IJPCBS 2013, 3(2), 294-304 Jayaroopa et al. ISSN: 2249-9504 INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES Available online at www.ijpcbs.com Research Article ISOXAZOLES: MOLECULES WITH POTENTIAL MEDICINAL PROPERTIES K. Ajay Kumar and P. Jayaroopa* Post Graduate Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore-570 005, India. ABSTRACT Isoxazole is a five membered heterocyclic compound having various pharmacological actions. The great interest associated with isoxazoles and their derivatives is based on their versatility as synthetic building blocks, their latent functionalities as enaminones, 1,3-dicarbonyl compounds, γ-amino alcohols, and β-hydroxy nitriles have been widely exploited for the synthesis of other heterocycles and complex molecules. This review paper comprises of up to date information on isoxazole analogs. More emphasis was given to critical discussion on the synthetic strategy of isoxazole derivative, their utility as building blocks in their transformation to more biologically potent molecules. Results of isoxazole derivatives and their substitutions effect on diverse biological activities also presented. Keywords: Isoxazoles, antioxidant, antimicrobial, analgesic, anti-platelet, anti-HIV. INTRODUCTION sulfisoxazole, oxacillin, cycloserine and acivicin Nitrogen containing heterocycles with an have been in commercial use for many years. oxygen atom are considered as an important Cycloserine is the best known antibiotic drug class of compounds in medicinal chemistry that possess antitubercular, antibacterial because of their diversified biological activities and in treatment of leprosy. Acivicin is applications. The exploitation of a simple an antitumour, antileishmania drug, while molecule with different functionalities for the isoxaflutole is used as herbicidal drug. synthesis of heterocycles is a worthwhile Isoxazoles have illustrious history; their contribution in the chemistry of heterocycles. chemistry is associated with Ludwig Claisen, Isoxazole (1a) is a five membered heterocyclic who first recognized the cyclic structure of 3- compound containing oxygen and nitrogen methyl-5-phenylisoxazole in 1888 and was atoms in the 1, 2 positions, its partially shown to possess typical properties of an saturated analogs are called isoxazolines (1b-d) aromatic system under certain reaction and completely saturated analog is isoxazolidine conditions; particularly in basic media, it is very (1e). highly labile. Dunstan and Dymond were the first to synthesize the isoxazole ring1. They isolated a liquid base by heating nitroethane with aqueous alkalies to obtain 3,4,5- trimethylisoxazole. A very significant contribution to the development of isoxazole chemistry came between 1930–1946 from Isoxazoles are an important class of Quilico’s studies on the synthesis of ring system heterocycles, which are largely employed in the from nitrile oxides and unsaturated 2 area of pharmaceuticals and therapeutics such compounds . as insecticidal, antibacterial, antibiotic, antitumour, antifungal, antituberculosis, SYNTHESIS OF FUNCTIONALIZED anticancer and ulcerogenic. Isoxazole ISOXAZOLES derivatives are used in the market as COX-2 Diverse applications associated with isoxazole inhibitor and anti-inflammatory drugs. Isoxazole moiety led the researchers to develop various derivatives such as sulfamethoxazole, novel synthetic approaches for the synthesis of isoxazole ring systems. For instance, recent 294 IJPCBS 2013, 3(2), 294-304 Jayaroopa et al. ISSN: 2249-9504 3-5 TM review by Ajay Kumar et al reports the use of Magtrieve (CrO2) in either toluene or MeCN at nitrile oxides as versatile intermediates in the 800C (Scheme-2). They observed the formation synthesis of isoxazole derivatives. Oximes on of minor amount of deoximation product along treatement with PhI(OCOCF3)2 (hypervalent with isoxazoles and isoxazolines. Their iodine) leads to rapid formation of nitrile oxides methodology has been shown to be equally which were trapped in situ with terminal and versatile for intramolecular nitrile oxide cyclic alkynes efficiently to give 3,5- cycloaddition (INOC) reactions. disubstituted and 3,4,5-trisubstituted isoxazoles X X in high yield (Scheme-1). The procedure is Cro , MeCN Cro , MeCN 2 OH 2 experimentally convenient, avoids the isolation O 0 N 800C, 2h 80 C, 2h O and handling of potentially harmful and N 6 N unstable hydroximoyl chlorides . X R' H X R' R' Isoxazole Isoxazoline Scheme-2 N OH PhI(TFA)2 R' C N O R' H MeOH, H2O Shravankumar and co-workers reported a facile R" catalytic approach to synthesize regioselectively 7 hr R' both 3,5-di- and 3,4,5-trisubstiututed isoxazoles R'' in high yields which involve the nucleophilic 2-5min organo-NHC-catalyzed 1,3-dipolar cycloaddition N R' O R" of nitrile oxide with alkynes. Triethylamine (Et3N) was employed as an effective base to 59-94% N generate both nitrile oxide and the organo-NHC R'' O in situ (Scheme-3)8. The multinucleus structures Scheme-1 84-95% like isoindole linked disubstituted isoxazoles and sterically crowded trisubstituted isoxazoles can be accessed easily selectively by this Sandeep Bhosale et al7 synthesized isoxazoles method, which could be useful in biology and and isoxazolines via 1,3-dipolar cycloaddition of material science. alkenes and alkynes with nitrile oxides generated in situ by treatment of aldoximes with Nagatoshi Nishiwaki et al9 reported one-step synthesis of different functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with β-keto esters. Among several salts, magnesium acetate was found to be the most efficient promoter affording isoxazole in 80% yield (Scheme-4). Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with Bhaskar Chakraborty and co-workers10 reported 1,3-dicarbonyl compounds in the presence of an aqueous phase cycloaddition reaction. They magnesium acetate that formed magnesium synthesized and studied the antibacterial enolate in situ. activities of some novel isoxazolidine derivatives by 1,3-dipolar cycloaddition reaction of nitrones with different dipolarophiles in water. Significant rate acceleration and high yield of these reactions are observed in water 295 IJPCBS 2013, 3(2), 294-304 Jayaroopa et al. ISSN: 2249-9504 with remarkable changes in stereo and regioselectivity compared to organic solvents. They have provided a green synthesis avoiding use of organic solvents. Stokes and co-workers11 reported that iron (II) catalyzes the formation of N-O bonds to transform azides into 2,1- benzisoxazoles under markedly benign conditions (Scheme-5). N-(4-(5-Arylisoxazol-3-yl)phenyl)- benzenesulfonamides were synthesized under conventional heating and microwave irradiation (Scheme-8)14. The method was found to be fast, efficient and economical. The reaction proceeded smoothly with better yields under microwave irradiation within 5-6 minutes; while under reflux conditions it required 6-8 Highly substituted isoxazoles can be formed in hrs. good to excellent yields using mild reaction conditions. For instance, 3,5-disubstituted 4- halo (seleno) isoxazoles have been synthesized by the reaction of various 2-alkyn-1-one O- methyl oximes with ICl, I2, Br2, or PhSeBr (Scheme-6)12. Rai et al13 reported that nitrile oxides generated A series of thirteen cycloadducts 3-Aryl-5N-aryl- in situ by the oxidative dehydrogenation of 4,6-dioxo-pyrrolo[3,4-d]-7,8- aldoximes with chloramine-T reacted with ,- dihydroisooxazolines were synthesized by the unsaturated compounds to afford ethyl 3,5- reaction of in situ generated nitrile oxides diarylisoxazole-4-carboxylates which exhibited obtained from the catalytic dehydrogenation of remarkable antimicrobial activity. In a typical aldoximes with chloramine-T on N-aryl reaction an equimolar mixture of aldoxime, ,- maleimides (Scheme-9)15. Later they unsaturated compounds and chloramine-T demonstrated the use of nitrile oxide as a trihydrate in ethanol was refluxed on a water dipolarophile in 1,3-dipolar cycloaddition with bath for 3 hours. After the completion of the acetyl acetone and obtained the substituted reaction, the unusual cycloadducts were isoxazolines in good yield. Here the nitrile oxide obtained in good yield. The products formed gets added to enolic double bond of acetyl with unusual elimination of HCN under reaction acetone (Scheme-9)16. conditions (Scheme-7). 296 IJPCBS 2013, 3(2), 294-304 Jayaroopa et al. ISSN: 2249-9504 4-Arylidene-3-phenylisoxazol-5-ones were Cu(OAc)2 effected the rate of the cross-coupling synthesized by three-component condensation reaction; however, in some cases, Cu(OAc)2 also of ethyl benzoylacetate, hydroxylamine and promoted the protodesilylation of the silanol. aromatic aldehydes in ethanol using DABCO as base under reflux condition (Scheme-10)17. It was observed that the good yields were obtained with faster reaction rate with the aldehydes bearing electron-donating groups when compared to aldehydes with electron- withdrawing groups. O O O + NH2OH.HCl + Ph OEt Ar H DABCO C2H5OH,Reflux Ph Ar N H O O Scheme-10 Fluorinated isoxazoline were synthesized in one pot by the reaction of fluorinated chalcones and Recently Vasanth Kumar et al18 synthesized a hydroxylamine in acetic acid medium under series of 3-aryl-5-(4-methoxyphenyl)-isoxazole- reflux conditions (Scheme-13)20. The products 4-carbonitriles by the in situ generated nitrile have been evaluated for their antibacterial oxides obtained by the catalytic oxidation of activities. By introducing