Search of New Lead Bioactive Molecules with Potential for Drug Development

Abstract

Discovering novel drugs for the treatment of human diseases is a complex process. Historically, the main source of biologically active compounds used in drug discovery programs has been natural products, isolated from plant, animal or fermentation sources. A lead compound in drug discovery is a chemical compound that has pharmacological or biological; activity and whose chemical structure is used as a starting point for chemical modification in order to improve potency, selectivity, or pharmacokinetic parameters. A significant increase in the number of new therapeutic chemical and biological entities has been observed in past few years. The molecular modification of a prototype known to possess biological activity has been one of the most fruitful approaches in the discovery of new lead for bioactive molecules. Bioactive lead is responsible for the interaction with a particular receptor site and interaction with receptor plays an important role in drug designing. Estrogens are endocrine regulators of the vertebrate reproductive system that have important effects in many non-reproductive tissues as well (bone, liver, cardiovascular system, CNS and so on). Many estrogen pharmaceuticals based on both natural and synthetic substances have been developed as agents for regulating fertility, preventing and controlling hormone-responsive breast cancer, and menopausal hormone replacement. These substances display a spectrum of agonist to antagonist activity that can show remarkable tissue and cell selectivity. The identification of numerous coactivators and co-repressors which modulate receptor function and the realization of two subtype of ER attest to the potential complexity through which SERMs produce diverse tissue-specific responses. The thesis entitled “Search of New Lead Bioactive Molecules with Potential for Drug Development” describes our endeavour leading to the accomplishment of newer SERMs agents. The thesis has been organized under four main chapters as summarized below: The first chapter compiles literature review of the information and drug development technologies that are used to develop small molecules as potential drug leads for the modulation of therapeutically relevant bioactive molecules, a brief introduction of Selective Estrogen Receptor Modulators, the multifunctional therapeutical profile of SERMs in Osteoporosis, Cardiovascular Health, Neurodegenerative Disorders, Menopause, Breast Cancer & as Contraceptive agents . The second chapter has been divided into two parts Part A: highlights the emergence of 3,4,6-triarylpyranones as a potential new class of anti- breast cancer agents. Continuing further and exploring the possibility of structural modifications in triarylpyranones for the enhancement of biological efficacy, several new 4-aroyl-3,6- diarylpyranones have been prepared through a facile Michael addition of active methylene compounds to 1,2-diaroylacetylenes. Their synthesis and characterization forms the basis of part B of 2nd chapter. Part A of chapter three of the dissertation describes a versatile method of conjugate addition of nucleophiles to α,β-unsaturated enones and alkynones through Michael reactions forming 1,5-diketones in very good yield. Further, cyclisation of these 1,5- diketones through McMurry coupling formed conformationally constrained tricyclic compounds. Their synthesis and biological screening as post-coital contraceptive activity forms the basis of part B of 3rd chapter. Lastly, in the fourth chapter part A describes the biological evaluation of hydrazones & hydrazines as possible cytotoxic agents and part B of 4th chapter describes the synthesis of novel tetracyclic indole derivatives as potential antifungal, antibacterial and anti mycobacterial agents.