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Authors: Madanlal, Lahoti Anandkumar
Issue Date: 2005
Abstract: Heterocyclic compounds are well known in organic chemistry for their various medicinal applications. Chemotherapy revealed that some heterocyclic compounds selectively destroy infectious micro-organisms without simultaneously destroying the host. However, many drugs available in the market exhibit serious toxic effects in human system, on there prolong use. Hence, synthesis ofbiologically active heterocyclic compounds has substantial interest in order to find an effective as well as safer substitute against the existing drugs having major side effects. Pyrimidine, a heterocyclic nucleus occurs in living cells and in considerable number of natural products, which are of great importance to living organisms. Anumber of pyrimidine derivatives have found applications as anti-cancer, anti-biotics, anti viral and anti-microbial agents. In the recent years some pyrimidine derivatives were also found to possess potent anti-inflammatory, analgesic and protein kinase inhibition activities. A part of the present dissertation is devoted to the synthesis of various novel pyrimidine derivatives and their screening for biological activities. In biological systems, electron-transfer reactions play an important role in energy conversion and substrate metabolism. However, these reactions are very complex in nature since the substrate molecule has to orients itself in a rather specific fashion before the electron-transfer can occur. Although oxidation reactions in biological systems occur at enzyme-solution interface, the best way ofgetting details oftheir in vivo redox chemistry is to examine them at the electrode-solution interface using electrochemical methods in combination with sophisticated instrumental methods like HPLC, GC, GC-MS etc. In contrast to the conditions of conventional oxidation using variety of oxidizing agents like H202, aqueous iodine etc., electrooxidation conditions are as close as possible to physiological systems i.e. similar pH, temperature and ionic strength of phosphate electrolyte. Apart ofthe dissertation presents electrochemical investigations of some biologically active heterocyclic compounds at pyrolytic graphite electrode (PGE). Wherever, possible enzymic oxidation of some of the selected compounds was also investigated and compared with that of electrooxidation. For simplicity and clarity the results are organized in the dissertation as follows. First chapter of the dissertation is 'General Introduction' and highlights the results of significant work reported in the literature on the synthesis of biologically active pyrimidine derivatives. An important class of pyrimidine is 2-thiopyrimidine (2-TP) and its derivatives. The basic skeleton of 2-TP is similar to cytosine with the only difference that the oxygen atom at 2-position is replaced by sulfur atom. Considering this assumption 2-TP compounds have attracted substantial interest of synthetic chemists. The chapter also provides information on the electrooxidation/reduction of pyrimidine derivatives and highlights the salient features of the techniques used in the electrochemical investigation. In view of the great importance of pyrimidine, second chapter of the thesis deals with the synthesis of variety of 2-TP derivatives (I to XVI). Various mono-, di- and tri-cyclic, di/tetrahydro-2-TP derivatives have been synthesized in reasonable yield by the condensation of P-isothiocyanato(aldehyde)ketone with different functionalized amines. Temperature and pH conditions played an important role in these reactions. All these compounds were purified by column chromatography or lecrystallization and characterized by correct elemental analyses, FT-IR, 'H/I3C NMR and mass (EI-MS/FAB-MS/HR-MS) spectrometry. The compounds were screened for their anti-inflammatory activity in the carrageenin- induced paw oedema model and analgesic activity in the phenylquinone writhing assay at Central Drug Research Institute, Lucknow. Protein kinase activities of these compounds were evaluated at CNRS Station Biologique de Roscoff, France. The compound XV has shown some promising anti-inflammatory (37% at 100 mg kg"1 p.o.) as well as analgesic (75% at 100 mg kg"1 p.o.) activities, with respect to standard drug Ibuprofen. The compound IX has shown iii good analgesic activity (75% at 100 mg kg'1 p.o.). Whereas, compound I has some interesting activity against CDKl (IC50 =5 uM) and it opens a wide area for researchers to investigate novel analogues of this important class of compounds as prospective CDK-1 inhibitors. Although other compounds have shown moderate to good anti-inflammatory (5-20%), analgesic (25-50%) and protein kinase (CDK-5, GSK-3) inhibition (IC50<10 uM) activities, it is expected that their biological screening is useful in studying the structure-activity relationship. ...................................
Other Identifiers: Ph.D
Appears in Collections:DOCTORAL THESES (chemistry)

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