Antimalarial 1,2,4-Trioxanes: Synthesis and Biological Evaluation

Abstract

Malaria is still one of the major health problems in the whole world along with tuberculosis and AIDS. The parasite responsible for the vast majority of fatal malarial infections is P. falciparum. The first effective antimalarial drug was quinine, which was isolated from the bark of Cinchona. Since then malaria has been treated with quinoline-based drugs such as quinine, chloroquine, mefloquine and primaquine. The burgeoning global problem of malaria is largely due to the emergence of parasite resistance to our limited armamentarium of antimalarial drugs. The prevalence of resistance to known antimalarial drugs has resulted in the expansion of antimalarial drug discovery efforts. The isolation of artemisinin in 1972 by Chinese scientists, and their development of all the derivatives now used in the treatment of malaria today, were of outstanding importance. The results which have accumulated both from the Chinese work and from that subsequently conducted on a worldwide, provided a comprehensive understanding of the chemistry, pharmacological profiles, toxicology, metabolism, and mode of action of these potent antimalarial peroxide. The optimal regimens for use in the field are also apparent, particularly in combinations with longer half-life quinoline antimalarials. Thus the future use of the artemisinin class of drug appears assured. The most important artemisinin derivatives like artesunate, artemether, arteether and dihydroartemisinin are fast acting drugs but they are eliminated quickly as they have short plasma half life. Their rapid onset makes them especially effective against severe malaria. Their rapid disappearance may be a key reason why artemisinin resistance has been so slow to develop, and may also explain the reason of recrudescence when used in monotherapy. In light of these facts, WHO has now recommended use of artemisinin derivatives in combination with classical drugs that have long plasma half-life. Efforts have been made to understand the mechanism of action and pharmacokinetics of artemisinin derivatives so as to synthesize compounds that have reduced neurotoxicity, better bioavailability, good solubility and longer plasma half life. Although artemisinin and its derivatives are still the best known antimalarials but they suffers real problem of poor natural abundance, high cost, poor bioavailability and high rate of recrudescence. The identification of 1,2,4-trioxane moiety as principal pharmacophore of artemisinin has led to the development of several synthetic peroxides that have shown potential antimalarial activity and have gone up to clinical stages. Central Drug Research Institute (CDRI), Lucknow is also one of the leading institutions in the World that have given huge contribution towards the development of artemisinin based antimalarials together with synthetic peroxides. The main objective of CDRI malaria research programme is to develop antimalarials that are effective against multidrug-resistant malaria and are commercially viable. As a part of this programme in search for better antimalarials, an attempt has been made to synthesize semisynthetic analogues of artemisinin and structurally simple synthetic 1,2,4-trioxanes that have high antimalarial potency. In this thesis synthesis of structurally diverse synthetic 1,2,4-trioxanes, their antimalarial activity and chemistry have been reported. The present thesis also covers the synthesis and antimalarial assessment of several semisynthetic derivatives of artemisinin as well. The results of these studies are discussed in five chapters as summarized below: The first chapter is a review which gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanism of resistance are explained. This review also covers all classes of antimalarials of which at least one drug candidate is in clinical development. The second chapter describes the details of synthesis and antimalarial assessment of amino functionalized 1,2,4-trioxanes in search for better substitutes for artemisinin analogues. The third chapter, describe the synthesis of bile acid-based 1,2,4-trioxanes and explores the role of polar substituent and side-chain length on antimalarial activity of these compounds. This chapter is divided into two sections. Section A, includes synthesis and antimalarial activity of bile acid-based 1,2,4- trioxanes. Section B, include synthesis and antimalarial activity of lithocholc acid-based 1,2,4-trioxanes with modified side-chain length. The fourth chapter describes the chemistry of 1,2,4-trioxanes, as a protecting group for ketone and its deprotection under neutral condition. The fifth chapter covers the details of synthesis and antimalarial activity of a new class of azaartemisinin derivatives having free hydroxy functionality.