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 oxygen atom next to the nitrogen. It is also the class of compounds containing this ring. Isoxazole rings are found in some natural products, such as ibotenic acid and also found in a number of drugs, including COX-2 inhibitor valdecoxib. Furoxan, a nitric oxide donor is containing isoxazolyl group & found in many beta- lactamase-resistant antibiotics, such as cloxacillin, dicloxacillin and flucloxacillin. The synthetic androgenic steroid danazol 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 alkaloids) 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 Pyrazole Imidazole Isoxazole Oxazole 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 LEFLUNOMIDE 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 cycloserine [13]; the monoamine oxidase their versatility towards chemical inhibitor isocarboxazide; isoxazole transformations to useful synthetic steroids, ibotenic acid; muscimol isolated intermediates. Isoxazole derivatives show from Amanita muscaria [14] and hypoglycemic, analgesic, isoxazoline-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. Pyrazoles exhibit aromatic analogue Compound A has shown more character with properties resembling those potent antitumor and molecular activities of both pyrrole and pyridine. 1-pyrazoline, both in parental and in MDR tumor cells. 2-pyrazoline and 3-pyrazoline are the three Isoxazole derivatives