Natural Product Inspired Design and Synthesis of Medicinally Active Heterocycles

Abstract

Natural products play an important role as source of inspiration for drug discovery and development and as tools for basic research. The therapeutic use of plants is as old as human civilisation. Even today plants remain the primary sources of health care for most people in the world. It is estimated that around 80% of the world’s population rely mainly on traditional medicine for their primary health care. After decades of very successful drug discovery and development, the pharmaceutical industry down scaled natural product research in the late 1990s in favour of automated high throughput screening (HTS) of compound libraries. Compound libraries assembled with the aid of combinatorial chemistry were thought to produce more hits than ‘old fashioned’ natural products. Despite this decline in the use of natural products in drug discovery, newly marketed drugs derived from natural compounds hold about the same share as before. The numerous and successful discoveries of compounds in the early times of modern drug discovery were quite exclusively based on the traditional use of the plant. Of all known organic molecules, only 1% is natural products, 99% are synthetici Today, the natural product inspired synthesis covers one the huge area in the drug discovery and generation of compound libraries to meet the criteria for highthroughput synthesis and activity. The work embodied in this thesis is an attempt to explore the hidden potential of natural product based compounds by providing them a place in drug discovery programme. , but more than one third of all drug sales are based on natural products. The thesis entitled “Natural Product Inspired Design and Synthesis of Medicinally Active Heterocycles.” describes our endeavors leading to the accomplishment of newer natural product inspired compound libraries as potential anti-hyperglycemic and anti-parasitic agents. The thesis has been organized under seven main chapters as summarized below: The first chapter presents a concise review on “Natural Product Inspired Synthesis of Compounds of Therapeutic Importance”. A large number of natural products are known from different families of plants and with diverse chemical classes. They are well known to posses’ excellent pharmacological property against different diseases. Nubers of approaches are reported in literature in order to modify the natural product moiety to improve its biological properties. This review comprises a brief description of how the changes in natural products have been carried out to get the enhanced pharmacological response. Review illustrates a disease wise description of natural product inspired synthesis of compounds of medicinal importance, which broadly consist of anticancer, antidiabetic, antimalarial, antitubercular, antibacterial and miscellaneous diseases. The second chapter describes the “Synthesis of Heterocyclic Curcumin Analogues as Potential Anticancer Agents.” Hetrocyclic curcumin analogues consisting heterocyclic pyran-2- one moiety were synthesized and evaluated for their in vitro anticancer activity. Interestingly, invitro anticancer activity evaluation exhibited that compounds 5 and 6 (IC50 = 6.82 μM and 4.46 μM) are potential A549 (lung carcinoma) inhibitors. The synthesized chalcone analogues were further converted to corresponding pyrazole derivatives. These synthesized pyrazole were screened for their inhibitory potential against various bacterial and fungal strains. Further study raveled that synthesised two of the pyrazoles pyrazoles 23, and 24, showing promising antibacterial activity with IC50 value of 1.5 μM. The third chapter of the thesis illustrates the “Synthesis of Spiropyrrolizine and Spiroquinazoline Derivatives as Potential Antihyperglycimic Agents”. Encouraged by the our lab work on the synthesis and promising anti hyperglycemic activity of spiroindoline derivatives prompted us to take some new spirooxindole derivatives from the curcumin based chalcones. Multicomponent reaction of Isatin, chalcone and proline were utilized for the synthesis of spirooxindole. The synthesized spirooxindole derivatives were further evaluated for their antidiabetic activity in vitro. The compounds selected from the in vitro enzyme inhibition criteria were further screened in SLM and STZ mouse model for antihyperglycimic activity. Two compounds of the series were found to posses’ potential to decrease the glucose. The fourth chapter of the thesis depicts the “Natural Product Inspired Design and Synthesis of Tryptanthrins and their aminoalkyl derivatives.” Tryptanthrin, known since 1915, has recently shown exciting potential as an antimycobacterial activity. Inspired by the pharmacological property of tryptanthrin, we reported here a environmentally benign green protocol for synthesis of tryptanthrin and its derivatives by using β-cyclodextrin as catalyst. Further these tryptanthrin derivatives were converted to their aminoalkyl analogues and they were evaluated for their antimalarial activity in plasmodium fasiperum 3D7 strain. These compounds exhibited excellent antimalarial property with IC50 values in low nano molar range. The fifth chapter of the thesis has been divided in two parts, first part (Chapter 5a) describes “Natural Product Inspired Synthesis of Tryptanthrin Glycoconjugate: Potential Antitubercular Agents.” Inspired from antibacterial propery of tryptanthrin and crucial role of sugars in dictating the biological property of molecule we synthesized novel tryptanthrin glycosyl triazole library. These synthesized glycoconjugates were further sreened for their inhibitory potential against protein kinase G. PknG was found to be one of the virulence factor for the survival of mycobacterium tuberculosis in host macrophages. Five compounds were exhibited good inhibition of kinases in comparison to known inhibitor AX20017. Second part (Chapter 5b) involves the “One Pot Synthesis of Tryptanthrin Based Aryl Triazoles as Potential Antitubercular Agents.” Here one pot synthesis of tryptanthrin triazoles have been achived from aniline via insitu diazotization and click chemistry. The synthesized compounds have shown promising antiltubercular activity with IC50 value of 3.25 μM. The sixth chapter of the thesis involves “Synthesis of Steroidal Triazoles as Potential Anti Breast Cancer Agents”. The steroidal hormone, estrone and 17β-estradiol, are naturally occurring human secondary metabolites, which governs the development and differentiation of estrogensensitive tissues. They play critical roles in human beings for development and maintenance of reproductive tissues. Inspired from biological significance of steroids we synthesized steroidal glycoconjugates by click chemistry approach. Further one pot methodology was applied for the synthesis of steroidal triazoles. The synthesized compounds exhibited excellent inhibitory activity against MCF-7 cell line with IC50 value of 2.4 μM. The Seventh chapter depicts the “One-Pot Tandem Synthesis of Macrocycles via Ugi Click Methodology”. The abundance of macrocycles in natural productsand their diverse pharmacological role prompted us to synthesize macrocycles. Here we have applied a multicomponent ugi reaction and ckick chemistry to achieve the synthesis of 11 membered macrocycles. Since triazole ring is considered to be bioisostere of peptide bond, therefore our synthesized macrocycle could be a cyclopeptide mimic.