Structurally Simple Synthetic Peroxides: Synthesis and Antimalarial Assessment

Abstract

Malaria is one of the most common infectious diseases and an enormous public health problem. The disease is caused by protozoan parasites of the genus Plasmodium and affects over 100 countries of the tropical and subtropical regions of the world including South-East Asia, Sub-Saharan Africa and South America. Every year, around 300 to 500 million clinical cases of malaria are reported, of which nearly 1 to 3 million people, mostly children, die due to complicated cases of malaria. As per an estimate, every 30 seconds a child dies of malaria. Malaria is commonly associated with poverty, but is also a cause of poverty and hence an economic burden on the affected countries. The situation is getting worse with the emergence and spread of multidrug-resistant parasites. Four identified species of the Plasmodium parasite responsible for human malaria are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. falciparum and P. vivax account for more than 95% of malaria cases in the world. The female anopheles mosquito is a vector for transmitting malaria parasites. Malaria is reemerging as the biggest infectious killer and is currently the first priority tropical disease of the WHO (World Health Organization). The widespread development of resistance by P. falciparum to chloroquine, the cheapest, efficacious and most widely used drug, has posed a major challenge to combat malaria. Artemisinin, isolated from Artemisia annua and its semisynthetic derivatives e.g. artemether, arteether, and artesunic acid are the only class of antimalarials, which are effective against multidrug-resistant malaria. The peroxide bond in the form of 1,2,4-trioxane is essential for the antimalarial activity of this class of drugs. Ever since the isolation of artemisinin and establishment of the peroxide bond as its active pharmacophore, synthesis and antimalarial assessment of structurally simple 1,2,4-trioxanes has become an area of hot pursuit. The thesis entitled “Structurally Simple Synthetic Peroxides: Synthesis and Antimalarial Assessment” describes a part of our efforts for developing organic peroxides as newer antimalarial agents. The thesis has been organized under five main chapters as summarized below: The first chapter presents a concise review that accommodates some of the most significant historical achievements and developments observed in the discovery of antimalarial drugs, with particular emphasis on the last 35 years. The second chapter describes synthesis and antimalarial activity of novel aminofunctionalized 1,2,4-trioxanes in search for an analog, better than β-arteether. The third chapter of the thesis describes synthesis and antimalarial activity of novel lipophilic ether- and ester-functionalized 1,2,4-trioxanes and hydrophilic hemisuccinate derivatives. The fourth chapter deals with synthesis and antimalarial assessment of novel nitrogencontaining peroxides having entirely different pharmacophore than 1,2,4-trioxanes. The fifth chapter describes synthesis and antimalarial assessment of novel dihydroartemisinin derivatives, which include dihydroartemisinin derived esters and hetero-dimers.