Nirma Univ J Pharm Sci; 2014, 1(1) 37-49 © 2014, Nirma University, Ahmedabad, Gujarat, India

INVITED ARTICLE A REVIEW ON SYNTHESIS AND PHARMACOLOGICAL DIVERSITY OF ISOXAZOLES & PYRAZOLINES

Kuntal Manna *, Udayan Banik, Partha Sakha Ghosh and Manik Das Department of Pharmacy, Tripura University (A Central University), Suryananinagar, Tripura-799 022. India.

Abstract

Isoxazole is an azole with an atom next to the . It is also the class of compounds containing this ring. Isoxazole rings are found in some natural products, such as and also found in a number of drugs, including COX-2 inhibitor . , a donor is containing isoxazolyl group & found in many beta- lactamase-resistant antibiotics, such as , and . The synthetic androgenic steroid also has an isoxazole ring. Pyrazoline is a five- membered heterocyclic having two adjacent nitrogen atoms within the ring. It has only one endocyclic double bond and is basic in nature. Among its various derivatives, 2-pyrazolines seem to be the most frequently studied pyrazoline type compounds. 2-Pyrazolines can be considered as a cyclic hydrazine moiety display a broad spectrum of potential pharmacological activities.

Keywords: Isoxazole, pyrazoline, synthesis, pharmacological diversity

*Correspondent Author: Email: [email protected], Phone: + 91 381 2374801 / 3 Introduction (uricosuric) [3]. Numerous pyrazoline derivatives have been found to possess Heterocyclic compounds forms a major considerable biological activities, which class of compounds in chemistry. These are stimulated the research activity in this cyclic compounds having at-least two field. They have several prominent effects, different elements as a part of the ring such as antimicrobial, antimycobacterial, system. On the other hand, a ring system antifungal, anti-amoebic, made up of same elements is considered as antiinflammatory, analgesic, antidepressant homocyclic compounds. and anticancer activities. They also possess some potent, receptor selective biological Fused saturated 5-membered rings activity like nitric oxide synthase (NOS) naturally occurring in both carboxylic inhibitor and cannabinoid CB1 receptor (Eg. Triquinane) and heterocyclic (Eg. antagonist activity [4]. The work provides Pyrrolizidin ) systems have an insight view to pyrazolines synthesis interesting pharmacological importance and its biological activities. Isoxazole [1]. (C3H3NO) is an azole with an oxygen atom Usually 6-membered rings have well next to the nitrogen. Isoxazolyl is the defined and readily determined univalent radical derived from isoxazole. conformations like chair and boat, but 5- Isoxazole ring is found in some natural membered rings are much flexible and products, such as ibotenic acid. Isoxazoles their conformations are difficult to also form the basis for a number of drugs, ascertain (Figure 1) [2]. including the COX-2 inhibitor valdecoxib (Bextra) (Figure 2). A derivative, furoxan,

N is a nitric oxide donor. An isoxazolyl group N N N N N is found in many beta-lactamase-resistant N N H H O O S S antibiotics such as cloxacillin, dicloxacillin Imidazole Isoxazole Isothiazole Thiazole and flucloxacillin. The synthetic androgenic steroid danazol also has an Figure 1: Structures of Various 5- isoxazole ring [5]. membered Heterocycles Isoxazoles are unsaturated aromatic Pyrazolines are well known and important heterocyclic compounds containing a ring nitrogen containing 5-membered with three carbon atoms, one oxygen atom heterocyclic compounds. 2-Pyrazolines and one nitrogen atom. The trivial name show a broad spectrum of pharmacological for the title five-membered fully activities and are present in a number of unsaturated heterocycles as “isoxazole” pharmacologically active molecules such was originally proposed by Hantszch as it as phenazone, amidopyrine, was the isomer “oxazole” discovered first. methampyrone (analgesic and antipyretic), The trivial name follows the Hantszch- azolid, tandearil (anti-inflammatory), Widman system of nomenclature: the indoxacarb (insecticide) and anturane prefix “iso” represents isomer, “oxa”

38 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines represents the oxygen atom “aza” high diversity and biological relevance [9- represents the nitrogen atom. The suffix 11]. The nitrogen hetero atom is more “ole” denotes the ring size as five- pronounced for electron withdrawing membered; altogether the derived name is effect, while the oxygen atom is more “isoxazole” [6]. This name has been pronounced for electron donating effect. accepted in IUPAC and has been used in As neutral molecules, isoxazoles undergo Chemical abstracts. In Chemical Abstracts, electrophilic substitution rather more the other systematic name 1,2-azole, is also readily at the position-4 than benzene. used. Isoxazole being an azole with an Effects of substituents can modify their oxygen atom next to the nitrogen, exhibits behavior. broad spectrum of biological activity and also forms a part of various biodynamic Substituents at the position-5 apparently agents [7]. have more activating and deactivating effect than substituents at the position-3. In Cl natural product synthesis, isoxazoles are

N O O Cl N used as latent synthons, such as masked H H H H N S N S new heterocyclic rings, masked fused O N O N Cl O O OH O rings, masked aromatic rings and masked O HO CLOXACILLIN DICLOXACILLIN aldol and related moieties. The capability of isoxazole undergoing reaction is

N CF diverse: protonation, quaternization, O O 3 H N 2 CH3 N complexation, oxidation, reduction, S H O N O O carbanionic condensations, thermolysis, VALDECOXIB photolysis, transformations into other heterocyclic ring systems and reaction with Figure 2: Isoxazole derivative having electrophiles, nucleophiles and Grignard established pharmacological activity reagents [12]. The substituted isoxazoles are also The naturally occurring antibiotic considered to be important synthons due to [13]; the monoamine oxidase their versatility towards chemical inhibitor isocarboxazide; isoxazole transformations to useful synthetic steroids, ibotenic acid; isolated intermediates. Isoxazole derivatives show from Amanita muscaria [14] and hypoglycemic, analgesic, -5-ones isolated from Legume antiinflammatory, antifungal, anti-bacterial seed [15] are potential isoxazole and HIV-inhibitory activities [8]. Synthesis derivatives. of hybrid natural products has gained momentum in recent years. It is expected Methods of synthesis of isoxazoles that combining features of more than one biologically active natural segment in a Figure 3 showed regioselective cyclo- single molecule may result in pronounced condensation of acrylophenone dibromide pharmacological activity while retaining derivatives with hydroxylamine

NUJPS - 2014 | Vol. 1 | Issue 1 39 hydrochloride giving corresponding treatment with hydroxylamine isoxazoles [16]. hydrochloride furnishes substituted 3- isoxazole esters (Figure 6) [19].

OH HN O R O R' NH OH.HCl / C H N R' R' 2 5 5 Diethyl o xalate NH2OH.HCl O O OH Cl C H OH H H Sodium e thoxide 2 5 OC2H5 R C C C R' OC2H5 in C 2H5OH O N O Br Br O O O N OH O THF

Cl NH2OH.HCl / C2H5OH R O

Cl Figure 6: Synthesis of 3-isoxazoles from acetophenones

Figure 3: Synthesis of isoxazoles from Pharmacological aspects of isoxazole acrylophenone dibromide Anti-convulsant activity 3-Alkyl, 5-aryl isoxazoles can be prepared from aryl cycolpropanes (Figure 4) with The search for antiepileptic compounds with more selective activity and lower NaNO2 in CF3COOH [17]. toxicity continues to be an area of

R' investigation in medicinal chemistry [20].

NaNO / CF COOH Many patients with epilepsy fail to 2 3 N R R' R O experience adequate control of their seizures, despite the optimal use of available antiepileptic drugs. Other Figure 4: Synthesis of isoxazoles from patients do so only at the expense of aryl cyclopropanes significant toxic side effects. In recent Solid phase synthesis of isoxazole years it has been established that inhibitors derivative from diaryl 1,3-diketones of GABA transport and in particular as (Figure 5) can be carried out in presence of troglial uptake can act as anticonvulsant hydroxylamine hydrochloride and silica agents and several isoxazole derivative gel [18]. (compound-A) (Figure 7) [21]. Compound-B is also a synthesized

X O NH2OH.HCl X O isoxazole derivative which affects the

O Silica gel O sodium channel to show its activity [22]. O O N O

O HN N Figure 5: Solid phase synthesis of OH N isoxazoles from diaryl 1,3-diketones N H C O O 3 COOCH 3

Reaction of various substituted A B acetophenones with diethyl oxalate in the presence of sodium ethoxide forms Figure 7: Isoxazoles having anti- resulting 2,4-diketo esters which on convulsant activity

40 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines Anti-cancer activity Pyrazoline

The effects of curcumin and of its Pyrazole is a π-excessive aromatic isoxazole analogue in breast cancer cell monocyclic heterocycle containing two line and in its multidrug-resistant (MDR) nitrogen atoms in a five membered 1,2- variant were examined. The isoxazole diazole ring. exhibit aromatic analogue Compound A has shown more character with properties resembling those potent antitumor and molecular activities of both and pyridine. 1-pyrazoline, both in parental and in MDR tumor cells. 2-pyrazoline and 3-pyrazoline are the three Isoxazole derivatives produces partially reduced forms of the pyrazole significantly higher direct inhibition of the structure with different positions of the COX-2 catalytic activity than curcumin. double bonds and exists in equilibrium one The isoxazole derivatives proved better with the other [29]. 2-pyrazoline exhibits because of minimum metal chelation when the monoimino character and hence more compared to curcumin [23]. The stable than the rest. Pyrazole is freely basic compound B has been found highly and forms salts with inorganic acids. The effective against human tumor cell lines imino hydrogen may be replaced by an especially on renal cancer, CNS cancer cell acyl group. Pyrazole is very resistant to and ovarian cancer cell lines [24]. Recently oxidation and reduction, but may be NO-NSAID has been established as potent hydrogenated catalytically, first to anti-cancer agents rather than their anti- pyrazoline and then to pyrazolidine [30]. inflammatory property [25]. Compound C is a NO donating compound used as anti- Phenylbutazone is a pyrazoline derivative cancer agent. known for its analgesic and anti- inflammatory and anti-pyretic properties Anti-microbial activity (Figure 9). Muzolimine is a pyrazoline derivative used as a diuretic which differs Drazoxolon is a commonly used fungicidal from the structures of other conventional agent. Acetyl Sulfisoxazole is another diuretic compounds. important anti-microbial agent from the NH2 isoxazole family which is widely used in OH N pediatric suspensions (Figure 8). O N HC CH3 Cycloserine is a well-established molecule N O N C6H5 widely known for its potency against Cl Cl H3C (CH2)3 O Mycobacterium tuberculosis [26-28]. MUZOLIMINE OXYPHENBUTAZONE

C6H5 H N 2 N Me Me O N C6H5 O N N O O O N Me O O Me Cl S O H C (CH ) O N N H N O N N 3 2 3 N CH3 Ph Ph N H3C H C H2N CH3 3 OH PHENYLBUTAZONE FORBISEN O Cycloserine Drazoxolon Acetyl Sulfisoxazole Figure 8: Isoxazoles having Figure 9: Pyrazoline derivative having antimicrobial activity established pharmacological activity

NUJPS - 2014 | Vol. 1 | Issue 1 41 Forbisen is a byproduct separated during Cycloaddition reaction (Figure 12) of synthesis of antipyrine. This pyrazoline is substituted styrenes with p-anisyl used in bovine analplasomosis. diazomethane at low temperature yield Oxyphenbutazone is a pyrazoline trans-3, 5-bis-(p-anisyl)-1-pyrazoline [36]. derivative similar to phenylbutazone. It is an active metabolite of phenyl butazone. Me

MeO CH CH2 + MeO C N N The difference with phenyl butazone is the H N presence of p-hydroxyphenyl group instead N MeO of phenyl at position 1 of phenylbutazone [31]. Figure 12: Synthesis of pyrazolines by cycloaddition reaction Methods of synthesis of pyrazolines Chalcone derivatives on reacting with α, β-unsaturated carboxylic acid esters hydrazine hydrate and glacial acetic acid, reacts with diazomethane to give 2- form corresponding N-phenyl-3,5-diphenyl pyrazolines (Figure 10). The primary pyrazoline & 3,5-diphenyl pyrazoline product of this reaction is a 1-pyrazoline, derivatives respectively (Figure 13) [37]. formed by 1, 3-dipolar cyclo addition, which spontaneously isomerizes into its Hydrazine hydrate R R' R R' thermodynamically more stable 2- glacial acetic acid NH pyrazoline isomer by a 1, 3-H shift [32]. O reflux N Figure 13: Synthesis of pyrazolines from MeOOC COOMe H COOMe MeOOC COOMe C CH2N2 Chalcone derivatives C N N H N N MeOOC H Pharmacological aspects of pyrazolines: Figure 10: Synthesis of pyrazolines from α, β-unsaturated carboxylic acid esters 2-pyrazoline is insoluble in water but soluble in propylene glycol because of its Figure 11 showed an example of synthesis lipophilic character [38]. 2-pyrazolines of a pyrazoline from the reaction of an α,β- display a broad spectrum of potential unsaturated ketone and diazomethane. pharmacological activities and are present Benzylidene-acetone on reaction with in a number of pharmacologically active diazomethane by 1,3- dipolar molecules such as phenazone, cycloaddition yield 2-pyrazolines [33-35]. amidopyrene, methampyrone (analgesic and antipyretic), azolid/ tandearil (anti- O Me Ph inflammatory), indoxacarb (insecticidal), CH2N2 Me HC HC N anturane (uricosuric), etc. Considerable N O H interest has been focused on the pyrazoline structure. The discovery of this class of Figure 11: Synthesis of pyrazolines from drugs provides an outstanding case history α, β-unsaturated ketone of modern drug development and also

42 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines points out the unpredictability of As the diverse pharmacological importance pharmacological activity from structural of pyrazoline have already been explained modification of a prototype drug molecule. in the earlier sections, some of the It is having a variety of medicinal pyrazoline derivatives showed potent anti- applications. Pyrazoline derivatives were cancer activity (Figure 14). found to have potential antipyretic- analgesic, tranquilizing, muscle relaxant, OCH3 N N psycho analeptic, antiepileptic, N CN N N antidepressant, anti-inflammatory, N HO B insecticidal, antimicrobial and anti- CH3 A hypotensive activities. Their derivatives O S N S N H were also found to exhibit cytotoxic N N H S H NH N N H CO 3 N H CO OH activity, inhibitory activity of platelet 3 N H CO N OCH3 3 aggregation, herbicidal activity and H3CO OCH3 C D E cannabinoid CB1-receptor modulators. Pyrazoline interest is also extended to dyes and dye couplers [39]. Given below is a Figure 14: Pyrazolines having Anti- brief account of various modifications cancer activity reported on chalcones, which resulted in a Compound A showed potential ALK5 variety of biological and pharmacological inhibitory activity as transforming growth activities. factor-β type 1 receptor kinase inhibitors Anti-cancer agents [42]. But this compound showed some extent of cytotoxicity. This problem is Cancer is a leading cause of death eradicated when p-methoxy phenyl worldwide, accounting for 8.7 million pyrazoline fragment is introduced to the deaths (around 14% of all deaths) in 2012. ring-D of steroid in Compound B [43]. Although many chemotherapeutic agents, Compound C is proven to be active with such as cisplatin, 5 fluorouracil and taxol, selective influence on colon cancer cell have been developed to treat different lines [44]. The above mentioned kinds of cancer effectively, some side compounds A and B have been examined effects could happen simultaneously. for anti-proliferative activity against Therefore, it is important and urgent to human colon carcinoma and highly develop novel compounds as anticancer metastatic human breast carcinoma [45]. agents with higher bioactivities and lower side effects [40, 41]. It is well known that a Anti-microbial agents number of multi-cyclic compounds containing heterocycle fragments exhibit a The pyrazoline nucleus is a ubiquitous wide variety of biological activities. feature of various compounds possessing Pyrazoline and pyrazole are important many pharmacological and physiological structural fragments of many bioactive activities and therefore they are useful compounds. materials in drug research. It was reported

NUJPS - 2014 | Vol. 1 | Issue 1 43 in the literature that different substituted 2- Analgesic agent pyrazolines possess antimicrobial activities (Figure 15). Pain is one of the most prevalent conditions that limits productivity and

OH CH O 3 diminishes quality of life. Although there O OH COOH N N N N is an arsenal of effective and widely used O N N analgesics, there is some concern regarding NH2 H N Cl A B C their safety and side-effects, making their clinical use problematic. In the recent Figure 15: Pyrazolines having Anti- years pyrazoline has emerged as Class of microbial activity analgesics having very high pharmacological activity [49]. Dipyrone Compound A have structural similarities to (metamizol) is a drug that belongs to the siderophores and evaluated as novel pyrazole derived family. Reports in the antimicrobials against Mycobacterium literature have shown that dipyrone, tuberculosis and Yersinia pestis [46]. although generally considered as belonging Compound B and C possess antibacterial to the nonsteroidal anti-inflammatory drug activities against Bacillus cereus, family, seems not to present the typical Staphylococcus aureus, Escherichia coli side effects of this drug class. Antipyrine and Pseudomonas putida [47]. (phenazone) is also a widely used Hypotensive agent analgesic belonging to pyrazoline family.

Clonidine and Clonidine like thiazolo- Anti-depressant activity imidazoline derivatives (Figure 16) Depression is a serious disorder with encouraged the development of pyrazoline estimates of lifetime prevalence as high as derivatives of this class which are proven 21% of the general population in some to have hypotensive activity. These developed countries [50]. Treatment for derivatives also bear structural and this disease is possible with antidepressant isosteric relationship to Clonidine [48]. medications and psychotherapy for some patients [51].

N N S N N N N N S S O Cl NH HO 2

Figure 16: Pyrazoline having Figure 17: Pyrazoline having anti- hypotensive activity depressant activity

44 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines Although antidepressants have been used References in the clinic for several decades, most of them are inadequate in efficiency and have [1] Comer FW, McCapra F, Qureshi IH, many serious adverse side effects. Scott AI. The structure and Pyrazolines were also reported as potential chemistry of hirsutic acid. antidepressant agents (Figure 17) which Tetrahedron, 1967, 23(12):4761- act by MAO inhibition. The compound 4768. shown above has been proven as a potent anti-depressant activity involving [2] Trost BM, Shuey CD, DiNinno Jr F. serotonergic system for its activity [52]. A stereo controlled total synthesis of hirsutic acid C. J. Am. Chem. Soc., Conclusion 1979, 101 (5):1284–1285. Review emphasizes on detailed [3] Rahman MDA, Siddiqui AA. information of Isoxazole and Pyrazoline. Pyrazoline derivatives: A worthy Isoxazole, an azole with an oxygen atom insight into the recent advances and next to the nitrogen, is found in many natural products and also found in number potential pharmacological activities. of drugs, including COX-2 inhibitor Int. J. Pharm. Sci. Drug Res., 2010, valdecoxib. Furoxan, is a nitric oxide 2(3):165-175. donor is containing isoxazolyl group is [4] Kumar S, Bawa S, Drabu S, Kumar found in many beta-lactamase-resistant antibiotics, such as cloxacillin, R, Gupta H. Biological activities of dicloxacillin and flucloxacillin. The pyrazoline derivatives - a recent synthetic androgenic steroid danazol also development. Rec. Pat. Antiinfect. has an isoxazole ring. Pyrazoline, a five- Drug Discov., 2009, 4(3):154-163. membered heterocycle having two adjacent nitrogen atoms within the ring, has only [5] Mandawad GG, Dawane BS, one endocyclic double bond and is basic in Beedkar SD, Khobragade CN, nature. Among its various derivatives, 2- Yemul OS. Trisubstituted thiophene pyrazolines seem to be the most frequently analogues of 1-thiazolyl-2- studied pyrazoline type compounds. 2- pyrazoline, superoxidase inhibitors Pyrazolines can be considered as a cyclic and free radical scavenger. Bioorg. hydrazine moiety display a broad spectrum Med. Chem., 2013, 21:365–372. of potential pharmacological activities. Both ring systems are having many [6] Rescifina A, Varrica MG, Carnovale pharmacological activity including but not C, Romeo G, Chiacchio U. Novel limited to anti-cancer, anticonvulsant, Isoxazole polycyclic aromatic antimicrobial, etc. These ring systems can hydrocarbons as DNA-intercalating further exploit in future to design novel agents. Euro. J. Med. Chem., 2012, pharmacologically active molecules. 51:163-173.

NUJPS - 2014 | Vol. 1 | Issue 1 45 [7] Lang Jr. SA, Lin YI. Isoxazoles and [14] Eugster CH, Prog. Chem. Org. Nat. their Benzo Derivatives. Comp. Prod., 1969, 27:261-321. Hetero. Chem., 1984, 6:1-130. [15] Lambein F, Kuo YH, Parijs RV. [8] Melo P, Teresa M.V.D. Recent Isoxazolin-5-ones, chemistry and advances on the synthesis and biology of a new class of plant reactivity of isoxazoles. Curr. Org. products. Heterocycles, 1976, Chem, 2005, 9:925-958. 4(3):567-593.

[9] Alcaide B, Almendros P, Salgado, [16] Thakare SS, Doshi AG. A novel NR. General and efficient synthesis synthesis of some isomeric of β-lactams bearing a quinone isoxazoles. Asian J. Chem., 2001, moiety at N1, C3 or C4 positions. 13:780-782. Tetrahedron Lett. 2001, 42:1503- 1505. [17] Sagniva LG, Alhamdan Mohammed Petrosyan Sev ekhim., 1994, 35:186. [10] Maria S, Faria MM, Iley J, Coles SJ, Hursthouse MB, Martins ML, [18] Chauhan SS, Joshi YC. Solid phase Moreira R. Reaction of synthesis of isoxazole derivatives naphthoquinones with substituted From diaryl 1,3-diketones under nitromethanes. Facile synthesis and microwave irradiation. Rasayan J. antifungal activity of naphtho[2,3- Chem, 2008, 1(3):475-480. d]isoxazole-4,9-diones. Bioorg. [19] Palin R, Abernethy L, Ansari N, Med. Chem. Lett., 2010, 20:193-195. Cameron K, Clarkson T, Dempster [11] Shen G, Blagg BSJ. Radester, a M, Dunn D, Easson AM, Edwards novel inhibitor of the Hsp90 protein D, Maclean J, Everett K, Feilden H, folding machinery. Org. Lett., 2005, Ho K, Kultgen S, Littlewood P, 7(11):2157–2160. McArthur D, McGregor D, McLuskey H, Neagu I, Neale S, [12] Murai K, Miyazaki S, Fujioka H. Nisbet LA, Ohlmeyer M, Pham Q, Reactivity of the ester group Ratcliffe P, Rong Y, Roughton A, attached isoxazoline, Sammons M, Swanson R, Tracey H, and isoxazole: a facial preparation of Walker G. Structure–activity studies 3-acyl-substituted these of a novel series of isoxazole-3- heterocycles. Tetrahedron Lett., carboxamide derivatives as TRPV1 2012, 53(29):3746–3749. antagonists. Bioorg. Med. Chem. Lett., 2011, 21:892–898. [13] McConnell D. The Problem Of The Carbonate Apatites. J. Am. Chem. [20] Lepage F, Tombret F, Cuvier G, Soc., 1955, 77(8):2344-2345. Marivain A, Gillardin JM. New N- aryl isoxazole carboxamides and N-

46 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines isoxazolyl benzamides as Cardile V, Miljkovic D, Harhaji L, anticonvulsant agents. Euro. J. Med. Dabideen D, Cheng KF, Bevelacqua Chem., 1992, 27(6):581–593. Y, Donia M, Garotta G, Al-Abed Y, Stosic-Grujicic S, Nicoletti F. Novel [21] Bolvig Y, Larsson OM, Pickering nitric oxide-donating compound DS, Nelson N, Falch E, Krogsgaard- (S,R)-3-phenyl-4,5-dihydro-5- Larsen P, Schousboe A. Action of isoxazole acetic acid–nitric oxide bicyclic isoxazole GABA analogues (GIT-27NO) induces p53 mediated on GABA transporters and its apoptosis in human A375 melanoma relation to anticonvulsant activity. cells. Nitric Oxide, 2008, Euro. J. Pharmacol., 1999, 19:177–183. 375:367–374. [26] Vyas DH, Tala SD, Dhaduk MF, [22] Eddington ND, Cox DS, Roberts Akbari JD, Joshi HS. Synthesis, RR, Butcher RJ, Edafiogho IO, antitubercular and antimicrobial Stables JP, Cooke N, Goodwin AM, activities of some new pyrazoline Smith CA, Scott KR. Synthesis and and isoxazole derivatives. J. Ind. anticonvulsant activity of Chem. Soc., 2007, 84:1140-1144. enaminones. 4.Investigations on isoxazole derivatives. Euro. J. Med. [27] Anderson JR, Horsgood RK. Chem., 2002, 37:635–648. Studies on the degradation of an isoxazolone fungicide by pure [23] Paola P, Monica N, Manuela L, cultures of soil bacteria. Soil Biol. Annamaria M, Valeria C, Alessandra Biochem., 1971, 3(4):271–280. A, Michele R, Daniele S, D’Alessandro N. The antitumor [28] Clark DG, McElligott TF. Acute and activities of curcumin and of its short-term toxicity of drazoxolon(4- isoxazole analogue are not affected (2-chlorophenylhydrazone)-3- by multiple gene expression changes methyl-5-isoxazolone). Food. in an MDR model of the MCF-7 Cosmet. Toxicol., 1969, 7:481–491. breast cancer cell line: analysis of the possible molecular basis. Int. J. [29] Awadallah FM, Piazza GA, Gary Mol. Med., 2007, 20:329-335. BD, Keeton AB, Canzoneri JC. Synthesis of some [24] Bhaskar VH, Mohite PB. Synthesis, dihydropyrimidine - based characterization and evaluation of compounds bearing pyrazoline anticancer activity of some tetrazole moiety and evaluation of their anti- derivatives. J. Optoelec. Biomed. proliferative activity. Euro. J. Med. Mat., 2010, 2(4):249–259. Chem., 2013, 70:273-279.

[25] Mijatovic S, Maksimovic-Ivanic D, [30] Hu S, Zhang S, Hu Y, Tao Q, Wu A. Mojic M, Malaponte G, Libra M, A new selective pyrazoline-based

NUJPS - 2014 | Vol. 1 | Issue 1 47 fluorescent chemo-sensor for Cu2+ in [38] Eisinger J, Boens N, Flores J. aqueous solution. Dyes Pigments, Fluorescence polarization study of 2013, 96(2):509-515. human erythrocyte membranes with 1 - p h e n y l - 3 - ( 2 - n a p h t h y l ) - 2 - [31] Shaharyar M, Abdullah MM, Bakht pyrazoline as orientational probe. MA, Majeed J. Pyrazoline bearing Biochim. Biophysic. Acta., 1981, : Search for 646(3):334-343. anticancer agent. Euro. J. Med. Chem., 2010, 45(1):114-119. [39] Rahman MA, Siddiqui AA. Pyrazoline derivatives: A worthy [32] Pechmann HV. Ueber Diazomethan. insight into the recent advances and Ber. Dtsch. Chem. Ges., 1894, potential pharmacological activities. 27:1888-1891. Int. J. Pharm. Sci. Drug Res., 2010, 2(3):165-175. [33] Azzarello, J., Gazz. Chim. Ital., 1906, 36:50. [40] Metwally MA, Gouda MA, Harmal AN, Khalil AM. Synthesis, [34] Smith LI, Howard KL. The action of antitumor, cytotoxic and antioxidant aliphatic diazo compounds upon evaluation of some new α,β-unsaturated ketones. III. pyrazolotriazines attached to Benzalacetone and diazomethane. J. antipyrine moiety, Euro. J. Med. Ame. Chem. Soc., 1943, Chem., 2012, 56:254-262. 65(2):165–166. [41] Sangthong S, Krusong K, [35] SubbaRaju GV, Rao KS. Synthesis Ngamrojanavanich N, Vilaivan T, and characterization of some new 3- Puthong S, Chandchawan S, acetyl-4-aryl-2-pyrazoline. Curr. Sci, Muangsin N. Synthesis of rotenoid 1989, 58:1030-1032. derivatives with cytotoxic and topoisomerase II inhibitory [36] Overberger CG, Weinshenker N, activities. Bioorg. Med. Chem. Lett., Anselme JP. The synthesis and the 2011, 21(16):4813-4818. decomposition of cis- and trans-3,5- bis(p-anisyl)-1-pyrazolines. J. Amer. [42] Jin CH, Krishnaiah M, Sreenu D, Chem. Soc., 1965, 87(18):4119- Subrahmanyam VB, Rao KS, 4124. Mohan AVN, Park CY, Son JY, Sheen YY, Kim DK. Synthesis and [37] Chovatia YS, Gandhi SP, Gorde PL, biological evaluation of 1- Bagade SB. Synthesis and substituted-3-(6-methylpyridin-2- antibacterial activity of some yl)-4([1,2,4]triazolo[1,5-a]pyridin-6- pyrazoline derivatives. Orien. J. yl)pyrazoles as transforming growth Chem., 2010, 26(1):275-278. factor-β type 1 receptor kinase

48 Manna K. et.al: Review on Diversity of Isoxazoles & Pyrazolines inhibitors. Bioorg. Med. Chem. Lett., [47] Kbas EA, Berber I, Sener A,; 2011, 21(20):6049-6053. Hasanov B. Synthesis and antibacterial activity of 4-benzoyl-1- [43] Frank E, Mucsi Z, Zupko I, Rethy methyl-5-phenyl-1H-pyrazole-3- B, Falkay G, Schneider G, Wolfling carboxylic acid and derivatives. Il J. Efficient approach to androstene- Farmaco, 2005, 60(1):23-26. fused arylpyrazolines as potent anti- [48] Turan-Zitounia G, Chevallet P, Kiliç proliferative agents. Experimental FS, Erol K. Synthesis of some and theoretical studies of substituent thiazolyl-pyrazoline derivatives and effects on BF3-catalyzed preliminary investigation of their intramolecular [3+2] cycloadditions hypotensive activity. Euro. J. Med. of olefinic phenyl hydrazones, J. Chem., 2000, 35:635"641. Amer. Chem. Soc., 2009, 131(11):3894-3904. [49] Milano J, Oliveira SM, Rossato MF, Sauzem PD, Machado P, Beck P, [44] Havrylyuk D, Zimenkovsky B, Zanatta N, Martins MAP, Mello CF, Vasylenko O, Zaprutko L, Gzella A, Rubin MA, Ferreira J, Bonacorso Lesyk R. Synthesis of novel HG. Antinociceptive effect of novel thiazolone-based compounds trihalomethyl-substituted pyrazoline containing pyrazoline moiety and methyl esters in formalin and hot- evaluation of their anticancer plate tests in mice. Euro. J. activity. Euro. J. Med. Chem., 2009, Pharmacol., 2008, 581:86–96. 44(4):1396-1404. [50] Wong ML, Licinio J. Research and treatment approaches to depression. [45] Ciupa A, De Bank PA, Mahon MF, Nat. Rev. Neurosci., 2001, 2:343- Wooda PJ, Caggiano L. Synthesis 351. and anti-proliferative activity of some 3-(pyrid-2-yl)-pyrazolines. [51] Kaplanckl ZA, Ozdemir A, Turan- Med. Chem. Commun., 2013, 4:956- Zitouni G, Altıntop MD, Can OD. 961. New pyrazoline derivatives and their antidepressant activity. Euro. J. [46] Stirrett KL, Ferreras JA, Med. Chem., 2010, 45:4383-4387. Jayaprakash V, Sinha BN, Renc T, [52] Ozdemir Z, Kandilci HB, Gumuşel Quadri LEN. Small molecules with B, Calis U, Bilgin AA. Synthesis structural similarities to and studies on antidepressant and siderophores as novel antimicrobials anticonvulsant activities of some 3- against Mycobacterium tuberculosis (2-furyl)-pyrazoline derivatives. and Yersinia pestis. Bioorg Med Euro. J. Med. Chem., 2007, Chem. Lett., 2008, 18:2662-2668. 42:373–379.

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