No description available.

Magnesidin is a magnesium chelate of the 3-hexanoyl and 3-octanoyl tetramic acid derivatives isolated from Psuedomonas magensiorubra. Its activity against grampositive bacteria was found to be a specific target for Gingivitis, a dental plaque.Although the synthesis of magnesidin has been reported earlier, it was not reproducible. The highly polar nature and it’s ability to exhibit tautomerization makes their chemical behavior complex and difficult to predict its structure. A variety of reactions and an in depth understanding of the chemical structure is necessary to attain the synthesis of these compounds. This dissertation focuses on addressing the attempts towards the synthesis of Magnesidin by identifying the important intermediates necessary for the synthesis as β- keto esters, α,β-unsaturated amino esters. The focus of the work has been addressed by developing a TAG molecule approach, which is similar to the concept of solid phase synthesis except for the fact that the TAG molecule can be identified under UV and also can be detected using various spectroscopic techniques. Microwave synthesis has been explored and applied in to the synthesis of benzyl mono and di bromination, 1,3- benzodioxoles have been established. The benzyl mono bromination is applied to synthesize the TAG molecule, which is then applied in developing a method of synthesis for β-keto esters. The azide approach was used to synthesize the α,β- unsaturated amides, which are another essential class of compounds in the synthesis of magnesidin.

This thesis describes the synthesis and biological evaluation of a library of compounds containing the tetramic acid core in search of novel antibacterial drug candidates. Chapter 1 discusses the need for new antibiotics due to the emergence of virulent bacterial strains resistant to clinically available drugs and the hiatus in the discovery of new replacement antibitoics that has become a global threat to human health. Different platforms for antibacterial drug discovery and the re-emergence of natural products-based approach that has gained importance in the quest for novel antibiotics are discussed. In this regard, the intrinsic antibacterial activity of natural products containing a tetramate core structure and the strategies developed to synthesise the core scaffold are described. Chapter 2 discusses the use of ʟ-serine and ʟ-cysteine in tetramic acid synthesis and the application of ʟ-cysteine-derived thiazolidine templates suitable for stereoselective ring closing reactions to obtain the tetramic acid core with scope for further functionalization. Chapters 3 and 4 describe a range of synthetic routes for appropriate substitutions of the tetramate core for compound library generation. Elaboration of the tetramate core via carboxamide tetramate synthesis, Suzuki-Miyaura cross-coupling reactions, glycosylations and their aglycone analogue synthesis, etherification, tetramate-pyroglutamate systems, Buchwald aminations/amidations, cycloadditions and β-lactam hybrids as possible chemical modifications of the tetramate core structure are discussed. Chapter 5 describes the antibacetiral activity and physicochemical properties of the library of compounds synthesised. A preliminary evaluation of their antibiotic activity was conducted against S. aureus and E. coli using the hole-plate method. MICs of the tetramates synthesised were determined against several Gram-negative strains; Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Gram-positive strains; MRSA, Enterococcus faecalis and Streptococcus pneumoniae, in whole-cell bioassays. Physicochemical properties of the compound library were analysed to map the chemical space occupied by tetramates with potent antibacterial activity. Enzyme inhibition studies were conducted to identify possible modes of action that contribute to whole-cell antibiotic activity and in this regard, the inhibition of enzymes S. aureus topoisomerase IV, S. aureus RNA polymerase, E. coli RNA polymerase, E. coli gyrase and M. tuberculosis gyrase are discussed. Since plasma protein binding of compounds is an important factor that determines the bioavailability of antibiotics and their clinical outcome, a study of the binding affinity of these drug candidates to Human Serum Albumin (HSA) by both whole-cell bioassay and NMR spectroscopy-based protein binding experiments are discussed. Finally, a brief note on the potential of tetramic acids to function as proteasome inhibitors in anticancer chemotherapy is included at the end of this chapter.

4, 4'-Dihydroxybenzophenone-2, 4-dinitrophenylhydrazone (A-007) has recently completed a phase-I clinical trial, and objective responses were seen in advanced breast cancer, lung cancer, ovarian cancer, melanoma, skin cancer and non-Hodgkin's lymphoma. Despite the promising results in the clinical trials, the major disadvantage to using A-007 as a broad-scale therapeutic is its poor water solubility. To make use of this promising anticancer drug either orally or intravenously, the short-term obstacle must be to overcome the limited solubility of A-007 in water. There are several approaches to overcome this obstacle. The first approach is to make hydrolysable prodrugs of A-007. The second approach is to make an A-007 complex with a water soluble host, such as cyclodextrin. We used a combination of these two previously described methods, i.e. transforming A-007 into a more water soluble prodrugs and then further increasing the prodrug water solubility by making their cyclodextrin inclusion complexes. Our syntheses and spectroscopic explorations of A-007 prodrugs are presented in this dissertation. Tetramic acid (2, 4 pyrrolidine-2, 4-dione ring system) containing compounds have been found to display a remarkable diversity of biological activities and have attracted the interest of medicinal and synthetic chemists. Magnesidin (1-acetyl-3-octanoyl-5-ethylidene tetramic acid) has strong antimicrobial activity against bacteria that cause gingivitis and dental plaque. Current efforts toward the synthesis of Magnesidin are discussed along with the plans for the completion of synthesis.