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Chemistry of Mesoionic Sydnones As Versatile Heterocyclic Compounds

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Chemistry of Mesoionic Sydnones As Versatile Heterocyclic Compounds INTERNATIONAL JOURNAL OF PHARMACEUTICS & DRUG ANALYSIS VOL.7, ISSUE 12, 2019; 88 - 95; http://ijpda.com; ISSN: 2348-8948 Keywords: Sydnone, Mesoionic, Heterocycles, Review Article imines, biological activity. Chemistry Of Mesoionic Introduction Sydnones are mesoionic heterocyclic chemical compounds possessing a 1,2,3-oxadiazole core Sydnones As Versatile with a keto group in the 5 position.[1-3] Like other mesoionic compounds they are di-polar, Heterocyclic Compounds possessing both positive and negative charges which are delocalized across the ring. Recent computational studies have indicated that syd- Konda Ravi Kumar*, N. Hasya Harshitha, B. Sai nones and other similar mesoionic compounds are nonaromatic, "though well-stabilized in two Keerthana. separate regions by electron and charge delocali- zation."[4]A sydnone imine in which Department of Pharmaceutical Chemistry, the keto group of sydnone (=O) has been re- Hindu college of Pharmacy, Guntur. placed with an imino (=NH) group can be found as a substructure in the stimulant Date Received: 10th October 2019; Date accepted: drugs feprosidnine and mesocarb. Sydnones are 6th December 2019; Date Published: 15th De- the most studied compounds amongst the cember 2019 mesoionic family due to their interesting struc- Abstract tures, chemical properties, synthetic utility and Sydnones are mesoionic heterocyclic aromatic biological activities. Many reports stated that one compounds. They have been widely studied for covalent structure is not sufficient to represent some important biological activities like antivi- the sydnone molecule satisfactorily. However, ral, antitumor, antimicrobial, anti-inflammatory, 1,2,3-oxadiazolium bearing a carbonyl function anticancer, analgesic, anthelmintic and anti- has recently been the major representative of hypertensive activities. The aim of the present sydnones because FTIR spectroscopy showed a article is to review the available information on carbonyl stretch frequency attached to C5 of the sydnones and the derivatives of sydnones and ring like in 4-acetyl-3-tolylsydnone which exhib- also a look at the future perspectives. Sydnone ited a strong band at 1783 cm-1. X-ray analysis can be defined as a five-membered pseudo- revealed a bond length of 1.196 Å which corre- aromatic heterocyclic molecule. Classically, 1,2,3- sponds to an exocyclic C=O double bond. Classi- oxadiazole forms the main skeleton of sydnone. cally, the sydnone ring can be prepared from the The molecule has delocalized balanced positive cyclization of N-nitroso amino acids with acetic and negative charges. The five annular atoms Anhydride[5]. Later, many attempts were em- share the positive charge and the enolate-like ployed to improve the yield of cyclization by exocyclic oxygen atom bears the negative charge. using a stronger dehydrating agent such as The hydrogen atom at the position C4 was trifluoroacetic acid anhydride or thionyl chlo- proved to have acidic and nucleophilic function- ride[6]. Since their first preparation, sydnones alities making the sydnone ring reactive towards attracted the attention of medicinal chemists and electrophilic reagents. These unique chemical pharmacologists to investigate their biological features enable sydnones to interact with bio- applications. Their distinguished chemical struc- molecules resulting in important therapeutic ture enables them to bind and deactivate a vari- effects like anticancer, antidiabetic, antimicrobial, ety of biomolecules like DNA and enzymes. A antioxidant and anti-inflammatory. Conse- vast range of therapeutic properties has been quently, we aim from the current article to re- demonstrated including antimicrobial, anti- view the available chemical and pharmacological inflammatory, anti-cancer, antioxidant and information on sydnone and its derivatives. antidiabetic[7]. The present review demonstrates the important chemical and biological data on 88 Konda Ravi Kumar et al; Int J. Pharm. Drug. Anal, Vol: 7, Issue: 12, 2018; 88 - 95 Available online at http://ijpda.com sydnones starting from their early discovery in 1935 until today. Chemistry of Sydnone Over 120 years ago, Emil Fischer oxidized di- thizone; yielding an orange, crystalline com- pound he entitled dehydrodithizone. Fischer assigned the bicyclic structure to this species however, better understanding of the nature of (structure 20,R=H, R'=Ph) with acetic anhy- such species was gained as time progressed and dride afforded a neutral, anhydro derivative more advanced analytical techniques became to which the bicyclic structure (structure 21, available. In 1946, Baker, Ollis, and Poole coined R=H, R=Ph) was assigned. the term mesoionic (mesomeric/ionic) to de- Baker, Ollis and Poole showed that the as- scribe the monocyclic, dipolar nature of com- signed structure for sydnones was incorrect pounds such as dehydrodithizone. In 1955, these and that they were actually monocyclic, dipo- three authors published a paper in Chemistry lar oxadiazolone derivatives with many reso- and Industry which specifically defined the term nance forms contributing to the resonance mesoionic. Using their definition, dehydrodi- hybrid, designated using representation. With thizone is considered the first known mesoionic regard to the cyclodehydration step, Earl and species and is assigned the dipolar, monocyclic Mackney originally employed acetic anhy- structure.[8] A significant portion of the research dride at room temperature for six days. Since in heterocyclic chemistry has been devoted to then, several modifications have been forth- sydnones containing different moieties, as evi- coming and now include: heating in acetic [9-10] dent from the literature. Sydnones have anhydride or thionyl chloride, treatment with played a crucial role in the development of the- phosphorus pentoxide or the use of ory in heterocyclic chemistry and have been trifluoroacetic anhydride (TFAA). The reaction used extensively as synthons in organic synthe- with TFAA has become the method of choice sis. Sydnone are unique, dipolar, heteroaromatic since it usually occurs rapidly (<15 minutes), member of the general class of mesoionic com- at low temperature (-5 ˚C to 0 ˚C) and in high pound. Their derivatives are associated with an yields (> 90% for N-phenylsydnone). The only array of physiological activities. It is also re- foreseeable drawback to its use is the far ported that the ionic resonance structures of the greater cost of this reagent compared to the hetericyclic ring of sydnones promote significant others. Some alkyl sydnones with a functional interactions with biological molecules, which group in the side chain are extensively de- also fulfill many of the spatial and electronic composed by hot acetic anhydride. Hahn et requirements ascribed to their biological activi- al. Synthesized sydnone compounds by the ties. ultrasonic technique in 1987. Two main types, depending formally upon the origin of the electrons in the system, have been identified, they are exemplified by compound (22) and (23). The lactone, which is a 1,2,3-oxadiazole-5-one heterocycle was named as Sydnone in honour of University of Sydney (Sydney + lactone) In structure the nitrogen and oxygen atoms, 1,3 where it was prepared for the first time by to each other, are shown as donating two elec- trons each other to the total of eight electrons in Earl and Mackney in 1935. Earl and Mackney the whole π systems, where as in structure the reported that treatment of N-nitroso-N- two middle nitrogen atoms, 1,2 to each other, are phenylglycine. the two electron donors. The term “satisfacto- rily” in the definition refers to the fact that the charge in the ring cannot be associated exclu- 89 Konda Ravi Kumar et al; Int J. Pharm. Drug. Anal, Vol: 7, Issue: 12, 2018; 88 - 95 Available online at http://ijpda.com sively with one ring atom. Thus these com- organic Light Emitting Diodes. The oxadiazole pounds are in sharp contrast with other dipolar ring is electron deficient, resulting in poor hole structures, such as ylides (for example, structure, transport but good electron transport properties. and such compounds are not considered Sydnones are derivatives of 1,2,3-oxadiazole. mesoionic. Mesoionic compounds are most The IUPAC name of sydnone is 1,2,3- commonly represented as follows compound oxadiazolium-5-olates. Sydnone is a typical (22) as structure (25) and compound (23) as mesoionic compound and its chemical proper- structure(26). ties are unique. Sydnone compounds seem to be fairly different from other aromatic compounds in both reactivity and stability. The aromaticity of the ring is explained by the classical sextet theory. Total of seven 2Pz electrons are contrib- uted by the five atoms of the ring with one 2Pz electron on the exocyclic atom. A sextet of elec- trons will be obtained when one of the seven 2Pz electrons is paired with the single electron on the exocyclic atom. The circle indicates the delo- calization of six electrons which is detected as ring current by 1H-NMR spectroscopy. The circle represents six π electrons, the posi- This polarization of charges is evidenced by tive charge is shared by all the rings atoms. large dipole moments (4-6 D) for the mesoionic The unequal electron densities of the atoms rings. The ring will be positively charged, bal- lead to the different natures of N(3) and C(4). anced by the negative charge on the exocyclic In general it is believed that C(4) possesses atom. Sydnones have played a crucial role in the negative character and N(2) is positive, based development of
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