Literature Review: Heterocyclic compounds are of particular interest in medicinal chemistry. The chemistry of heterocyclic compounds is one of the most complex branches of chemistry. It is equally interesting for its theoretical implication for the diversity of its synthetic procedure and for the physiological and industrial significances. Synthetic heterocyclic chemistry has influenced almost every place of human life and the heterocyclic compounds have found their application in diverse field as medicine, agriculture, polymer, and various industries. Synthetic heterocyclic drugs are used as hypnotics, anticonvulsants, antiseptics, antineoplastics, antiviral, antihistaminics, anti-tumor etc. Majority of the large number of drugs being introduced in pharmacopeias every year are heterocyclic compounds. Heterocyclic compounds containing the five-membered oxadiazole nucleus possess a diversity of useful biological effects. 1,3,4-Oxadiazole moieties are important because of their versatile biological actions. During the last decades, chemistry, synthesis and transformations of five membered heterocyclic compounds has received considerable attention and importance due to their remarkable and wide variety of applications. 2,5-Disubstituted-1,3,4-oxadiazole and its derivatives constitute an important family of heterocyclic compounds. Due to their remarkable unique properties, 1,3,4-oxadiazole and its derivatives have been frequently employed in drug synthesis, various commercial and industrial applications. In fact, 1,3,4-oxadiazole ring carrying substitution in an appropriate position and substituent with a nucleophilic center are excellent precursors for further synthesis of heterocyclic compounds. For example, ring rearrangements for the synthesis of five and six membered heterocycles. 5-Substituted-2-mercapto-1,3,4- oxadiazoles are interesting and important class of compounds. They have general formula (1) (R = alkyl or aryl group). This type of compounds is known to exist in the tautomeric thiol (1) and the thione (2) form. From this fact it is also indicated that the ionization of the compounds occur from the thione form (2). HMO calculations indicate that thione form is more stable than thiol. A satisfactory correlation between the observed pka values and the difference between the π- electronic energies (ΔE) of the thioamide tautomer and of the common resonance stabilized anion has been observed, thus supporting the assigned tautomeric structure. Several reactions have been reported such as preparation of Mannich bases where the N-substitution is done instead of S-substitution which further supports the existence of thione form. 20-22
In the recent past extensive study of 1,3,4-Oxadiazole and thiadiazole derivatives, show diverse biological activities, such as anti-tuberculostatic, antiinflamatory, analgesic, antipyretic, anticonvulsant, antibacterial and antifungal activity. 23-27 It is also well documented that some agents possessing a pyrazine or pyridine ring, such as pyrazinamide and isoniazide are a very effective antitubercular drug. These compounds also have been shown to exhibit antimycotic 28 and analgesic action 29. Substituted-1,3,4-oxadiazoles and 5-substituted-2-mercapto-1,3,4- oxadiazoles are of considerable pharmaceutical interest. They have been well documented by a steadily increasing number of publications and patents. They display remarkable biological activities. For instance, 2-amino-1,3,4-oxadiazoles have been reported as muscle relaxants, analgesic, anti-inflammatory, anticonvulsive and diuretic properties were revealed for 5-aryl-2- hydroxymethy1-1,3,4-oxadiazole derivative. 22 Whereas derivatives of 2-mercapto-1,3,4- oxadiazoles have been reported to exhibit antimicrobial, anticancer, antifungal, nematocidal, anti-hiv. 30-34 As part of interest in heterocycles derived from Schiff bases that have been explored for developing pharmaceutically important molecules, 2-azetidinones 35,36, 4- thiazolidinones 36,37, fused thiazolidinones 38,39 have played a pivotal role in medicinal chemistry. Moreover they have been studied extensively because of their ready accessibility, diverse chemical reactivity and broad spectrum of biological activity. Substituted-1,3,4-oxadiazoles and 5-Substituted-2-mercapto-1,3,4-oxadiazoles are of considerable pharmaceutical interest. They have been well documented by a steadily increasing number of publications and patents. They display remarkable biological activities. For instance, 2-Amino-1,3,4-oxadiazoles have been reported as muscle relaxants. Analgesic, antiinflammatory, anticonvulsive and diuretic properties were revealed for 5-Aryl-2- hydroxymethy1-1,3,4-oxadiazole derivatives. 40 Whereas derivatives of 2-Mercapto-1,3,4- oxadiazoles have been reported to exhibit antimicrobial 41, antiinflammatory 42, and so forth. Substituted-1,3,4-oxadiazoles and biological activities of this class of compounds are presented below in Table- 1. Table- 1: Biological Activities of 2,5-Disubstituted-1,3,4-oxadiazoles.
Sr. No. Structure Activity 1 Potential antitumor and anti-hiv agents 2 Anticancer 3 Insecticidal 4 Antibacterial 5 Antiinflammatory 6 Antimicrobial 7 Anticonvulsant, antiinflammatory, antimicrobial
8 Antiinflammatory 9 Nematocidal 10 Anti-HIV-1 11 Antitumor 12 Tyrosinase inhibition activity 13 Antibacterial, Antifungal and M.tuberculosis. 14 Antifungal activity The usage of most antimicrobial agents is limited, not only by the rapidly developing drug resistance, but also by the unsatisfactory status of present treatments of bacterial and fungal
infections and drug side-effects. 43 Therefore, the development of new and different antimicrobial drugs is a very important objective and many research programs are directed the design of new antimicrobial agents. As per the review about the recent trends in the chemistry of 4-Amino-1,2,4-oxadiazole- 2-thiones. It is a five-membered heterocycles containing three nitrogens in the ring and its derivatives have biological activities such as antibacterial, antifungal, antimycobacterial, antiinflammatory, analgesic, anticancer, antihypertensive, anticonvulsant, antiviral, antidepressant, antiasthmatic, diuretic and hypoglycemic. All these facts were driving force to develop novel 4- Amino-1,2,4-oxadiazole-2-thiones derivatives with wide structural variation. Thus 4-Amino- 1,2,4-oxadiazole -2-thiones derivatives plays pivotal role in medicinal chemistry. As part of interest in heterocycles derived from Schiff bases that have been explored for developing pharmaceutically important molecules, 2-Azetidinones 44-45, 4-Thiazolidinones 45,46, fused Thiazolidinones 47,48, have played a pivotal role in medicinal chemistry. Moreover they have been studied extensively because of their ready accessibility, diverse chemical reactivity and broad spectrum of biological activity. The area in which derivatization of 4-Amino-1,2,4-oxadiazole-2- thiones into above heterocycles has not been reported so far. The area in which the heterocycle compounds of oxadiazole-2-thione and heterocyclic compound has not been reported so far. Hence it was thought to undertake such study. The heterocyclic compounds such as, azetidinones,4-thiazolidinones, 2-pyrrole and 2- pyrrolidinones have prominent role in pharmaceutical. Literature assessment reveals that oxadiazole indicate that they have coordinating behaviors with the transition metal ions. oxadiazole also display biochemical and physiochemical effects. Hence, it was thought of interest to merge both of azetidinones,4-thiazolidinones, 2-pyrrole and 2-pyrrolidinones moiety with oxadiazole moieties which may enhance the drug activity of compounds to some extent or they might possess some of the above mentioned biological activities. Hence the present work comprises the synthesis of thiazolidine, azetidinones, 2-pyrrole and 2-pyrrolidinones. The synthetic approach is shown in scheme. The proposed work is in context with the compounds having thienopiperidine moiety. The other moieties like azetidinones, thiazolidines, pyrrole and pyrolidines etc. also present and these moieties containing drugs have potential utility. Thus the combined molecules of
thienopiperidine and these heterocyclics, it is expected that the novel heterocycles will have good antimicrobial properties and will be applied as drug.