INTRODUCTION:

Heterocyclic compounds are those cyclic compounds whose ring contain besides, carbon, one or more atoms of other elements. The non-carbon atoms such rings are referred to as hetero atoms. The most common hetero atoms are nitrogen, sulphur and oxygen. The heterocyclic compounds having lesser common atoms such phosphorus, tin, boron, silicon, bromine, etc. have been a subject of much investigation in recent years. The heterocyclic compounds having three to six carbons in the ring are numerous, but only those having five or six atoms in the ring are by far the most important. Heterocyclic compounds are very widely distributed in nature and are particularly important because of the wide variety of physiological activities associated with this class of substances. Several of the important compounds contain heterocyclic rings, e.g. most o the members of vitamin B complex, alkaloids, antibiotics, chlorophyll, other plants pigments, amino acids, dyes, drugs, enzymes, the genetic material, DNA etc. Few of the basics rings of the heterocyclic compounds are listed below.¹

Received on 04.04.2012 Modified on 12.05.2012

Asian J. Research Chem. 5(6): June, 2012; Page 808-815

Fig. 1: Different Heterocyclic Rings Compounds

QUINOLINE:

Examples of drugs involving quinoline nucleus are as follows:

Fig. 2: Different Derivatives of Quinoline

Quinoline (1-aza naphthalene) is an aromatic nitrogen compound characterized by a double-ring structure and contains benzene fused with pyridine at two adjacent carbon atoms. It can be obtained by the distillation of coal tar. Quinoline can be prepared from aniline with acrolein in presence of heated sulfuric acid and is popularly known as Skraup synthesis. Various quinoline compounds can be prepared by this synthesis using a series of different oxidizing agents. Isoquinoline differs from quinoline in nitrogen at 2-position. Quinoline family compounds are widely used as parent compounds to make drugs especially anti-malarial medicines, fungicides, biocides, alkaloids, dyes, rubber chemicals and flavoring agents. They have antiseptic, antipyretic and antiperiodic properties. They are also used as catalysts, corrosion inhibitors, preservatives and as solvents for resins and terpenes. They are used in transition-metal complex catalyst chemistry for uniform polymerization and also in luminescence chemistry. They are used as antifoaming agents in refinery field. Some of the derivatives of quinoline such as quinaldine, 2-methylquinoline are used as anti-malarials and for preparing other anti-malarial drugs. It is used in manufacturing oil soluble dyes, food colorants, pharmaceuticals, pH indicators and other organic compounds. Quinaldic acid is a carboxylic acid substituted quinoline at 2-position, a catabolite of tryptophan (aromatic side chain amino acid). Quinazoline (diazanaphthalene) at 1, 3-positions is used as a chemical intermediate for making medicines and other organic compounds. It is a fundamental structure in some antihypertensive agents such as prazosin and doxazosin which are peripheral vasodilators. Quinoxaline at 1, 4-positions is used as a chemical intermediate for making fungicides and other organic compounds.²

Classical methods of synthesizing quinolines³:

Skraup synthesis (1980):

Fig. 3: Synthesis of quinoline from aniline.

Friedlander synthesis (1982):

Fig. 4: Synthesis of quinoline from o-acylarylamines and ketone aldehyde.

Conrad-Limpach-Knorr synthesis (1987):

Fig. 5: Synthesis of quinoline from o-acylarylamines and beta ketoester

Combes synthesis (1988):

Fig. 6: Synthesis of quinoline from aniline and dicarbonyl compounds:

The present work is undertaken to explore more possibilities of finding suitable derivatives with enhanced activity compared to that of known quinoline derivatives.

1.1b. Review of biological and pharmacological actions of quinoline:

Antimalarial activity of quinoline is universal, although it possesses a wide range of biological activities i.e. antifungal, anti-inflammatory, antimicrobial, nematocidal, hypocholesterolemic, antineoplastic, MCHr1 antagonists. It also possesses chiral anion exchanger and corrosion inhibitor like properties.

Antimalarial activity:

Jaime E. Charris, Jose N. Domínguez reported that (E)-2-quinolinylbenzo- cycloalcanones shown to be antimalarial activity.⁴

Anti-neoplastic activity:

M. G. Ferlin, B. Gatto studied the antineoplastic activity of pyrrolo-quinoline derivatives.⁵

Anti-inflammatory activity:

Yeh-Long Chen, I-Li Chen et al reported the anti-inflammatory evaluation of 4-anilinofuro [2, 3-b]quinoline.⁶

Anti-diabetic activity:

Jacques Chenault et al carried out the synthesis and studied the in vivo activities of a series of substituted quinoline carboxyguanidines as a possible novel class of antidiabetic agents.⁷

Nematocidal and trichomonacidal activity:

Mercedes Martínez-Grueiro et al studied that 2-substituted quinoline have nematocidal and trichomonocidal activities.

Hypocholesterolemic agents:

Zhengyan Cai, Weicheng Zhou and Lixin Sun reported the 4-thiophenyl quinoline as HMG CoA reductase inhibitors.⁸

MCHr1 antagonists:

Andrew J. Souers; Dariusz Wodka reported that 2-amino-8-alkoxy quinoline are having Melanin-concentrating hormone inhibitory activity.⁹

Chiral anion exchanger:

Michael Limmerhofer and Wolfgang Lindner reported the use of quinine and quinidine as a chiral stationary phase for high-performance liquid chromatography.¹⁰

Corrosion inhibitor:

Ganesha Achary H. P.; Sachin Y. et al found that 3-formyl-8-hydroxy quinoline in hydrochloric acid medium act as corrosion inhibition of mild steel.¹¹

1.2. PYRAZOLES:

As early as in 1884, Knorr discovered the anti-pyretic action of a pyrazole derivative in man he named the compound antipyrine. Also various pyrazole derivatives show various pharmacological actions including anti-inflammatory, anti-fungal, anti-diabetic, etc. This stimulated interest in pyrazole chemistry.

Examples of drugs involving pyrazole nucleus are as follows:

Fig. 7: Different Derivatives of Pyrazole

Pyrazoles may be prone to aromatic hydroxylation. The pyrazole ring is present in two different environments in the crystal and averaged molecular dimensions. The physical properties of the pyrazole can be usefully compared and contrasted with those of their 1, 3- isomeric counter parts. Echoing the higher boiling point of pyrazole which is only one of the trio to be solid at room temperature, also has much higher

B.P. (187^oC) than isoxazole (95^oC) and again reflecting the intermolecular hydrogen bonding available only to pyrazole. This association probably takes the form of dimers, trimers and oligomers. The dihydro and tetrahydro heterocycles are named pyrazoline/ pyrazolidine.

Pyrazoles¹²represent one of the most active classes of compounds possessing a wide spectrum of biological activities. Many of the therapeutically useful compounds such as phenylbutazone, oxyphenbutazone, antipyrine and aminopyrine are having analgesic and muscle relaxant action.¹³ Anti-inflammatory, antipyretic activity is associated with several compounds possessing pyrazole and benzothiazole rings.¹⁴ A dramatic increase is observed in the anti-inflammatory activity of cortisone and other steroids, by incorporating pyrazole nucleus in the molecule.¹⁵

Antipyrine is the one of the earliest synthetic drugs and is named after its antipyretic properties. Butazolidine, another pyrazolone is a powerful anti-inflammatory¹⁶drug used in rheumatic conditions, but it has dangerous side effects. Many pyrazole derivatives are associated with anti-fungal, anti-diabetic and anti-inflammatory properties. The pyrazolo pyridine nucleus has aroused great interest in recent years due to a wide variety of biological activities like anti-inflammatory, anti-pyretic, analgesic, bactericidal, vasodilating, respiratory stimulant and hypotensive activities.

Classical methods of synthesizing pyrazoles:

Fig. 8: Synthesis of pyrazole from diketone/dialdehydes

ii)

Fig. 9: Synthesis of pyrazole from diketone/dialdehydes

iii)

Fig. 10: Synthesis of pyrazole from diketone/dialdehydes

The present work is undertaken to explore more possibilities of finding suitable derivatives with enhanced activity compared to that of known pyrazoles.

Review of biological and pharmacological actions of pyrazole:

Fungicidal:

Mazahir Kidwai and Richa Sharma reported the antifungal activity of pyrazole.¹⁷

Anti- inflammatory agent:

Coli B et al reported pyrazole derivatives have anti-inflammatory activity.

Example: Benzylan (Tantum).¹⁸

Cyclo-oxygenase-2-inhibitors:

Joule J A and Mills K reported number of selective cyclo-oxygenase-2-inhibitors which show great promise as anti-inflammatory and analgesic agents without any side effects associated with other NSAIDs in which celecoxib is the first to market.¹⁹

Anti-diabetic activity:

Froesch E.E et al has reported anti-diabetic activity of the 5-methyl pyrazole–3- carboxylic acid.²⁰

Hypoglycemic agent:

Smith D.L. et al reported that 3,5-dimethyl pyrazole and 3-methyl pyrazole-5- carboxylic acid exhibited hypoglycemic activity.²¹

Vasodilator:

Brunner H.R et al have reported vasodilator action in pyrazole derivative.²²

Calcium channel blocker

Ikno A; Terno Y et al tested 4, 7-dihydro pyrazolo (3,4-d) pyridine derivatives for a Ca⁺⁺ channel blocking activity in isolated guinea pig portal vein, anti-hypertensive activity in rats and vasodilating effect in isolated guinea pig heart.²³

SCHIFF’S BASE:

The history of Schiff bases can be traced back to the early work done by Rassi et al who reported certain aromatic amines that give rise to compounds known as Schiff’s bases.²⁴

RCHO + H₂NR’ → R-CH=NR’ + H₂O

A Schiff’s base (or azomethine), named after Hugo Schiff is a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group but not hydrogen.²⁵ Schiff’s bases are of the general formula R₁R₂C=N-R₃, where R₃ is an aryl or alkyl group that makes the Schiff’s base a stable imine. A Schiff’s base derived from aniline, where R₃ is a phenyl or substituted phenyl, can be called an anil.²⁶Schiff’s bases play an important role in inorganic chemistry as they easily form stable complexes with most transition metal ions.²⁷

Review of synthesis and biological activity of Schiff’s base:

1. Sandhya Bawa and Suresh Kumar reported the synthesis of Schiff’s bases of 8-methyl-tetrazolo[1,5-a]quinoline as a potential anti-inflammatory and antimicrobial agent.²⁸

Fig. 11: Synthesis of Schiff’s base from quinoline

2. Amit Nayyar and Rahul Jain studied synthesis and antituberculosis activity of 2, 4-disubstituted quinoline containing Schiff’s bases.²⁹

Fig. 12: Synthesis of Schiff’s base from quinoline

β-LACTAMS:

A beta-lactam ring (β-lactam) is a lactam with a hetroatomic ring structure, consisting of three carbon atoms and one nitrogen atom. A lactam is a cyclic amide. The β-lactam ring is part of the structure of several antibiotic families, principally the penicillins, cephalosporins, carbapenemes and monobactams, which are therefore also called β-lactam antibiotics. These antibiotics work by inhibiting bacterial cell wall synthesis. This has a lethal effect on bacteria, especially on gram-positive ones³⁰. In the history of drug design, an attempt was made during investigation to synthesize some of the substituted azetidinones derived from different chemical entities. The 2-carbonyl derivatives of azetidine (Four membered heterocyclic rings with nitrogen as the hetero atom) are designated as 2-azetidinones or most commonly known as β-lactams.

In the review of literature, it was found that compounds containing 2- or 4- azetidinones possess some biological activities. This observation is a guiding principle in the present work i.e. the synthesis of some new compounds desired to obtain highly potent, more specific and less toxic drugs. The present work is undertaken to explore more possibilities of finding suitable derivatives with enhanced activity compared to that of known β-lactam antibiotics.

The activities of a large number of 2-azetidinones containing β-lactam moieties are greatly influenced by different substituents. A large number of 3-chloro monocyclic β-lactams possess powerful antibacterial,^{31, 32} anti-inflammatory,³³antifungal, antimicrobial,³⁴ sedative, anticonvulsant,³⁵ antitubercular and analgesicproperties.

Examples of drugs involving β-lactam nucleus are as follows:

Classical methods of synthesizing β-lactam :

Fig. 13: Synthesis of ß-lactam (i)

Fig. 14: Synthesis of ß-lactam (ii)

Review of synthesis and biological activity of ß-lactams:

Jigisha A Patel; B D Mistry and K R Desai reported synthesis and antimicrobial screening of quinoline linked with ß-lactam.³⁶

Fig. 15: Synthesis of ß-lactam with quinoline

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Received on 04.04.2012 Modified on 12.05.2012

Asian J. Research Chem. 5(6): June, 2012; Page 808-815

Classical methods of synthesizing quinolines3:

1.1b. Review of biological and pharmacological actions of quinoline:

Antimalarial activity:

Anti-neoplastic activity:

Anti-inflammatory activity:

Anti-diabetic activity:

Hypocholesterolemic agents:

MCHr1 antagonists:

Chiral anion exchanger:

Corrosion inhibitor:

1.2. PYRAZOLES:

Review of biological and pharmacological actions of pyrazole:

Fungicidal:

Anti- inflammatory agent:

Cyclo-oxygenase-2-inhibitors:

Anti-diabetic activity:

Hypoglycemic agent:

Vasodilator:

Calcium channel blocker

SCHIFF’S BASE:

Review of synthesis and biological activity of Schiff’s base:

Classical methods of synthesizing β-lactam :

Review of synthesis and biological activity of ß-lactams:

Classical methods of synthesizing quinolines³: