Synthesis and bio-evaluation of hybrid molecules based on aromatics, heterocycles & sugars

Abstract

The discovery of efficacious new human therapeutic agents is one of humanity’s most crucial responsibilities. Medicinal chemistry is a multidisciplinary science including synthetic organic chemistry, natural products chemistry, enzymology, chemical biology and computational method. It is concened with the design and synthesis of new chemical entities in order to produce new medicins for the prevention and treatment of human diseases. It also includes the study of existing drugs, their biological properties and their structure activity relationship. One of the approaches in drug design is the synthesis of library of compounds based on the existing knowledge of biological targets. Human genome sequence has enabled the understanding of the genetic and molecular bases of diseases and the identification of new molecular targets, followed by their validations for drug development. The drug is most commonly an organic small molecule which activates or inhibits the function of biomolecules such as protein which in tems results in a therapeutic benefit to the patient. The most abundant source of organic materials has revolutionalized the drug discovery process from carbohydrates. A great deal of drug molecules has been developed and tremendous works are in progress from carbohydrates. The developments of glycoconjugates or glycohybrids as information carrier during various biological processes such as trafficking of different biomolecules, modulation of protein function, energy storage, intercellular adhesion, signal transduction, malignant transformation, viral and bacterial cell surface recognition, as well as involvement in selective binding and several other molecular recognition phenomenon make them superb in pharmaceutical, medicinal and biological sciences. Drug discovery is the multidisciplinary and multistep laboratories processes to tackle one of the biggest fundamental issues in health sciences are the design and creation of smarter, safer and better drugs against different diseases such as tuberculosis, cancer, diabetes and AIDS etc is fundamental goal of medicinal chemists. ii The work embodied in this thesis has been carried out in the Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow- 226001, CSIR, India during the period 2008 to 2013. The thesis is divided into four chapters. Chapter 1: Illustrates an overview on ‘Drug development pipeline for the treatment of tuberculosis: needs, challenges, success and opportunities for the future’. This review provides an overview of the new anti-TB agents with different molecular structures that are being clinically used and advanced stages of preclinical as well as clinical stages and also attempted to highlight the efforts that are being made in the development of new drug molecules as lead anti-TB agents. Chapter 2: Includes the Lewis acid catalysed synthesis of 1-[(4-benzyloxyphenyl)-but-3- enyl]-and 1-(4-benzyloxyphenyl cylcopropyl methyl)-1H-azoles from cyclopropyl phenyl methanols via substitution reaction. All Synthesized compounds were evaluated against antitubercular, antimicrobial and antifungal activities. Chapter 3: Describes an efficient synthesis of 1,2,3-1H-triazolyl glycohybrids with two or more than two sugar units or a chromenone moiety via copper-catalysed azide-alkyne cycloaddition. The synthesised glycohybrids were screened for their α-glucosidase, glycogen phosphorylase and glucose- 6-phosphatase inhibitory activities. Chapter 4: Comprises of two sections: Chapter 4A: Deals with the one pot stereoslective synthesis of (EE)-1-glycosyl-4-aryl-1,3- butadienes via in-situ tandem O-methanesulphonylation and elimination reactions of the corresponding 1-glycosyl-4-aryl buten-2-ols in presence of Et3N. Chapter 4B: Involves the synthesis of C-aryl glycosides using Diels−Alder reaction of the glycosyl diene and dienophiles followed by oxidative aromatization. Relevant references are given at the end of each chapter. Parts of this thesis have already been published and the list of publication is given at the end of thesis.