Download or read book The Synthesis and Development of Novel Inhibitors of the Plasmodium Falciparum Chloroquine Resistance Transporter written by Karen Joy Deane and published by . This book was released on 2014 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The work detailed in this thesis has been directed towards the synthesis of inhibitors of the Plasmodium falciparum chloroquine resistance transporter (PfCRT). Mutations in this protein are responsible for resistance of the malaria parasite to the antimalarial drug, chloroquine. Inhibitors of PfCRT are known as resistance reversers, and include the antihistamine chlorpheniramine, which has been used as the basis of all the structures that have been developed in this work. Chapter 1 provides an introduction to the disease malaria, caused by Plasmodium parasites. A brief review of antimalarial drugs is presented, with a focus on the most successful of these, chloroquine, and the development of resistance to this drug. Chapter 2 reports the synthetic route to the synthesis of 30 analogues of chlorpheniramine, which includes the preparation and characterisation of 29 previously unreported compounds. Analogues were assayed for and showed the ability to inhibit chloroquine transport by PfCRT, which was correlated to the ability to lower the IC50 of chloroquine in resistant strains of Plasmodium falciparum. The development and synthesis of 10 novel reversed chloroquines is presented in Chapter 3. The targeted structures were analogues of a hybrid structure based on chloroquine and chlorpheniramine, and possessed potent antimalarial activity in addition to their strong activity as inhibitors of PfCRT. 32 new compounds were prepared and characterised. A second generation approach is detailed in the synthesis of 10 reversed sontochins in Chapter 4. The sontochin/chlorpheniramine hybrids showed enhanced activity as inhibitors of PfCRT compared to the previous series. 25 new compounds were synthesised and characterised en route. Chapter 5 describes the synthesis of two chlorpheniramine analogues that have been adapted for inclusion in a reversed tetraoxane. These structures showed no improvement to the activity of chlorpheniramine at inhibiting PfCRT, but possess features for incorporation into an endoperoxide antimalarial. The preparation and characterisation of 20 new compounds is reported.
Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.
Download or read book Synthesis of Novel Chloroquine Derivatives and Insights Into the Interactions of a Resistance Protein written by Benita Kapuku and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The human toll caused by malaria remains devastating. In 2018 alone, there were 228 million cases, which resulted in 405,000 deaths. Malaria is caused by the Plasmodium parasite transmitted by the Anopheles mosquito. There are five species: P. malariae, P.falciparum, P. vivax, P. ovale and P. knowlesi, in which P. falciparum is the most common and most deadly. An antimalarial drug called chloroquine (CQ) was first introduced in the 1940s and is considered the gold-standard antimalarial drug due to its high efficacy, low-cost, and low-toxicity. It is listed under the World Health Organization (WHO) essential medicines and showed great promise in their endeavor to eradicate malaria.Unfortunately, after two decades of use resistance began to arise, which led to its gradual withdrawal for P. falciparum cases. The WHO has reported an increase in the number of malaria cases over the last six years (214, 216, 228 million cases in 2014, 2016 and 2018, respectively), this is alarming as it greatly hampers the effects of eradication. Therefore, it remains crucial to invest in the research and development of new antimalarial drug candidates. Recent studies have reported the re-sensitization of chloroquine in countries where it was once completely banned, such as Malawi, Zambia and certain regions of The Ivory Coast. This indicates that resistance is reversible because it requires a fitness deficit. When drug pressure is removed, the frequency of resistance alleles is reduced but not eliminated. Therefore, the reintroduction of drug pressure will cause a rapid reemergence of resistance. As CQ was the ideal drug, many derivatives with varying sidechains and aryl substituents such as amodiaquine and piperaquine have emerged as commercial drugs. Aminoquinolines (AQs) continue to be prepared and tested, and two AQs wereIIIrecently undergoing phase II clinical trials, demonstrating the robustness of the AQ core and their future potential.My research centres around the repurposing of chloroquine via modification at the 3-position of the quinoline ring. In chapter 2 I describe the synthesis and optimization of 3-aminochloroquine (3-NH2CQ). The synthesis of this derivative allows for expansion at the 3-position for the synthesis of a diverse library of antimalarial candidates.In chapter 3, I describe the synthesis of novel substituted chloroquine analogs. The structure- activity relationship (SAR) was determined as I synthesized a library of compounds with varying steric and electronic effects. It was determined that electron-withdrawing substituents at the para- position gave the best antimalarial activity. Although the synthesized compounds were not as effective as CQ, they may be candidates for combination therapy with chloroquine.In chapter 4, I describe the synthesis of a CQ photoaffinity label with minor modifications. An aryl azide is installed at the 3rd-position on the quinoline ring, making it the first AQ photoaffinity label in the literature with the least number of modifications whilst retaining all features of the parent compound, to our knowledge. Labelling studies were then carried out to determine the lability of the photoaffinity label.Lastly, the protein responsible for CQ resistance, Plasmodium falciparum chloroquine resistance transporter (PfCRT), has been isolated for the first time. In chapter 5, I describe binding studies carried out with PfCRT. In collaboration with Prof. Fidock's group at Columbia University,IVfluorescence and UV-Vis binding studies were carried out to determine binding affinities of heme and CQ with PfCRT"--
Download or read book Characterization of Plasmodium Falciparum Resistance to Novel Drugs written by Sonia Edayé and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Plasmodium falciparum is the deadly protozoan parasite responsible for malaria. Malaria is one of the most important infectious diseases that has been raging for millennia and affecting almost half of the world's population. The treatment regimen that was based on quinoline drugs such as chloroquine (CQ), was efficient for decades. Nowadays, the use of this class of drugs is doomed to failure due to the emergence of quinoline-resistant parasites. Today, artemisinin-based combination therapies (ACTs) are the first-line drugs for uncomplicated falciparum malaria treatment. ACTs improve the cure rate of malaria and thus are seen as efficient treatment against uncomplicated forms of the disease. Despite their efficiency, these drugs are currently facing the development of resistance. PfCRT and PfMDR1, which are membrane transporters, have been shown to be involved in malaria parasites drug resistance. To tackle the inefficiency of existing drugs in regard to the development of resistance, alternative therapies must be discovered. In this thesis, antimalarial activity of novel potential drugs against P. falciparum is assessed and the interaction of these drugs with PfCRT and PfMDR1 is determined. Furthermore, because many ABC transporter genes play a key role in drug resistance, the characterization of an ABC transporter member of the ABCG family in Plasmodium is addressed and its role in drug resistance investigated.In the first part of this thesis, MK571 (a quinoline analogue) activity against P. falciparum parasites is investigated. MK571 is found to be more toxic to most of the CQ-resistant strains than to the CQ-sensitive strains. In addition, we determine that MK571 is not a substrate of PfCRT as are other quinoline drugs, but is instead a substrate of PfMDR1. Therefore, it can be a good complement to existing quinoline drugs in the treatment of uncomplicated malaria. In the second part, novel compound analogues of chloroquine are tested for their antimalarial activity against CQ-sensitive and -resistant parasites. Although chloroquine analogues tested possess the quinoline ring structure of chloroquine, they are less efficient than chloroquine and are not substrates of PfCRT. One of the analogues (3-ICQ) reverses the resistance of CQ-resistant strains to chloroquine and therefore, could be used in combination with chloroquine in cases of CQ-resistant malaria. In the third part of the thesis we conduct the characterization of PfABCG, the sole member of the P. falciparum ABCG family. The characterization study demonstrates that PfABCG is localized on the parasite plasma membrane and is expressed throughout the asexual life cycle of the parasite. In addition, PfABCG is differentially expressed in various Plasmodium strains. This expression does not correlate with the resistance to chloroquine but to the sensitivity of the parasite to an antihistaminic drug named ketotifen. Overall, this thesis sheds light on challenges and understanding of the complex resistance machinery deployed by the P. falciparum parasite from novel drug discovery to characterization of proteins. " --
Download or read book Saving Lives Buying Time written by Institute of Medicine and published by National Academies Press. This book was released on 2004-09-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africaâ€"currently just over one million per yearâ€"are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called "artemisinins" are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.
Download or read book Antimalarial Agents written by Graham L. Patrick and published by Elsevier. This book was released on 2020-05-30 with total page 624 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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
Download or read book World Malaria Report 2015 written by World Health Organization and published by World Health Organization. This book was released on 2016-01-30 with total page 283 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Malaria Report 2015assesses global malaria disease trends and changes in the coverage and financing of malaria control programs between 2000 and 2015. It also summarizes progress towards international targets, and provides regional and country profiles that summarize trends in each WHO region and each country with malaria. The report is produced with the help of WHO regional and country offices, ministries of health in endemic countries, and a broad range of other partners. The data presented are assembled from the 96 countries and territories with ongoing malaria transmission, and a further five countries that have recently eliminated malaria. Most data are those reported for 2014 and 2015, although in some cases projections have been made into 2015, to assess progress towards targets for 2015.
Download or read book Assessment of Long Term Health Effects of Antimalarial Drugs When Used for Prophylaxis written by National Academies of Sciences, Engineering, and Medicine and published by National Academies Press. This book was released on 2020-04-24 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.
Download or read book Treatment and Prevention of Malaria written by Henry M. Staines and published by Springer Science & Business Media. This book was released on 2012-01-06 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has defeated previous efforts at eradication and remains a massive global public health problem despite being readily preventable and treatable. It is a devastating disease that also extracts huge economic costs from the poorest countries in endemic regions. Starting with an overview of the disease and its current political, financial and technical context, this Milestones in Drug Therapy volume describes the history, chemistry, mechanisms of action and resistance, preclinical and clinical use, pharmacokinetics and safety and tolerability of the current range of antimalarial drugs. There is particular emphasis on artemisinins and related peroxides, as these drugs have now become the frontline treatment for malaria. Next generation antimalarials, molecular markers for detecting resistance, the importance of diagnostics and disease prevention are also covered in detail.
Download or read book Handbook of Antimicrobial Resistance written by Matthias Gotte and published by Springer. This book was released on 2018-02-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: While many volumes have been written about various aspects of antimicrobial resistance, this book is a comprehensive reference work. All manifestations of resistance are addressed: viral; bacterial, parasitical and fungal are given dedicated sections. The underlining molecular mechanisms, which depend not only on the microbe but on the specific drug (target), are highly diverse. This work discusses and compares the biological, biochemical and structural aspects of resistance and its evolution.
Download or read book Malaria Drugs Disease and Post genomic Biology written by David Sullivan and published by Springer Science & Business Media. This book was released on 2006-01-09 with total page 447 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite rapid increases in knowledge, malaria continues to kill more than a million people each year and causes symptomatic disease in a further 300 million individuals. This volume brings some of the world's best investigators to describe recent advances in both the scientific and clinical aspects of malaria, and bridges between the two.
Download or read book Apicomplexan Parasites written by Katja Becker and published by John Wiley & Sons. This book was released on 2011-01-19 with total page 548 pages. Available in PDF, EPUB and Kindle. Book excerpt: This handbook is the first dealing with the discovery of drugs directed against apicomplexan parasites. Amongst others, this group of endoparasites includes the causative agents of Malaria, Toxoplasmosis, and Babesiosis, the latter occurring mainly in animals. Written by renowned scientific experts from academia and industry, the book focuses on currentdrug development approaches for all apicomplexan diseases making it appealing to a large audience, ranging from research labs in academia to the human and veterinarian pharmaceutical industry. This work is the second volume of the new book series 'Drug Discovery in Infectious Diseases', edited by Prof. Dr Paul M. Selzer.
Download or read book World Malaria Report 2019 written by World Health Organization and published by . This book was released on 2019-08-28 with total page 224 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Malaria Report 2019 provides a comprehensive update on global and regional malaria data and trends. The report tracks investments in malaria programs and research as well as progress across all intervention areas: prevention, diagnosis, treatment, elimination, and surveillance. It also includes dedicated chapters on the consequences of malaria on maternal infant and child health the "High Burden to High Impact" approach as well as biological threats to the fight against malaria. The 2019 report is based on information received from more than 80 countries and areas with ongoing malaria transmission. This information is supplemented by data from national household surveys and databases held by other organizations.
Download or read book Protein Kinases as Drug Targets written by Bert Klebl and published by John Wiley & Sons. This book was released on 2011-03-16 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt: This timely guide to kinase inhibitor drug development is the first to cover the entire drug pipeline, from target identification to compound development and clinical application. Edited by the pioneers in the field, on the drug development side this ready reference discusses classical medicinal chemistry approaches as well as current chemical genomics strategies. On the clinical side, both current and future therapeutic application areas for kinase inhibitor drugs are addressed, with a strong focus on oncology drugs. Backed by recent clinical experience with first-generation drugs in the battle against various forms of cancer, this is crucial reading for medicinal, pharmaceutical and biochemists, molecular biologists, and oncologists, as well as those working in the pharmaceutical industry.
Download or read book Encyclopedia of Malaria written by and published by Springer. This book was released on 2018-07-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Encyclopedia of Malaria represents a vast databank of information about the study of malaria. It provides an overview of the historical, rapid and significant developments that have occurred in malaria research, including the 2002 genome sequencing of Plasmodium falciparum and its mosquito vector, Anopheles gambiae. This work provides a concise source of up-to-date research findings in the form of definitions and essays and present comprehensive coverage of topics from history to findings to diagnosis and treatment, written by recognized malaria researchers with practical experience. It appeals to a diverse audience, including malaria researchers, teachers, investigators and public health professionals.
Download or read book Natural Remedies in the Fight Against Parasites written by Hanem Khater and published by BoD – Books on Demand. This book was released on 2017-07-12 with total page 250 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book emphasizes past and current research efforts about principles of natural control of major parasites affecting humans, animals, and crops. Each chapter is a complete and integrated subject that presents a problem and confers on the safe alternatives to chemicals. This book discusses and updates information about three major topics of natural remedies. The first topic is represented in a chapter outlining important information on biological control of parasites, the second topic is represented in three chapters dealing with botanicals as promising antiparasitic agents, and the last four chapters deal with miscellaneous control strategies against parasites. This easily readable book is designed precisely for students as well as professors linked with the field of parasitic control. We enhanced words with breathing areas in the form of graphical abstracts, figures, photographs, and tables.
Download or read book Innovations and Implementations of Computer Aided Drug Discovery Strategies in Rational Drug Design written by Sanjeev Kumar Singh and published by Springer Nature. This book was released on 2021-02-02 with total page 334 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents various computer-aided drug discovery methods for the design and development of ligand and structure-based drug molecules. A wide variety of computational approaches are now being used in various stages of drug discovery and development, as well as in clinical studies. Yet, despite the rapid advances in computer software and hardware, combined with the exponential growth in the available biological information, there are many challenges that still need to be addressed, as this book shows. In turn, it shares valuable insights into receptor-ligand interactions in connection with various biological functions and human diseases. The book discusses a wide range of phylogenetic methods and highlights the applications of Molecular Dynamics Simulation in the drug discovery process. It also explores the application of quantum mechanics in order to provide better accuracy when calculating protein-ligand binding interactions and predicting binding affinities. In closing, the book provides illustrative descriptions of major challenges associated with computer-aided drug discovery for the development of therapeutic drugs. Given its scope, it offers a valuable asset for life sciences researchers, medicinal chemists and bioinformaticians looking for the latest information on computer-aided methodologies for drug development, together with their applications in drug discovery.
