Antimalarial Agents

Design and Mechanism of Action

Graham L. Patrick

• Publisher: Elsevier
• Year: 2020
• Print ISBN: 9780081012109
• eBook ISBN: 9780081012413
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

Antimalarial Agents: Design and Mechanism of Action seeks to support medicinal chemists in their work toward antimalarial solutions, providing practical guidance on past and current developments and highlighting promising leads for the future.Malaria is a deadly disease which threatens half of the world's population. Advances over several decades have seen vast improvements in the eff ectiveness of both preventative measures and treatments, but the rapid adaptability of the disease means that the ongoing search for improved and novel antimalarial drugs is essential.Beginning with a historical overview of malaria and antimalarial research, this book goes on to describe the biological aspects of malaria, highlighting the lifecycle of the parasite responsible for malaria, the problem of resistance, genetic mapping of the parasite's genome, established drug targets, and potential drug targets for the future. This sets the scene for the following chapters which provide a detailed study of the medicinal chemistry of antimalarial agents, with a focus on the design of antimalarial drugs.Drawing on the knowledge of its experienced authors, and coupling historic research with current fi ndings to provide a full picture of both past and current milestones, Antimalarial Agents: Design and Mechanism of Action is a comprehensive yet accessible guide for all those involved in the design, development, and administration of antimalarial drugs, including student academic researchers, medicinal chemists, malaria researchers, and pharmaceutical scientists.- Consolidates both past and current developments in the discovery and design of antimalarial drugs- Presents content in a style that is both thorough and engaging, providing a supportive and guiding reference to students and researchers from interdisciplinary backgrounds- Highlights drug targets currently considered to be the most promising for future therapies, and the classes of compounds that are currently being studied and perfected

Chapter 1

History of malaria and its treatment

Morag Dagen* University of the West of Scotland, Blantyre, Glasgow, United Kingdom

Abstract

Malaria is a very ancient disease. In the past it occurred across much of the globe, inflicting a heavy burden of morbidity and mortality on affected populations. It remains endemic in much of the tropics and climate change could lead to its resurgence in regions which are currently malaria-free. The first effective treatment, an extract of the bark of the South American cinchona tree, was introduced to Europe by the Jesuits in the 17th century. The discovery of the malaria parasite in the late 19th century was followed by identification of the anopheles mosquito as vector. Understanding of the life cycles of parasites and vectors then led to improvements in disease control. Quinine, the active principle of cinchona, was isolated in the 19th century and remained the unrivalled malaria treatment until the 1940s. Many advances were made in the development of synthetic drugs and insecticides during the World War II, leading to the belief that complete eradication of malaria was an achievable goal. However, the subsequent evolution of drug-resistant parasites and insecticide-resistant mosquitoes led to the resurgence of malaria in areas where it had been controlled. Resistance remains a major challenge, and new drugs, treatment regimens, and vector control methods are urgently required due to the evolution of strains of malaria parasites resistant to all available treatments.

Keywords

malaria parasite

anopheles mosquito

cinchona

quinine

drug resistance

1.1. Introduction

Malaria is endemic in many countries and is particularly prevalent in tropical regions. The World Health Organization (WHO) estimates that 3.3 billion people were at risk of infection in 2013, leading to around 200 million cases and more than half a million deaths worldwide. An estimated 90% of malaria deaths occur in Africa, with more than two-thirds of these being in children aged under 5 years. Of the communicable diseases, only tuberculosis causes more fatalities. Malaria and poverty are closely linked, with the burden of malaria morbidity and mortality being borne by the world’s poorest communities. This has the effect of holding back economic growth and creating a cycle of poverty that is difficult to break. The prevalence of this debilitating disease has particularly devastating effects in regions where war and famine have destroyed social infrastructure.¹

The name, malaria, derives from the mediaeval Italian words for bad air-mal aria. The then widely held miasma theory of humoral medicine attributed many infectious diseases to the presence of foul or corrupt air, poisoned by noxious vapors produced by putrefying materials. In terms of public health measures, this led to the removal of foul smelling waste that could be a source of many infections, and the draining of ditches and ponds containing stagnant water. Stagnant water plays an important role in the spread of malaria, as this is where mosquitoes lay their eggs and where their larvae develop. Around 30 of the 400 species of anopheline mosquitoes transmit malarial infections with varying efficiencies.

Malaria is caused by protozoan parasites of the genus Plasmodium, which are transmitted into the blood supply of human hosts by the bite of female anopheles mosquitoes. The species of protozoa that are responsible for malaria infections in humans are Plasmodium vivax, P. malariae, P. ovale, P. falciparum, and P. knowlesi. P. vivax and P. falciparum pose the greatest threat to public health, with P. falciparum being more prevalent and causing the greatest morbidity and mortality. P. vivax can develop in the mosquito host at lower temperatures than P. falciparum and survives at higher altitudes. Consequently, it has a wider geographical distribution, which explains why it causes more infections than P. falciparum in regions outside Africa. The parasite also has a dormant liver stage that can reactivate after months or even years, causing relapses without reinfection. P. falciparum is a very ancient human parasite, and DNA studies have shown that it coevolved with humans-an example of parasite host cospeciation. The other parasite species transferred to humans from other primates.² For example, P. knowlesi causes malaria in monkey species in parts of Southeast Asia, and there have been reports of human infections in recent years.^1,3

Many of the symptoms of malaria, such as chills, high fever, profuse sweating, headache, muscle pains, malaise, diarrhea, and vomiting commonly occur in other diseases. However, malaria is characterized by periodic paroxysmal febrile episodes (i.e., sudden recurrence or intensification of fever), and untreated infection leads to enlargement of the spleen. P. falciparum can cause potentially fatal damage to lungs, liver, and kidneys, as well as severe anemia and coma in cerebral malaria that frequently result in death. Chronic infection with P. malariae can cause kidney damage, leading to nephrotic syndrome which may be fatal. Repeated malarial infections are extremely debilitating and make the sufferer susceptible to other diseases.⁴

From the first appearance of Homo sapiens in East Africa, the evolution of humans and their parasites has run in parallel, and as early humans migrated out of Africa to the wider world, their parasites spread with them. Many factors, such as the development of agriculture and the concentration of populations in ur...

Table of contents

• Cover
• Title page
• Contents
• Copyright
• Contributors
• Chapter 1: History of malaria and its treatment
• Chapter 2: Knowing one’s enemy: the Plasmodium parasite
• Chapter 3: The cinchona alkaloids and the aminoquinolines
• Chapter 4: Artemisinin and artemisinin-related agents
• Chapter 5: Agents acting on pyrimidine metabolism
• Chapter 6: Antimalarial agents acting on hemoglobin degradation
• Chapter 7: Plasmepsins as targets for antimalarial agents
• Chapter 8: Falcipains as drug targets in antimalarial therapy
• Chapter 9: Drug targets in the apicoplast
• Chapter 10: Drugs targeting mitochondrial functions
• Chapter 11: The Plasmodium falciparum proteasome as a drug target
• Chapter 12: Transferases and their inhibition
• Chapter 13: Kinases and kinase inhibitors
• Chapter 14: Miscellaneous agents of clinical interest
• Chapter 15: Inhibitors of purine and pyrimidine pathways
• Chapter 16: Miscellaneous targets
• Index