isoxazole-5(4H)-ones in water catalyzed by sodium citrate

Synthesis of arylmethylidene-isoxazol-5(4H)-ones via three-component reaction in water catalyzed by sodium tetraborate

Synthesis of 4-arylmethyleneisoxazole-5-one derivatives via a one-pot three-component reaction in water catalyzed by sodium azide

Potassium phthalimide as efficient basic organocatalyst for the synthesis of 3A4-disubstituted isoxazol-5a4Ha-ones in aqueous medium

Sodium saccharin as a clean and efficient catalyst for the synthesis of 4-arylidene-3-methylisoxazol-5 (4H)-ones via one-pot three-component reaction in aqueous medium

Boric acid-catalyzed multi-component reaction for efficient synthesis of 4H-isoxazol-5-ones in aqueous medium

Nbromosuccinimide(NBS)-promoted, three-component synthesis of α,β-unsaturated isoxazol-5(4H)-ones, and spectroscopic investigation and computational study of 3-methyl-4-(thiophen-2-ylmethylene)isoxazol-5(4H)-one

Microwave-assisted synthesis of 3,5-disubstituted isoxazoles and evaluation of their anti-ageing activity

Isoxazole substituted chromans against oxidative stressinduced neuronal damage

Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents

Design, synthesis and pharmacological evaluation of some novel derivatives of 1-{[3-(furan-2-yl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]methyl}-4-methyl piperazine

Synthesis and biological evaluation of novel triazoles and isoxazoles linked 2-phenyl benzothiazole as potential anticancer agents

Synthetic antibacterial peptide exhibits synergy with Oxacillin against MRSA

Efficient regioselective synthesis of 4-and 5-substituted isoxazoles under thermal and microwave conditions

Substituted isoxazoles as potent inhibitors of p38 MAP kinase

Synthesis and antimicrobial activity of (1,4-phenylene)bis(arylsulfonylpyrazoles and isoxazoles)

Synthesis of 5-isoxazol-5-yl-2′-deoxyuridines exhibiting antiviral activity against HSV and several RNA viruses

Fungitoxicity of acid and alkali hydrolysis products of Drazoxolon and related arylhydrazonoisoxazolones

Copper nitrate-mediated chemo-and regioselective annulation from two different alkynes: a direct route to isoxazoles

Synthesis and biological evaluation of novel 2-(substituted isoxazol-4-yl)-5-arylamino-1,3,4-oxadiazoles

Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression

Synthesis and biological evaluation of 3,4-diaryl-5-aminoisoxazole derivatives

Isoxazoles and isoxazolines by 1,3-dipolar cycloaddition: base-catalysed condensation of primary nitro compounds with dipolarophiles

Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors

Antibacterial activity of sulfamethoxazole transformation products (TPs): general relevance for sulfonamide TPs modified at the para position

Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2,5-dione derivatives as anticonvulsants

Design and synthesis of (5-amino-1, 2, 4-triazin-6-yl)(2-(benzo[d] isoxazol-3-yl) pyrrolidin-1-yl)methanone derivatives as sodium channel blocker and anticonvulsant agents

Cloxacillin induced agranulocytosis: a rare adverse event of a commonly used antibiotic

A review on synthesis and pharmacological diversity of isoxazoles & pyrazolines

Synthesis and antituberculosis activity of novel mefloquineisoxazole carboxylic esters as prodrugs

Mannan changes induced by 3-methyl-5-aminoisoxazole-4-thiocyanate, a new azole derivative, on Epidermophyton floccosum

A convenient one-pot synthesis of 5-carboxyisoxazoles: Trichloromethyl group as a carboxyl group precursor

Synthesis of novel isoxazolines via 1,3-dipolar cycloaddition and evaluation of anti-stress activity

Antioxidant and antimicrobial studies on fused-ring pyrazolones and isoxazolones

The metabolism of anabolic-androgenic steroids in the greyhound

Synthesis and evaluation of indole-containing 3,5-diarylisoxazoles as potential pro-apoptotic antitumour agents

Through scaffold modification to 3,5-diaryl-4,5-dihydroisoxazoles: new potent and selective inhibitors of monoamine oxidase B

Metal-free DBU promoted regioselective synthesis of isoxazoles and isoxazolines

Synthesis and in-vivo hypolipidemic activity of some novel substituted phenyl isoxazol phenoxy acetic acid derivatives

Design, synthesis and antimycobacterial activity of various 3-(4-(substituted sulfonyl)piperazin-1-yl)benzo[d]isoxazole derivatives

Synthesis and in vitro cytotoxic activity of novel triazoleisoxazole derivatives

Synthesis of 5-substituted 4-aminoalkylpyrazol-3-ones (isoxazol-3-ones) from 3-acyllactams

Ruthenium-catalyzed cycloadditions of 1-haloalkynes with nitrile oxides and organic azides: synthesis of 4-haloisoxazoles and 5-halotriazoles

5-Alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridines: a novel class of central nicotinic receptor ligands

Isoxazole derivatives as potent transient receptor potential melastatin type 8 (TRPM8) agonists

Antimicrobial and anticancer effects of some 2-(substitutedsulfanyl)-N-(5-methyl-isoxazol-3-yl)acetamide derivatives

Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives

Synthesis and antioxidant activity of oxazolyl/thiazolylsulfonylmethyl pyrazoles and isoxazoles

Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists

New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies

Synthesis, antiinflammatory and antibacterial activity of novel indolyl-isoxazoles

Synthesis and biological evaluation of coumarin based isoxazoles, pyrimidinthiones and pyrimidin-2-ones

Synthesis and Antidepressant activity of some new 5-(1H-indol-3-yl)-3-(substituted aryl)-4,5-dihydroisoxazoline derivatives

Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as antiinflammatory and anticancer agents

4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38α mitogen activated protein kinase and casein kinase 1δ

New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase

Design, synthesis and insecticidal activities of novel phenyl substituted isoxazolecarboxamides

Synthesis of 3,5-disubstituted isoxazoles and isoxazolines in deep eutectic solvents

Isoxazole-based-scaffold inhibitors targeting cyclooxygenases (COXs)

Environmentally benign synthesis, molecular properties prediction and anti-inflammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones via vinylogous Henry nitroaldol adducts as synthons

One-pot synthesis of 3,5-disubstituted isoxazoles from propargylic alcohols through propargylic N -hydroxylamines

Synthesis, optimization and structure-activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis agents

Synthesis and antibacterial activity of novel 5-(heteroaryl) isoxazole Derivatives

Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2H-Chromene derivatives and their cytotoxic activity

Synthesis, analgesic and antimicrobial activities of some novel isoxazole derivatives

One-Pot Three-component heteroannulation of β-oxo dithioesters, amines and hydroxylamine: regioselective, facile and straightforward entry to 5-substituted 3-aminoisoxazoles

Synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives and their cytotoxic activity

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone

The reappearance of a monamine oxidase inhibitor (isocarboxazid)

Synthesis of novel 3, 5-disubstituted-4,5-dihydroisoxazoles and 3,4,5-trisubstituted isoxazoles and their biological activity

Synthesis and biological evaluation of novel isoxazoles and triazoles linked 6-hydroxycoumarin as potent cytotoxic agents

Synthesis and biological evaluation of novel N-phenyl-5-carboxamidyl isoxazoles as potential chemotherapeutic agents for colon cancer

Curcuminoid-derived 3,5-bis (styryl)isoxazoles -mechanochemical synthesis and antioxidant activity

Weight changes in obese adults 6-months after discontinuation of double-blind zonisamide or placebo treatment

Synthesis and antimicrobial activities of some new pyrazoles, oxadiazoles and isoxazole bearing benzofuran moiety

New isoxazole derivatives designed as nicotinic acetylcholine receptor ligand candidates

Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptosis-resistant cells

Synthesis and in vitro study of methylene-bis-tetrahydro[1,3]thiazolo[4,5-c]isoxazoles as potential nematicidal agents

Synthesis and in vitro study of a new class of methylene-bis-4,6-diarylbenzo[d] isoxazoles as potential antifungal agents

Isoxazole ring as a useful scaffold in a search for new therapeutic agents

Acid-basecatalysed condensation reaction in water: Isoxazolines and isoxazoles from nitroacetates and dipolarophiles

Antiproliferative novel isoxazoles: Modeling, virtual screening, synthesis, and bioactivity evaluation

Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N -substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles

Efficient and convenient method for the synthesis of isoxazoles in ionic liquid

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles

Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors

Synthesis and pharmacological screening of derivatives of isoxazolo[4,5-d]pyrimidine

Synthesis and pharmacological assessment of derivatives of isoxazolo[4,5-d]pyrimidine

Substituted 1H -pyrazoles and isoxazoles from cyclopropyl oximes

Potent and selective agonists of sphingosine 1-phosphate 1 (S1P1): Discovery and SAR of a novel isoxazole based series

The synthesis and antimicrobial evaluation of a new series of isoxazolinyl oxazolidinones

Novel microwave-assisted onepot synthesis of isoxazoles by a three-component couplingcycloaddition sequence

Discovery of novel N-(5-(tertbutyl)isoxazol-3-yl)-N′-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo

Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists

Synthesis, antimicrobial, antimycobacterial and structure-activity relationship of substituted pyrazolo-, isoxazolo-, pyrimido-and mercaptopyrimidocyclohepta[b]indoles

Synthesis, preliminary structure-activity relationships and biological evaluation of pyridinyl-4,5-2H-isoxazole derivatives as potent antitumor agents

Structure-activity relationship studies of substituted 2-(isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide analogues: identification of potent exchange proteins directly activated by cAMP (EPAC) antagonists

(Arylthiomethyl)isoxazole-4,5-dicarboxamides: chemoselective nucleophilic chemistry and insecticidal activity

Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity

Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Greenhouse and field evaluation of isoxaflutole for weed control in maize in China

Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents

Acknowledgements The authors thank the authorities of GLA University, Mathura, India for their praise worthy inspiration and constant encouragement.

Conflict of interest The authors declare that they have no conflict of interest.