Novel Applications of the Pictet-Spengler Reaction Leading to the Synthesis of N-rich Polyheterocycles of Biological Interest

Abstract

Malaria remains the most fatal infectious parasitic disease that affects 300-500 million people each year and results annually in 1-2 million deaths, mostly among children. Presently, the most effective way of dealing with malaria is the administration of chemotherapeutic agents. The two most widely used antimalarial drugs, chloroquine and sulfadoxine/pyrimethamine, are failing at an accelerating rate in most malariaendemic regions owing to the development of resistance to these agents and pose major threat to human health. The discovery of artimisinin has brought promises; however, researchers apprehend that exorbitant clinical practice with artimisinine may trigger drug resistance to the parasite, and therefore demolishing our most effective weapon against the disease. Since most of the clinically used antimalarial agents have been either isolated from plants or are inspired from natural products, we directed our efforts to scrutinize some of the recently reported and unexplored structures isolated from plants with antimalarial activity. Among variety of structures, pyrimidine-β-carboline based macrocyclic structures attracted our attention. It is interesting to note that even tetrahydro-β-carboline (TBC) without any substitution and isolated from plants called “harmine” also exhibited potent antimalarial activity in vitro. Besides, TBC, pyrimidine ring is yet another nature's most versatile building blocks with established medicinal pedigree and its presence in thymine, cytosine and uracil, which are the essential building blocks of nucleic acids, DNA and RNA, is one possible reason for their activity. The motif has been given the privileged label as it is found to be present in a variety of therapeutic molecules exhibiting activity ranging from anti-inflammatory, antibacterial, anticancer, antiviral, antiHIV, antimalarial, antihypertensive, sedatives and hypnotics, anticonvulsant to antihistaminic. Investigation of their potential use in malaria therapy has therefore become a pressing priority. Pyrimethamine is a specific inhibitor of the plasmodial DHFR, which is essential for the DNA synthesis. This led us to focus our attention on Pyrimidine and TBC based polyheterocycles for our ongoing antimalarial program. The present endeavor embodies studies pertaining to design and synthesis of novel substrates for the Pictet-Spengler reaction. The thesis has been divided into two parts. The first part includes an overview on the Modified Pictet-Spengler reaction, the second part concerns with the synthesis of polyheterocycles based on privileged structures using modified Pictet-Spengler reaction. Depending on the substrates used for the generation of the small organic molecules, the second part is further divided into four chapters. Chapter 1 includes novel application of the Pictet-Spengler reaction to pyrimidine based substrates leading to the generation of pyrimido[5,4-c]quinolin-2-ylamine whereas chapter 2 deals with the regioselective synthesis of pyrido[1,2-c]quinazolinone and benzo[h][1,6] naphthyridines ring system using the modified Pictet-Spengler reaction. Third chapter of the thesis deals with the application of modified Pictet-Spengler reaction on a alkaloid (meridianin) leading to the synthesis of Pyrimido-β-carbolines and realated skeletons. The fourth chapter comprises application of the Pictet-Spengler reaction to the synthesis of an alkaloid: Pyrimidine-β-carbolines with antimalarial activity.