Synthesis of Carbohydrate Derived Scaffolds and Glycosylated Quinoline Derivatives as Potential Bioactive Agents

Abstract

Drug discovery and development is a multidisciplinary process. Among different steps in the process, the first step is the lead generation which involves the design and synthesis of the bioactive molecules. The synthetic strategies provide the initial access to the preparation of new prototype and its derivatives as new chemical entities (NCEs) for biological evaluation and also help in scaling up the chemical process for the candidate drug. The design of a total synthesis involves number of chemical reactions that allow the preparation of the compounds of interest from already available synthetic or natural starting materials. Medicinal chemistry is a discipline with a traditional focus on organic synthetic chemistry with the broad goals of drug discovery and optimization. The role of the medicinal chemistry is in the design and synthesis through different possible synthetic strategies. The medicinal chemist also develops the approaches towards the structural diversification for overcoming poor bioavailability, toxicity and the undesirable side effect. In view of the above, the work reported in this thesis has been broadly divided in four chapters. The first chapter entitled “Expedient synthetic methodologies for the stereoselective synthesis of fagomine and 1-deoxynojirimycin and their isomers. It involves the total synthesis of four fagomine isomers i.e. D-3,4-epi-fagomine, D-4-epi-fagomine, L-fagomine and L-3-epifagomine by using Prins cyclization as a key step. The new methodology consisting of one pot conversion of carbohydrates alcohol into chloride via benzotriazole sulfonate. The last section deals with synthesis of two 1-deoxynojirimycin isomers using novel methodology consisting of reductive cyclization of azido alcohols followed by in situ Ugi reaction as the important step. The second chapter entitled “First example of carbohydrate-based [1,4]-furodiazepin- 5-one: a novel class of sugar-annulated diazepinones” describes the synthesis of novel scaffold [1,4]-furodiazepin-5-one, by using D-glucose and enentiopure amino acids by amine mediated cyclization method. The third chapter entitled “Synthesis of Primaquine Glyco-conjugates possessing persuasive tissue-schizontocidal antimalarial activities” deals with the synthesis of glycoconjugates of Primaquine e.g. Amadori rearranged, N-glycoside and N-triazole linked Primaquine with natural occurring hexoses. The synthesized molecules were evaluated for their tissue-schizontocidal antimalarial activities where the N-glycosides of Primaquine showed promising tissue-schizontocidal activities and N-galactoside was found to be more effective than Primaquine. The fourth chapter of this thesis has been divided in two parts, first sub-chapter 4.1 deals with the design, synthesis and antibacterial evaluation of novel glycoconjugates of 8-fluoro Norfloxacin as potential probes for gentamycin resistant Staphylococcus aureus. Some of the compound have shown potential antibacterial activities better than Gentamycin and the best among them was 4 times less active than the norfloxacin and two times more effective than gentamycin. The second subchapter 4.2 describes the synthesis of 3-carboxy-4- quinolones via ipso- nitration and their evaluation against Brugia malayi thymidylate kinase (bmTMK) enzyme a potential target for antifilarial agents. Three of these compounds have shown potent bmTMK inhibitory activities with their IC50 values in the range of 2.9-3.4 mol.