Parasitic Infections E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Parasitic Infections Understand and defeat a scourge of public health with this cutting-edge guide Parasitic diseases are considered as an important public health problem due to the high morbidity and mortality rates, particularly in countries where climate and level of economic development create serious challenges to the creation of public health infrastructure, thus can make parasitic infections both graver and more difficult to contain. As we come to understand the global ramifications of public health, there has never been a more crucial time to understand these infections and the processes by which they can be managed and defeated. Parasitic Infections is a comprehensive overview of parasitic immunopathology, including the fundamentals of parasite biology, mechanisms and processes of infection, and the key steps of drug discovery and treatment. In addition to detailed coverage of the most commonly encountered infectious parasites, analysis of the immune system provides material pertinent to any possible parasitic infection. The result is an essential contribution to public health research. Parasitic Infections readers will also find: * A careful balance of parasite immunopathology and pharmaceutical analysis * Detailed discussion of parasites such as protozoans, helminths, and ectoparasites * Case studies and in-depth analyses written by authors around the world on the basis of first hand investigation Parasitic Infections is a must-read for researchers or professionals in immunology, biology, medicinal chemistry, drug development or pharmaceutical research, and all related fields.
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Veröffentlichungsjahr: 2023
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Parasitic Infections
Immune Responses and Therapeutics
Edited by
Abhay Prakash Mishra
University of the Free State,Bloemfontein, South Africa
Manisha Nigam
Hemvati Nandan Bahuguna Garhwal University,Srinagar Garhwal, India
Copyright © 2024 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
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Hardback ISBN: 9781119878025; ePub ISBN: 9781119878049; ePDF ISBN: 9781119878056; oBook ISBN: 9781119878063
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Set in 9.5/12.5pt STIXTwoText by Integra Software Services Pvt. Ltd, Pondicherry, India
We dedicate Parasitic Infections: Immune Responses and Therapeutics to frontline corona warriors––doctors and healthcare workers who sacrificed their lives while saving patients during the ongoing COVID-19 pandemic.
The sacrifice of doctors and healthcare workers across the globe will not go to waste. Humanity will always be grateful to them for what they did during these unprecedented times.
First and foremost, Abhay Prakash Mishra dedicates this book to his parents, Mr. Jay Prakash Mishra and Mrs. Kavita Mishra, who gave birth to him and moulded him into the person he is today. Another word of gratitude is extended to his beloved wife Priyanka Mishra, who has stood by him steadfastly over the years.
Manisha Nigam dedicates this book to her late mother, Adarsh Nigam, who has always inspired her with strength and inspiration. She also appreciates her husband Anand Kaushal for his support, encouragement, and love throughout this journey.
Contents
Cover
Title Page
Copyright Page
Dedication
List of Contributors
Preface
Acknowledgements
1 Introduction: Back to the Future ‒ Solutions for Parasitic Problems
2 Induction of Immune Responses and Inflammation to Parasitic Infections
3 Animal Parasites: Insight into Natural Resistance
4 Immune Response against Protozoan Parasites
5 Immune Response against Helminths
6 Ectoparasites Host Resistance and Tolerance
7 Microorganisms as Drivers of Host‒Parasite Interactions
8 Neglected Parasitic Infections: History to Current Status
9 Molecular Techniques for the Study and Diagnosis of Parasite Infection
10 Drugs for the Control of Parasitic Diseases: Current Status and Case Studies
11 Opportunities and Challenges in the Development of Antiparasitic Drugs
12 Phytopharmaceuticals as an Alternative Treatment against Parasites
13 Nanoparticles for Antiparasitic Drug Delivery
14 Vaccination Against Parasitic Infection: From Past to Current Approaches in the Development of a Vaccine
15 Current Trends in Parasitic Diseases and Precautionary Measures
Index
End User License Agreement
List of Tables
CHAPTER 07
Table 7.1 Specific components of the microbiota...
CHAPTER 09
Table 9.1 Brief outline classification...
Table 9.2 Some important parasites...
Table 9.3 Diagnostic techniques...
CHAPTER 10
Table 10.1 Parasitological results of the...
Table 10.2 Wuchereria bancrofti prevalence...
Table 10.3 Wuchereria bancrofti prevalence...
CHAPTER 11
Table 11.1 Some recent potential antiparasitic...
Table 11.2 Typical repurposed or repositioned...
CHAPTER 12
Table 12.1 Current phytopharmaceutical...
CHAPTER 13
Table 13.1 Some parasitic diseases...
Table 13.2 Types of nanoparticles.
Table 13.3 Nanoparticle delivery...
CHAPTER 14
Table 14.1 Different types of vaccine with...
List of Illustrations
CHAPTER 02
Figure 2.1 Role of dendritic cells...
CHAPTER 05
Figure 5.1 Host-related variables...
CHAPTER 06
Figure 6.1 The life cycle of tick in three hosts.
Figure 6.2 The life cycle of a bed bug.
Figure 6.3 The life cycle of tsetse fly in human host.
Figure 6.4 The life cycle mosquito.
Figure 6.5 Major mechanisms...
CHAPTER 07
Figure 7.1 Model of bacteria...
CHAPTER 08
Figure 8.1 Landmarks in the development...
Figure 8.2 Classification systems....
Figure 8.3 List of neglected parasitic...
CHAPTER 09
Figure 9.1 Serology testing...
Figure 9.2 Typical RDT for malaria...
Figure 9.3 Assessment of LIPS for...
Figure 9.4 Multiplex real-time...
Figure 9.7 LAMP in the diagnosis...
Figure 9.6 Luminex xMAP technology...
Figure 9.5 Luminex xMAP technology...
CHAPTER 10
Figure 10.1 Chemical structure of drugs used...
Figure 10.2 Chemical structure of drugs...
CHAPTER 11
Figure 11.1 Comparative time pathways for de...
CHAPTER 12
Figure 12.1 Antiparasitic phytopharmaceuticals...
CHAPTER 14
Figure 14.2 Different stages of...
Figure 14.1 Development cycle of...
CHAPTER 15
Figure 15.1 Current trends in parasitic diseases.
Guide
Cover
Title Page
Copyright Page
Dedication
Table of Contents
List of Contributors
Preface
Acknowledgments
Begin Reading
Index
End User License Agreement
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List of Contributors
Ayodeji Mathias AdegokeCancer Research and Molecular Biology LaboratoriesDepartment of BiochemistryFaculty of Basic Medical SciencesCollege of MedicineUniversity of IbadanNigeria
Kayode Olayinka AfolabiPathogenic Yeast Research GroupDepartment of Microbiology and BiochemistryFaculty of Natural and Agricultural SciencesUniversity of the Free StateBloemfonteinSouth Africa
and
Molecular Epidemiology and PublicHealth Research GroupDepartment of Biological SciencesAnchor UniversityLagosNigeria
Mustapha Abdullahi AkpakiDepartment of BiochemistryFederal University of TechnologyOwerriImoNigeria
Jacob Kehinde AkintundeApplied Biochemistry and MolecularToxicology Research GroupDepartment of BiochemistryCollege of BiosciencesFederal University of AgricultureAbeokutaNigeria
Yahya S. Al-AwthanDepartment of BiologyFaculty of ScienceIbb UniversityIbbYemen
Omar BahattabDepartment of BiochemistryFaculty of SciencesUniversity of TabukTabukSaudi Arabia
Luit Moni BarkalitaDepartment of Animal BiotechnologyCollege of Veterinary ScienceAssam Agricultural UniversityAssamIndia
Maryam Bello-AkinoshoPathogenic Yeast Research GroupDepartment of Microbiology andBiochemistryFaculty of Natural and AgriculturalSciencesUniversity of the Free StateBloemfonteinSouth Africa
Munni BhandariDepartment of MicrobiologySchool of Life SciencesHemvati Nandan Bahuguna GarhwalUniversitySrinagar GarhwalUttarakhandIndia
Anupam BrahmaSRFKrishi Vigyan KendraDudhnoiAssamIndia
Harish ChandraDepartment of Botany andMicrobiologyGurukul Kangri (Deemed to be University)HaridwarUttarakhandIndia
Abdulkadir Mohammed DanyaroDepartment of BiochemistryBauchi State UniversityGadauBauchiNigeria
Sarmistha DebbarmaVeterinary OfficerAnimal Resources Development DepartmentGovt of TripuraPrani Sampad Bikash BhawanPandit Nehru ComplexGurkhabustiKunjabanWest Tripura
Aqsa FarooquiDepartment of NursingIndian Institute of Health and Technology (IIHT)DeobandSaharanpurUttar PradeshIndia
Arti GautamPharmacology DivisionNational Botanical Research Institute (NBRI-CSIR)LucknowUttar PradeshIndia
Seetha HarilalFaculty of Pharmaceutical SciencesKerala University of Health SciencesKeralaIndia
Fida HussainDepartment of PharmacyUniversity of SwabiSwabiPakistan
Swinder Jeet Singh KalraDepartment of ChemistryD.A.V. CollegeKanpurIndia
Salah-Ud-Din KhanDepartment of BiochemistryCollege of MedicineImam Mohammad Ibn Saud Islamic University (IMSIU)RiyadhSaudi Arabia
Shahanavaj KhanDepartment of Medical Lab TechnologyIndian Institute of Health and Technology (IIHT)Deoband, SaharanpurUttar PradeshIndia
and
Department of Health SciencesNovel Global Community Educational FoundationAustralia
Rajesh KumarFaculty of Pharmaceutical SciencesKerala University of Health SciencesKeralaIndia
Vijay Jyoti KumarDepartment of Pharmaceutical SciencesH. N. B. Garhwal UniversitySrinagar GarhwalUttarakhandIndia
Prabhakar MauryaConsultantCEHTRA Chemical Consultants Pvt. LtdB1/A5Mohan Co-Operative Industrial EstateNew DelhiIndia
Dearikha Karina MayashintaDepartment of ParasitologyFaculty of MedicineUniversitas BrawijayaMalangEast JavaIndonesia
Abhay Prakash MishraDepartment of PharmacologySchool of Clinical MedicineFaculty of Health SciencesUniversity of the Free StateBloemfonteinSouth Africa
Tribhuvan Mohan MohapatraDepartment of MicrobiologyInstitute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
Adeline Lum NdeDepartment of PharmacologySchool of Clinical MedicineFaculty of Health SciencesUniversity of the Free StateBloemfonteinSouth Africa
Rahul NegiDepartment of MicrobiologySchool of Life SciencesHemvati Nandan Bahuguna Garhwal UniversitySrinagar GarhwalUttarakhandIndia
Manisha NigamDepartment of BiochemistryHemvati Nandan Bahuguna Garhwal UniversitySrinagar GarhwalUttarakhandIndia
Shakir Mayowa ObidolaDepartment of Crop Production TechnologyFederal College of ForestryJosPlateauNigeria
Olalekan OgunroDepartment of Biological SciencesKola Daisi UniversityIbadanOyoNigeria
Ahmed OlatundeDepartment of Medical BiochemistryAbubakar Tafawa Balewa UniversityBauchiNigeria
Carolina Pohl-AlbertynPathogenic Yeast Research GroupDepartment of Microbiology and BiochemistryFaculty of Natural and Agricultural SciencesUniversity of the Free StateBloemfonteinSouth Africa
Abdu RaufDepartment of ChemistryUniversity of SwabiSwabi, AnbarKhyber PakhtunkhwaPakistan
Muhammad RizwanCentre for Biotechnology and MicrobiologyUniversity of SwatKhyber PakhtunkhwaPakistan
SairaDepartment of ZoologyUniversity of SwabiSwabiPakistan
Yulia Dwi SetiaDepartment of ParasitologyFaculty of MedicineUniversitas BrawijayaMalangEast JavaIndonesia
and
Department of ParasitologyDepartment of Infectious DiseaseFaculty of MedicineUniversity of MiyazakiJapan
Syed Muhammad Mukarram ShahDepartment of PharmacyUniversity of SwabiSwabiPakistan
Rahime ŞimşekDepartment of Pharmaceutical ChemistryFaculty of PharmacyBaşkent UniversityAnkaraTurkey
Gurdeep SinghSchool of Pharmaceutical SciencesLovely Professional UniversityPhagwaraPunjabIndia
Mukesh SinghSchool of Pharmaceutical SciencesIFTM UniversityMoradabadUttar PradeshIndia
Nisha SinghHemvati Nandan Bahuguna Garhwal University (A Central University)Srinagar (Garhwal)UttarakhandIndia
Rahul Kunwar SinghDepartment of MicrobiologySchool of Life SciencesHemvati Nandan Bahuguna Garhwal UniversitySrinagar GarhwalUttarakhandIndia
Kishawar SultanaCentre of Biotechnology and MicrobiologyUniversity of PeshawarKhyber PakhtunkhwaPakistan
Pratichi Singh SwetanshuDepartment of BiosciencesSchool of Basic and Applied SciencesGalgotias UniversityGreater NoidaUttar PradeshIndia
Jupi TalukdarConsultantMahisah Perspicientia LLPIrkuchi GuwahatiAssamIndia
Habibu TijjaniDepartment of BiochemistryBauchi State UniversityGadauBauchiNigeria
Abhishek TiwariPharmacy AcademyIFTM UniversityMoradabadUttar PradeshIndia
Varsha TiwariPharmacy AcademyIFTM UniversityMoradabadUttar PradeshIndia
Archana YadavDepartment of MicrobiologyInstitute of Biosciences and BiotechnologyC.S.J.M. UniversityKanpurUttar PradeshIndia
Shikha YadavDepartment of PharmacySchool of Medical and Allied SciencesGalgotias UniversityGreater NoidaUttar PradeshIndia
Nasib ZamanCentre for Biotechnology and MicrobiologyUniversity of SwatKhyber PakhtunkhwaPakistan
Preface
Parasitic infections remain a significant cause of morbidity and mortality in the world today. Indeed, many of the key parasites found today existed and were widely distributed before written records were created, and our forefathers must have been aware of the presence of the largest and most frequent worms, as well as some parasitic disorders. Often endemic in developing countries, many parasitic diseases are neglected in terms of research funding and much remains to be understood about parasites and the interactions they have with the immune system. These diseases result in more severe consequences in tropical and subtropical countries due to their low economy that makes it even more difficult to design and implement health control programs. This situation opens the door to the emergence and reemergence of these diseases; therefore, it is essential to study and update the immunopathological behavior of parasitic diseases with the objective of the designing of strategy that could eradicate it fully. Remarkable achievements in parasitic infections and immune responses, both basic and translational, have occurred over the last ten years, and we have incorporated these into the this book. We have added around 1,000 references to document these advances. There exists great variation in the degree to which parasites are fastidious with respect to their hosts. This is exemplified by the expression “host range,” a descriptive feature of a given parasite used to characterize the variety of species that can be infected by that parasite. Many parasites are highly selective (i.e., host specific), their range of hosts being limited to one, or a few related, species. This book encompasses the status of research concerned with natural resistance of prospective hosts toward animal parasites and indicates profitable directions of future research. Featuring the work and dedication of several world experts, this book emphasizes the immunopathology by delineating the concepts of immunity and inflammation against parasitic infections. It covers almost all the current issues in the concerned area of parasitic infections from its induction to treatment. This current knowledge of immune responses to parasitic infections affecting humans, including interactions that occur during co-infections and how immune responses may be manipulated to develop therapeutic interventions against parasitic infection, has been thoroughly discussed. For easy reference, the most commonly studied parasites are examined in individual chapters written by investigators at the forefront of their fields. An overview of the immune system, as well as introduction to parasites, is included to guide background reading that will cover immunopathology of all types of parasitic infections i.e. protozoan, helminths and ectoparasites. Also included will be the discussions of drug development and associated challenges so far. An important feature of this book is the discussion of neglected parasitic infections and nanoparticles for antiparasitic drug delivery, a recently emerging topic. Neglected parasitic infections (NPIs) are a group of parasitic infections that are common in low-income populations in those who struggle to meet their daily basic needs and inaccessibility of primary health care services. The current status of neglected parasitic infections in and around the world and salient achievements resulting from the implementation of the proper control strategies recommended by World Health Organization has been covered in this book. As an emerging novel drug carrier, nanoparticles provide a promising way for the effective treatment of parasitic diseases by overcoming the shortcomings of low bioavailability, poor cellular permeability, nonspecific distribution and rapid elimination of antiparasitic drugs from the body. The progress of the enhanced antiparasitic effects of different nanoparticles payloads, the transport and disposition process in the body and their influencing factors has been elaborated. The challenges and prospects of nanoparticles for antiparasitic drug delivery is also discussed. This will help readers to understand the development trend of nanoparticles in the treatment of parasitic diseases and explore strategies in the development of more efficient nanocarriers to overcome the difficulty in the treatment of parasite infections in the future. The chapter “Microorganisms as drivers of host–parasite interactions” investigates the role of host- and parasite-associated microorganisms in host–parasite interactions at the individual, local and regional level leading to a holistic understanding of how the co-evolution of the different partners influences how the other ones respond, both ecologically and evolutionary. Some phenotypic alterations induced by parasites may also arise from conflicts of interests between the host or parasite and its associated microorganism. It is important and relevant to understand the proximate basis of parasite strategies, to predict their evolutionary dynamics and potentially to prevent therapeutic failures. The number of recently discovered molecular techniques for the study and diagnosis of parasite infection has completely re-structured our comprehension of how our defence system works to produce protection against infection/reinfection, or in some cases, how it becomes subverted by the offending pathogen to enable it to endure inside us for long periods of time. A plethora of molecular-based diagnostic tests have found their way into the routine of the parasitology diagnostic laboratory, improving the ease at which the offending pathogen can be rapidly identified. Newer drugs and vaccinations, many with less harmful side-effects, have come on the market that make controlling parasite populations at the community level possible without the risk of harming the very ones we wish to help. In parasitology, routine laboratory diagnosis involves conventional methods, such as optical microscopy, used for the morphological identification of parasites. Currently, molecular biology techniques are increasingly used to diagnose parasite structures in order to enhance the identification and characterization of parasites. The chapter “Molecular techniques for the study and diagnosis of parasite infection” reviews the current and new diagnostic techniques for the confirmation of parasite infections that affect people worldwide, helping to control parasitic disease mortality. The demand for novel antiparasitic drugs is extraordinarily high, but the pharmaceutical industry is not very enthusiastic about supporting development. Industrial partners are often only interested in compounds close to or already undergoing Phase-I trials. However, drug development costs are enormous, and focus more on the know-how of an industrial partner than on that of the scientist who developed the pharmacological model. Also, socio-economic conditions in endemic countries are often insufficient to allow the emergence of new weapons against parasitic diseases, and alternative strategies therefore need to be considered. Because vaccinations do not work in most instances and the parasites have sometimes become resistant to the available synthetic therapeutics, it is important to search for alternative sources of anti-parasitic drugs. Plants produce a high diversity of secondary metabolites with interesting biological activities, such as cytotoxic, anti-parasitic and anti-microbial properties. These drugs often interfere with central targets in parasites, such as DNA (intercalation, alkylation), membrane integrity, microtubules and neuronal signal transduction. Plant extracts and isolated secondary metabolites that can inhibit parasites have been discussed in detail. We also discuss the challenges and opportunities related to antiparasitic drug discovery, highlighting the progress that has been made in recent years.
In order to participate in the global initiative that is already under way and has everything to do with enhancing the fitness and survival of the vast majority of the human species, it is our intent that readers of this book will be adequately prepared with fundamental knowledge of parasites, immune responses, and therapeutics.
Acknowledgements
This book would not have been possible without the assistance of many people, especially the academic colleagues who worked alongside us along the way. It is the result of a collaborative effort, and it would not have been possible without the amazing people who supported us at every stage.
We are grateful to all the authors who choose our book as a way to help future generations traverse the complexity of parasitology. We hope that this edition proves useful for you and your students in the coming years. Thanks to all the experts (Luigi Milella, Ph.D.; Raffaele Pezzani, Ph.D.; Henrique Douglas Melo Coutinho, Ph.D.; Raja Loganathan, Ph.D.; Divya Kamaraju, Ph.D.; Ruma Jas, Ph.D.; Lubna Shamshad, Ph.D.; Amir Ali Khan, Ph.D.; Syed M. Hassan Shah, Ph.D. and Maria S. Atanassova, Ph.D.) who have given their time and expertise to review this book prior to its publication, and we thank them for the many corrections and suggestions they gave us.
We lack the space here to acknowledge all the other individuals whose special efforts went into this book. We offer instead our sincere thanks—and the finished book that they helped guide to completion. We, of course, assume full responsibility for errors of fact or emphasis.
We are grateful to the students and staff of our research groups, who helped us balance the competing demands on our time; to our colleagues in the Department of Biochemistry at the Hemvati Nandan Bahuguna Garhwal University, Uttarakhand, India and Department of Pharmacology, University of the Free State, Bloemfontein, Free State, South Africa, who helped us with advice and criticism. We hope our readers will continue to provide input for future editions.
Our hats are off to everyone at Wiley publishers. We enjoy collaborating with this enthusiastic, dedicated, and talented team of publishing professionals. Our thanks to the entire team.
Finally, we would like to thank our family and life partners for their unwavering support and patience with our book.
1 Introduction Back to the Future ‒ Solutions for Parasitic Problems
Rahime Şimşek1, Aqsa Farooqui2, Salah-Ud-Din Khan3 and Shahanavaj Khan4,5,*
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey 2 Department of Nursing, Indian Institute of Health and Technology (IIHT), Deoband, Saharanpur, UP, India 3 Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia 4 Department of Medical Lab Technology, Indian Institute of Health and Technology (IIHT), Deoband, Saharanpur, Uttar Pradesh, India 5 Department of Health Sciences, Novel Global Community Educational Foundation, Australia* Corresponding author
1.1 Introduction
Parasites are organisms that range widely in size. Parasites can be bacteria, protists, fungi, viruses, plants or animals. Parasites that live, feed, and harm the host in or on the host organism may be large enough to be visible. It is known that they infect millions of people around the world and cause thousands of deaths. In this respect, parasitic infections are an important health problem worldwide, especially in developing countries [1–3]. Today, parasitic diseases have ceased to be epidemics and have become the problem of the whole world. For example, according to the data of the World Health Organization, 1.5 billion people, in other words, 24% of the world’s population, is infected with helminths transmitted from the soil (https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections).
Diseases caused by parasites have not been adequately studied. The displacement of populations has led to the spread of regional parasitic diseases in the world and treatment and preventive health services are needed everywhere. However, the pharmaceutical industry is still not as interested in developing drugs for the treatment of parasitic infections as in other drugs. Even antiparasitic drugs discovered at the beginning of the twentieth century are still used today. This is important in terms of showing how insufficient are the efforts to develop drugs for parasitic infections. In addition, the COVID-19 pandemic we have been through has also been a risk factor for the spread of parasitic infections. Both the disease itself and the drugs used in the treatment of COVID-19 infection have caused individuals with weakened immunity have become more susceptible to opportunistic parasitic infections.
The treatment of microbial infections or tumoral diseases caused by bacteria, protozoa, fungi, parasites and viruses with drugs is called chemotherapy. In this context, the treatment of infections caused by parasites is also called chemotherapy. Difficulties such as the development of resistance in the treatment of microorganisms other than parasites are also valid for the treatment of infections caused by parasites. Moreover, natural factors such as humidity and temperature also affect the incidence, spread and treatment of some parasitic infections. Mass movements such as travels to these affected regions, and the movement of immigrants also facilitate the spread of parasitic diseases [4–6].
Parasitic infections are most common in tropical climates due to poor hygiene conditions and are less common in developed countries. However, although they affect people who are disadvantaged in many respects, they spread all over the world with mass movements. Thus, parasitic infections affect millions of people around the world every year and can cause deaths. For these reasons, parasitic infections remain current and important as the subjects of drug research and development studies.
Today, there is a need for effective antiparasitic drugs with minimized side effects. In recent years, the factors related to the diseases caused by parasites have been clarified with mechanistic studies of parasitic infections. Thus, more data are available to derive selective and active compounds. With these data, it will be possible to reach new and active drugs having less side effects and increase the success of treatment in the near future.
1.2 Parasite and the Phenomenon of Parasitism
Parasite is a word of Greek origin, and it refers to microorganisms that have evolved to living in or on another organism and feeding by damaging it. Symbiosis is a word of greek origin and means “to live together”. It refers to a long-term and close relationship between two different biological organisms. Parasitism, which is a type of symbiosis, is an opportunistic relationship and expresses the relationship in which one species benefits while the other species is harmed [7–9].
1.3 Role of Parasites in Health and Diseases
The fight against parasites dates back to ancient times with the use of drugs and herbal methods being a success for humanity. According to studies, with the complete eradication of microorganisms such as viruses, bacteria and protozoa, human deaths will decrease and the quality of life will increase [10–13]. However, in a scenario where the parasites are completely destroyed, the ecological role of the parasites in the ecosystem can be better understood. The only parasite that humanity has managed to completely eradicate is variola, the smallpox parasite. Although only one parasite has been eradicated so far, intense efforts are also being made for the eradication of parasitic infections such as leprosy and Chagas disease, which are thought to be eradicated. In certain regions of the world, this eradication has been achieved [14].
In spite of the fact that they are harmful to human health, removing parasites from an ecosystem, especially from ecologically effective species, could be problematic in terms of disturbing the ecological balance. Fighting with parasites is an issue that is almost impossible to completely eradicate and needs to be evaluated in all its dimensions in terms of its consequences. The eradication of one parasite species can lead to the increase or extinction of other parasite species, as well as completely changing the balance of the ecosystem. Although it is thought that as a result of urbanization, healthier and more hygienic conditions will be created, this has not always been the case. In some cases, an increase in parasitic infections has been observed.
However, it is essential to fight parasites and to make efforts for the treatment of parasitic infections, but while doing this, they should not disturb the balance of nature, and strategies should be developed for all species in which life is possible without adversely affecting one another.
1.3.1 Ancient Information of Parasite Towards Health Problems
Medical struggles with microorganisms that cause disease in humans dates back to 3000 BCE. Parasites initially evolved long before the evolution of human beings, and early writings from Egypt mention some such as roundworms and tapeworms. Francesco Redi and Antonie van Leeuwenhoek in the seventeenth century began to research them and created an early version of the branch of parasitology. The pioneer experiments of various great scientists have helped us to understand the pathogenic mechanisms of the parasite.
Our information regarding infections of parasites extend into antiquity, and descriptions of parasites and parasitic infections are observed in the earliest writings and have been confirmed by the discovery of parasites in archaeological material. Human beings are hosts to approximately 300 different species of worms parasite and more than 70 species of various protozoans, several derived from our ancestors primate condition while others have been acquired from animals. Some parasites cause the most important diseases in the world; certainly these are parasites that have received the great attention. Since most of such parasite diseases occur in tropical regions, the parasitology field has tended to overlap with that of tropical medicine, and consequently the histories of these fields are intertwined. The organized study of parasites started with the rejection of the theory of spontaneous generation and the promulgation of the germ theory. After that, the history of human parasitology continued along two lines: the finding of a parasite and its subsequent connection with particular disease, and the identification of particular disease and the subsequent discovery that it was caused through the infection of the particular parasite.
It is known that many plants are used as chemotherapeutic treatments in Chinese medicine. Avicenna defined microbes and treated the diseases caused by microbes. Galenos tried to treat diseases by using the large plant flora of Anatolia. In the seventeenth and eighteenth centuries, plant extracts began to be used for the treatment of febrile illness. In this period, chemotherapy started with the use of Cinchona alkaloids in the treatment of malaria.
Parasites have been defined and characterized depending on a wide variety of factors, from parasite-related factors to host-related factors. Throughout history, humans have been confronted with a large number of parasites, including about 300 species of helminths, and 100 species of protozoa. These microorganisms have caused and continue to cause diseases in humans [10, 15].
1.3.2 Current Information on Parasites Causing Health Problems
Diagnostic methods of parasitic infections have been developed from the past to the present, and many drugs with various chemical compounds have been introduced for treatment. In addition, surgical operations are also performed for the treatment of some parasitic infections. Research on parasites and new drug development studies continue in line with the available data.
The pandemic period we are going through can also be associated with parasitism. COVID-19 treatment has been effective in the diagnosis, treatment and eradication of parasitic infections. For example, cough and dyspnea seen in COVID-19 are also symptoms of some parasitic infections, in which case misdiagnosis or treatment is possible. It is possible to confuse symptoms of parasitic infections, particularly those caused by protozoa, trematodes, and nematodes, with symptoms of COVID-19. In addition, an immune system weakened by parasitic infections can complicate the treatment of COVID-19 [16].
1.4 Control of Parasites
The control and proper treatment of parasites are essential requirements for the health of living beings. In recent years, the inflammatory response resulting from infections caused by parasites has been confirmed by numerous studies. In a study of dogs with visceral leishmaniasis caused by the Leishmania donovani complex, inflammatory lesions were observed in the brain, although no parasites were detected. The aim of the studies carried out in recent years were to treat only the infection caused by the parasite and to improve the clinical status. In recent years, mechanistic studies have increased, and all pathways in parasite infections, including the interaction between the host and the parasite, are being investigated. With all these studies, the host‒parasite relationship, which involves complex interactions, is increasingly being understood. With the use of new and modern methods such as omic technologies, it will be possible to control parasitic infections in the near future [17, 18]. The control and treatment of parasites has been achieved using different therapeutics approaches.
1.4.1 Herbal Medicines
In the treatment of parasitic infections, herbal medicines as well as synthetic compounds can be the solution. For centuries, mankind has benefited from using plants to treat diseases. Today, some medicines have herbal active ingredients. It is known that many plants such as Melissa officinalis, Citrus limon, and Thymus vulgaris show antiparasitic activity. However, the use of herbal medicines in antiparasitic therapy is limited due to their cytotoxic effects and non-selective activity profiles.
In the current treatment of diseases caused by parasites, the inadequacy of vaccines and the resistance to the drugs used have initiated the search for new treatments. In this search, besides chemical molecules, plants have gained importance because of their secondary metabolites. Secondary metabolites can be effective in parasitism since these metabolites and parasites have common targets such as genetic material, membrane integrity, microtubules and neuronal signal transduction. It is also possible to reach active new derivatives by obtaining synthetic derivatives analogous to these compounds. Many plant products interact with the protein structures and microtubules, which are the main components of the parasite, and cause the death of the parasite. Synthetically derived drugs or herbal compounds must be active and not toxic to the host and compounds with a high selectivity index are needed. The cytotoxicity of herbal and synthetic drugs arises through interaction with genetic material, proteins and biomembranes. Alkylating agents cause genetic damage by alkylating DNA. This mechanism results in the death of the parasite.
Some secondary metabolites affect genetic mutations by chelating with DNA. In particular, some plants have alkaloids that cause the death of the parasite with this mechanism, such as topoisomerase enzyme inhibitors killing the parasite by disrupting DNA replication.
Destruction of the cell membrane results in impairment of the integrity of the cell. Cytotoxic effects are a result of cell damage, if the cell is a parasite cell, parasite death occurs. It is known that plants containing sesquiterpenes, phenylpropanoids and isothiocyanate structure show antiparasitic activity by this mechanism [4, 19].
1.4.2 Drugs and Drugs Analogs
Wide varieties of drugs and analogs are used for the treatment and management of parasites.
1.4.2.1 Antiprotozoal Drugs
Infections caused by Plasmodium species are still an important problem in the world and cause deaths. Alternative treatment methods and more importantly, new synthetic compounds are needed due to the development of resistance to existing treatment drugs. In this context, it is clear that parasite-selective and low-toxicity molecules will have therapeutic success [20].
The life cycle of Plasmodium parasites continues on two hosts, Anopheles mosquitoes and humans. During blood feeding of infected female Anopheles, sporocytes enter the host human and infect liver cells. Sporosides transform into tissue schizonts that cleave and release merosocytes. Merosides pass into the blood and form tarophosites. The trophocytes mature into blood schizonts. These schizonts break down and infect healthy red blood cells [21].
Quinine was the first known antimalarial drug for the treatment of malaria. It was first obtained from the bark of the Cinchona tree . The first synthetic antimalarial compound is quinacrine, a 9-aminoacridine derivative. Upon understanding the structure‒activity relationships of quinine and its structural similarity with quinacrine, 4-aminoquinoline derivatives (chloroquine and hydroxychloroquine), 8-aminoquinoline derivatives (pamakine and primaquine) were synthesized. In the following years, the synthesis of compounds bearing the pyrimidine ring system continued and attempts were made to vaccinate against the disease.
Antimalarial drugs act by interacting with DNA, inhibiting dihydrofolate reductase, dihydroptereate synthesis, and protein synthesis.
According to their chemical structure, they can be classified as:
Cinchona
alkaloids and analogues;
4-aminoquinoline derivatives;
8-aminoquinoline derivatives;
9-aminoacridine derivative;
biguanidine derivatives;
diaminopyrimidine derivatives;
sesquiterpene lactones;
sulfonamides and sulfones; and
tetracyclines, clindamycin and azithromycin.
1.4.2.2 Cinchona Alkaloids and Analogues
It was known 400 years ago that Cinchona bark extract was used to reduce fever and treat malaria. A few centuries later the malaria parasite was discovered. Cinchona bark extract, first used by native South Americans, is the prototype for quinine and quinidine used to treat malaria.
For over a hundred years, studies have been carried out for the synthesis of quinine. Since it has four stereogenic centers, it has 16 different configurations, making the synthesis of pure quinine difficult. However, in 2001, the synthesis of pure quinine was achieved [22].
Quinine ((R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo [2.2.2] octan-2-yl]-(6-methoxy-quinolin-4-yl)methanol), is mainly used in the treatment of infections caused by P. falciparum. In addition, due to its weak analgesic and antipyretic effect, it is used in muscle and joint pain, in the treatment of leg cramps, and rarely to induce labor because it causes uterine contraction. It causes hypotension by relaxing vascular smooth muscle through myocardial depression.
It is used as a sulfate salt in the treatment of malaria, in combination with pyrimethamine, sulfadiazine or tetracycline.
Quinidine ((S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo [2.2.2] octan-2-yl]-(6-methoxy-quinolin-4-yl)methanol), is the (+)-isomer of quinine and is obtained from the bark of the Cinchona tree. Although it has antiarrhythmic effects, its use in treatment is almost negligible due to its side effects.
1.4.2.3 4-aminoquinoline Derivatives
Chloroquine (4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine), hydroxychloroquine (2-[4-[(7-chloroquinolin-4-yl) amino] pentyl-ethylamino] ethanol), amodiaquine (4-[(7-chloroquinolin-4-yl) amino]-2-(diethylaminomethyl) phenol) and mefloquine ([2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol) are 4-aminoquinoline derivatives available as therapies. These compounds are fast-acting, potent antiprotozoal drugs, especially against P. falciparum, acting on blood schizontocytes. However, resistance to these drugs is the most important problem in antiprotozoal therapy. Due to the high toxicity of chloroquine and the resistance of Plasmodium species to this drug, the -OH group was introduced, and the hydroxychloroquine synthesized. These drugs are used in the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, and diseases such as anti-phospholipid syndrome, due to their immunomodulatory and antithrombotic properties. Because of their antithrombotic mechanism and their potential to inhibit proinflammatory mediators, these drugs have also been used clinically in the treatment of SARS-CoV-2 infections. It has been argued that these drugs can treat COVID-19 infections by inhibiting the binding of the virus to the host cell membrane and preventing the virus from entering the cell. They are also thought to inhibit the formation and spread of new viral particles. Another proposed antiviral mechanism for chloroquine is to inhibit the zinc ionophores that allow zinc to enter the cell, thereby reducing the intracellular zinc levels of RNA viruses and reducing their pathogenicity. It has also been predicted that chloroquine may inhibit virus-receptor binding by acting on the terminal glycosylation of the ACE-2 enzyme. Due to these features, chloroquine and its hydroxy derivative hydroxychloroquine have been tried in the treatment of COVID-19 infections. However, neither drug has demonstrated significant clinical success. In addition, the side effects of these drugs have led to the abandonment of the use of these compounds in the treatment of COVID-19 [23,24].
1.4.2.4 8-aminoquinoline Derivatives
8-aminoquinoline derivatives exert their effects by killing hypnozoite forms. Although they have high antiprotozoal activities, their use is limited due to safety problems arising from interactions with glucose-6-phosphate dehydrogenase [25]. Approved by the FDA in 1952 and particularly effective against Plasmodium vivax and Plasmodium ovale species, primaquine is the prototype of 8-aminoquinoline derivative antimalarial compounds. It is used in combination with chloroquine or artemisinin in the treatment. It is effective against Plasmodium falciparum in a single dose and used as phosphate salt in treatment [26].
In addition to primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), 8-aminoquinoline derivatives such as pamaquine (1-N,1-N-diethyl-4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), pentaquine (N-(6-methoxyquinolin-8-yl)-Nˈ-propan-2-ylpentane-1,5-diamine) and isopentaquine (4-N-(6-methoxyquinolin-8-yl)-1-N-propan-2-ylpentane-1,4-diamine) are also used in the treatment.
Tafenoquine (4-N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy] quinolin-8-yl]pentane-1,4-diamine) is the latest approved 8-aminoquinoline derivative compound. It is a lipophilic derivative of primaquine, with a longer half-life and lower toxicity. It can also be used as a single dose due to its long half-life [27].
1.4.2.5 9-aminoacridine Derivative
Quinacrine (4-N-(6-chloro-2-methoxyacridin-9-yl)-1-N,1-N-diethylpentane-1,4-diamine) is a 9-aminoacridine derivative. It has a higher schizontoside effect than quinine. However, due to its high toxicity, it is not currently used in antiprotozoal therapy. It has toxic effects especially on the central nervous system.
1.4.2.6 Biguanidine Derivatives
Biguanide derivatives are antimalarial compounds that are frequently used for prophylactic purposes. Proguanil, chlorproguanil, and cycloguanil pamoate are drugs of this group.
Proguanil (1-[amino-(4-chloroanilino) methylidene]-2-propan-2-ylguanidine) was found while investigating the antimalarial activity of pyrimidine derivatives. Compounds carrying nitrogen heterocycles such as pyrimidine, quinazoline and quinoline with basic side chain and arylamino or arylguanidino substituents have antimalarial activity. The noncyclic biguanide structure has a similar tautomeric system. The antimalarial activity of compounds with biguanide structure showed that the part responsible for the activity in heterocyclic rings was the side chain. Proguanil is a prodrug, its metabolite with dihydrotriazine cycloguanil structure has antimalarial activity.
Another antimalarial drug in the biguanide structure is cycloguanil. Since cycloguanil is eliminated very quickly, the pamoate salt (cycloguanil pamoat: 1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine 4,4ʹ-methylene-bis[3-hydroxy-2-naftaote] (2:1)) formed with pamoic acid is used as a depot formulation.
Chlorproguanil (1-[amino-(3,4-dichloroanilino) methylidene]-2-propan-2-yl-guanidine), a chlorinated derivative of proguanil, has a similar activity profile and is used in malaria tropica chemoprophylaxis [10, 28, 29].
1.4.2.7 Diaminopyrimidine Derivatives
Pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) and trimethoprim (5-[(3,4,5-trimethoxyphenyl) methyl] pyrimidine-2,4-diamine), which are structurally similar to the pteridine part of dihydrofolic acid, are drugs that show dihydrofolate reductase enzyme inhibitory activity. The prototype of the group is pyrimethamine. Although pyrimethamine is safe at low doses, it causes megaloblastic anemia at high doses. Pyrimethamine inhibits the conversion of dihydrofolate to tetrahydrofolate by irreversibly binding to the enzyme dihydrofolate reductase. The compound shows higher affinity for the dihydrofolate reductase enzyme of Plasmodium than for the host dihydrofolate reductase enzyme. This feature makes the compound selective. Inhibition of the conversion of dihydrofolate to tetrahydrofolate reduces the folic acid synthesis required for nucleic acid synthesis in the parasite. Due to the development of pyrimethamine resistance, pyrimethamine-sulfadoxine combination is used in the treatment [10, 30, 31].
Trimethoprim is an antibacterial drug and its antimalarial activity was discovered later. Since it is less selective than pyrimethamine and has a shorter half-life, its use in therapy is limited. It is used in combination with other drugs [10].
1.4.2.8 Sesquiterpene Lactones
Sesquiterpene lactones are secondary metabolites of more than 5000 compounds, most commonly found in the families Cactaceae, Solanaceae, Araceae, and Euphorbiaceae. Artemisinin ((1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo [10.3.1.04,13.08,13] hexadecan-10-one) and its derivatives are antimalarial compounds with sesquiterpene lactone structure. These compounds are used in combination with resistant synthetic derivatives. Thus, it is possible to use drug combinations with a longer half-life and to prevent the development of resistance [32].
The antimalarial activity of artemisinin was discovered in China in the mid-twentieth century. Artemisinin and its derivatives are antimalarial compounds with sesquiterpene trioxane lactone structure isolated from Artemisia annua. Artemisinin and its derivatives (artemether ((1R,4S,5R,8S,9R,10S,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo [10.3.1.04,13.08,13] hexadecane), arteether ((1R,4S,5R,8S,9R,10S,12R,13R)-10-ethoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecane) and artesunate (4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]butanoic acid) have been included in antimalarial treatment protocols [33, 34].
These compounds can be administered in a variety of ways. Its metabolites have a longer half-life and therefore higher activity. The peroxide structure in the 1,2,4-trioxane ring system is essential for antimalarial activity. There is no activity in deoxy compounds that do not have a peroxide structure or in derivatives where one of the peroxide oxygens is replaced by carbon. One of the mechanisms of action predicted for artemisinins is that they show antimalarial activity by endoperoxide and carbon radical mechanism. According to this mechanism, artemisinins can be considered as prodrugs. In the infected erythrocyte, Fe2+ is present in the parasite’s food vacuole, where hemoglobin is digested and free iron is detoxified by accumulating in hemozoin. Fe2+ reacts with endoperoxide to form free oxy radical and Fe3+. The carbon radical formed by the oxy radical kills the Plasmodium in the erythrocyte. According to the second proposed mechanism, endoperoxide activation by the iron-dependent mechanism kills the parasite by targeting the parasite’s endoplasmic reticulum [35].
1.4.2.9 Sulfonamides and Sulfones
Sulfonamide and sulfone derivative compounds are used in the treatment of bacterial and fungal infections. These compounds target the folate metabolic pathway, where cofactors for amino acid and DNA synthesis are produced. This group of compounds has a wide variety of activities, including antimalarial activity. These compounds do not have strong antimalarial activity alone and are used in combination with pyrimethamine. While sulfadiazine, sulfadoxine, sulfamethoxypyridazine, sulphalen and sulfisoxazole are counted as antimalarial sulfonamide group compounds, dapsone and diformyldapsone are antimalarial sulfone group compounds.
1.4.2.10 Tetracyclines, Clindamycin and Azithromycin
Various antibiotics are used prophylactically alone or in combination with drugs such as quinine and artesunate in antimalarial therapy. Doxycillin, clindamycin, and azithromycin are examples of these antibiotics. These compounds act by inhibiting protein synthesis in the parasite. In addition, halofantrine (3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl) phenanthren-9-yl] propan-1-ol), lumefantrine (2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl) methylidene] fluoren-4-yl] ethanol) and atovaquone (3-[4-(4-chlorophenyl) cyclohexyl]-4-hydroxynaphthalene-1,2-dione) are also antimalarial compounds.
Halofantrine is a 9-phenanthrenemethanol compound. It is used in the treatment of malaria caused by chloroquine-sensitive and chloroquine-resistant Plasmodium species. It is taken orally. The most important side effect is cardiac toxicity.
Lumefantrine is an analogous compound to halofantrine. It is used in combination with artemether. It is an erythrocytic schizontocyte.
Atovaquone, a naphthoquinone derivative, is also used in combination with proquanil in the treatment of malaria, due to the side effects of existing drugs and resistance to these drugs. Compared to other drugs used in the treatment of malaria, it has fewer side effects [36].
Entamoeba species settle in the colon and Entamoeba gingivalis in the oral mucosa. The term amoebiasis refers to inflammation of the colon caused by E. histolytica. Amoebiasis is the most aggressive of the protozoal diseases and ranks second or third among the protozoal diseases that cause death. In infected individuals, amoebae in the colon lumen cause ulceration of the mucosa. The amoeba is excreted in the form of cysts in feces. The infection spreads through these cysts. Water and food contaminated with cysts cause the spread of the disease. Cysts ingested with water and food, pass through the small intestine and reproduce asexually to form trophocytes. The torophosites settle in the colon lumen and mature into amoebae. As a result of weakening of the host’s resistance or virulence of the amoeba, the amoeba causes ulceration of the colonic mucosa and ultimately diarrhea in the patient.
In chronic cases, amoebae entering the mucous vessels can be transported to the liver by the portal circulation, causing hepatitis. In addition, they can be carried to the lungs, brain, genital area and form lesions.
Untreated Entomoeba infections can become chronic and fatal. Antiamoebic drugs used in the treatment should be effective on both intestinal and extraintestinal forms of the parasite. Extracts obtained from Cephalis ipecacuanha were first used in the treatment of the disease. The active ingredient of the extract is emetine, an ipecac alkaloid. Due to the cardiotoxic and gastrointestinal side effects of emetidine, alternative compounds have been discovered and entered into therapy. Later, carbarson and glycobiarsol were synthesized and the antiamoebic effect of chloroquine having antimalarial effect was determined. Following the development of haloquinoline derivatives, haloacetamide derivatives, paromomycin, azomycin, metronidazole, nimorazole, ornidazole and tinidazole have introduced treatment [10, 37, 38].
Antiamoebic drugs are divided into two groups according to their sites of action:
tissue amoebicides; and
luminal amoebicides.
Tissue amoebicides are drugs that kill amoebae that have settled in tissues such as intestines and liver. These compounds are ineffective against amoebae in the intestinal lumen.
Luminal amoebicides are compounds that act on amoebae in the intestinal lumen.
There are also compounds such as metronidazole that act on amoebae located in both tissue and lumen.
Antiamoebic compounds can be classified according to their chemical structure as follows:
4-aminoquinoline derivatives;
antibiotics;
haloacetamides;
8-hydroxyquinoline derivatives;
ipecac alkaloids;
5-nitroimidazole derivatives;
organoarsenic compounds; and
other compounds.
1.4.2.11 4-aminoquinoline Derivatives
Chloroquine with 4-aminoquinoline structure, used in the treatment of malaria, also has antiamoebic activity. It has an equivalent activity to emetine in hepatic amoebiasis, since it accumulates in the hepatic parenchyma and reaches high concentrations. It is used orally [10].
Tetracyclines or paronomycin along with antiamoaebic drugs are used to treat invasive intestinal infection caused by amoebae. These drugs are ineffective in extracolon amobiasis. Tetracyclines have direct and indirect effects, respectively, by killing amoebae and the microorganisms with which amoebae live in symbiosis.
Paromomycin, on the other hand, has an antiamoebic effect by reaching high concentrations in the lumen of the large intestine. It acts by interacting with DNA [10].
1.4.2.12 Haloacetamides
Haloacetamide derivatives have the -N-COCHCl2- structure. Diloxanide furoate ([4-[(2,2-dichloroacetyl)-methylamino] phenyl] furan-2-carboxylate), chlorbetamide (2,2-dichloro-N-[(2,4-dichlorophenyl) methyl]-N-(2-hydroxyethyl) acetamide), clefamide (2,2-dichloro-N-(2-hydroxyethyl)-N-[[4-(4-nitrophenoxy) phenyl] methyl] acetamide), etofamide (2,2-dichloro-N-(2-ethoxyethyl)-N-[[4-(4-nitrophenoxy)phenyl]methyl]acetamide), quinfamide ([1-(2,2-dichloroacetyl)-3,4-dihydro-2H-quinolin-6-yl] furan-2-carboxylate) and teclozan (2,2-dichloro-N-[[4-[[(2,2-dichloroacetyl)-(2-ethoxyethyl)amino]methyl]phenyl]methyl]-N-(2-ethoxyethyl) acetamide) are haloacetamide derivatives. Among the haloacetamide derivatives, the most used compound in therapy is diloxanide furoate.
Diloxanide furoate is used to treat amoebic colitis caused by Entomoeba histolytica. It shows activity in the intestinal lumen. Since it has low water solubility, formulations to increase its solubility should be developed. It is a luminal amoebicide, used alone in luminal cases, and in combination with a tissue amoebic drug for tissue amoeba. It acts by disrupting protein synthesis in ribosomes [39].
14.2.13 8-hydroxyquinoline Derivatives
8-hydroxyquinoline derivatives were used as popular oral antiparasitic agents from the 1950s to the 1970s. However, due to its toxic effects, its oral forms were withdrawn from the treatment in 1970, although the topical forms continued to be used. Although the antiamoebic activity of 8-hydroxyquinoline derivatives has been proven, these compounds are not widely used today due to their side effects.
However, although myelo-optic neuropathy was observed, especially in Japanese patients, with the use of chinofon (8-hydroxy-7-iodoquinoline-5-sulfonic acid), clioquinol (5-chloro-7-iodoquinolin-8-ol) was used safely during this period. Topical formulations continue to be used in some countries. Clioquinol has fewer side effects and little is known about resistance to this compound.
Currently, clioquinol is being investigated for new indications beyond its antiamoebic effects [40].
1.4.2.14 Ipecac Alkaloids
Ipeca is a drug obtained from the plant Cephalis ipecacuanhae.
The Cephaelis plant was discovered in Brazil in the 1600s and was taken to Paris in the second half of the same century. Used to treat dysentery in France, it was discovered many years later to contain two alkaloids (emetine and cephaline). Emetine and cephaline are obtained from the dried roots and rhizomes of the plant Cephalis ipecacuanhae. In the nineteenth century, emetine was found to be effective in treating dysentery caused by amoebae.
These alkaloids, which have a reversible effect on DNA synthesis, cause cardiotoxicity and muscle weakness in addition to their side effects on the gastrointestinal tract [41, 42].
Emetine ((2S,3R,11bS)-2-[[(1R)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl] methyl]-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a] quinolizine) is a potent antiamoebic drug that kills trophosides. Although there are many stereoisomers of emetine with asymmetric centers in four positions, the most active isomer is the natural compound (-)-emetine. The active compounds were obtained by quaternizing the nitrogen atom in the emetine and replacing the substituents. Opening of the tetrahydroisoquinoline ring resulted in loss of activity.
The dehydro derivative obtained by saturating second and third positions is as active as emetine. Dehydroemetine ((11bS)-2-[[(1R)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl] methyl]-3-ethyl-9,10-dimethoxy-4,6,7,11b-tetrahydro-1H-benzo[a]quinolizine) is used when 5-nitroimidazole derivatives are ineffective or contraindicated. It has cardiovascular, gastrointestinal and neuromuscular side effects.
1.4.2.15 5-nitroimidazole Derivatives
Nitroimidazole is an essential and unique ring system discovered in the 1950s. After its discovery, many drug molecules containing this ring system with various activities such as anticancer, antibacterial and antiviral have been synthesized. The most effective drugs used in the treatment of systemic and intestinal amoebiasis are nitroimidazole derivatives. The prototype of the group is metronidazole. This group of compounds shows activity by reductive bioactivation and formation of reactive intermediates. Nitroimidazole derivatives are prodrug and the nitro group is responsible for the activity of the drug. Activity occurs when the nitro group is converted to nitric oxide and reactive nitrogen species. These products inhibit growth by interacting with the cellular components of the protozoa.
Metronidazole (2-(2-methyl-5-nitroimidazol-1-yl) ethanol) was the first compound found for the treatment of trichomoniasis infections caused by Trichomonas vaginalis. Later, it was also used for the treatment of various diseases. Today it is used in the treatment of parasitic infections such as gastrointestinal infections, giardiasis (G. duodenalis) and amoebiasis (caused by E. histolytica). It is also effective against gram-positive and gram-negative bacteria. Metronidazole is a well tolerated drug and can also be used in pregnant women.
Ornidazole (1-chloro-3-(2-methyl-5-nitroimidazol-1-yl) propan-2-ol) is a 5-nitroimidazole derivative antiprotozoal drug that is successful in 87% of protozoal cases. Although it was first used to treat trichomoniasis, it was later discovered to be broad-spectrum antiprotozoal and antibacterial agent. Ornidazole is used clinically in raceme form.
Secnidazole (1-(2-methyl-5-nitroimidazol-1-yl) propan-2-ol) is a well-tolerated drug used in amoebiasis, giardiasis, trichomoniasis and urogenital infections. Its antiamoebic activity is due to the reduction of the nitro group on the imidazole ring.
Tinidazole (1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole) is effective on intestinal amoebiasis activity as well as some other protozoa species and some bacteria. Although its effect profile and side effects are similar to metronidazole, it reaches higher blood levels and has a longer duration of action compared to metronidazole.
Nimorazole (4-[2-(5-nitroimidazol-1-yl) ethyl] morpholine) is also known as nitrimidazine. Despite its antiinfective and antiamoebic activities, it is mainly used for trichomoniasis infections [10,43].
1.4.2.16 Organoarsenic Compounds
Although carbarsone and glicobiarsol have been used as organoarsenic compounds in the past, today the use of organoarsenic compounds as antiamoebic agents is limited due to the availability of more active and less toxic compounds [10].
1.4.2.17 Other Compounds
Compounds with different chemical structures such as bialamicol and nitazoxanide are also used as antiamoebic. Bialamicol has the hydroxybiphenyl structure. It is used in the treatment of acute and chronic amoebiasis. Nitazoxanide is a thazolide compound, used in the treatment of invasive intestinal amoebiasis.
Leishmaniasis is the general name for infections caused by Leishmania species. The parasite is transmitted by the bite of humans by sandflies that feed on infected sources. Thus, infections caused by Leishmania occur and an immune response develops. Although cutaneous leishmaniasis is the most common form, visceral leishmaniasis is more serious and dangerous. Leishmania donovani, one of the Leishmania species that cause visceral leismaniasis or kala-azar and settles in the reticuloendothelial system, especially in the liver and spleen in humans. L. tropica causes cutaneous leishmaniasis and settles on the skin. In immunocompromized individuals, Lesichmania infections are seen as co-infection [2, 18, 44, 45].
Although many compounds have been synthesized subsequently, there is no definitive cure for the disease. Resistance to antileishmanial drugs reduces the treatment success of infections caused by leishmania by up to 33% [1]. Compounds used in the treatment of Leishmania can be classified as:
organic antimony compounds;
diamidine derivatives;
antibiotics; and
other compounds.
1.4.2.18 Organic Antimony Compounds
First, antimony potassium tartrate was found to be effective in leishmaniasis, then antimony compounds were studied and sodium stibogluconate (trisodium; (4R,5S,6R)-2-[[(4R,5S,6R)-4-carboxylato-6-[(1R)-1,2-dihydroxyethyl]-5-hydroxy-2-oxo-1,3,2λ5-dioxastibinan-2-yl]oxy]-6-[(1R)-1,2-dihydroxyethyl]-5-hydroxy-2-oxo-1,3,2λ5-dioxastibinane-4-carboxylate;nonahydrate) was synthesized. Among the antimony compounds discovered to date, the two compounds used today are sodium stibogluconate and meglumine antimonate (hydroxy(dioxo)-λ5-stibane;(2R,3R,4R,5S)-6-(methylamino) hexane-1,2,3,4,5-pentol).
The structure of sodium stibogluconate was proven by chromatographic methods and meglumine antimonate structure was clarified by FAB-MS (fast-atom bombardment mass spectrometry) studies. Accordingly, two meglumine molecules are symmetrically coordinated with an Sb atom.
The action mechanism of antimony compounds is not fully known. One of the proposed models is the prodrug model, and antileishmanial activity occurs as a result of the conversion of the pentavalent antimony atom to the trivalent form. The second model explains antileishmanial activity of antimony compounds by the interference of the antimony atom in cellular mechanisms. The third hypothesis proposes that antimony compounds exert antileishmanial activity by activating the host’s immune system [45].
1.4.2.19 Diamidine Derivatives
Diamidines are a very large family of compounds with pharmacological and biological properties. From this group, hydroxystilbamidine isethionate (4-[(E)-2-(4-carbamimidoylphenyl) ethenyl]-3-hydroxybenzenecarboximidamide; 2-hydr
