Approaches to Design and Synthesis of Antiparasitic Drugs (eBook)

N. Anand, S. Sharma (Herausgeber)

eBook Download: PDF

1997 | 1. Auflage
510 Seiten
Elsevier Science (Verlag)
978-0-08-052752-9 (ISBN)

Infos

This book presents a comprehensive and up to date account of the chemotherapy of parasitic diseases, both human and veterinary. The book starts with an overview of parasitic diseases. The body of the book is divided into two parts: antihelminthic drugs, and antiprotozoal drugs. Both parts start with chapters highlighting the 'biochemical targets' available for chemotherapeutic interference. Individual chapters deal with one chemical class of compounds and describe their origin, structure-activity relationship, mode of action, and methods of synthesis and their status both in clinical and veterinary practice. The book will be useful to a wide spectrum of readers: students embarking on a research career in parasitic chemotherapy, clinicians (and veterinarians) and clinical pharmacologists desiring detailed information about the drugs currently in use, and pharmaceutical technologists wanting to update their knowledge of the methods of manufacture.

Inhalt

Cover 1
CONTENTS 12
PART I: INTRODUCTION 14
Chapter 1. Parasitic diseases: An overview 14
PART II: ANTHELMINTIC AGENTS 59
Chapter 2. Biochemical targets for anthelmintic 59
Chapter 3. Natural products 84
Chapter 4. Organometallics 137
Chapter 5. Piperazines 161
Chapter 6. Tetrahydropyrimidines 184
Chapter 7. Imidazothiozoles 194
Chapter 8. Benzimidazoles 208
Chapter 9. Salicylanilides 252
Chapter 10. Nitroaryl compounds 271
Chapter 11.Tetrahydroquinolines and isoquinolines 286
Chapter 12. Miscellaneous anthelmintics 309
PART III: ANTIPROTOZOAL AGENTS 338
Chapter 13. Biochemical targets for antiprotozoal activity 338
Chapter 14. Natural products 360
Chapter 15. Organometallics 397
Chapter 16. Quinolines 406
Chapter 17. Nitroheterocycles 434
Chapter 18. Antifolates 452
Chapter 19. Bisamidines 468
Chapter 20. Haloacetamides 475
Chapter 21. Miscellaneous antiprotozoals 481
IDXSubject Index 502

Textauszug

Chapter 1

Parasitic Diseases : An Overview

Satyavan Sharma    Medicinal Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, India

Nitya Anand    Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, India

1 INTRODUCTION

Parasitic diseases continue to be the major public health problems in tropical developing countries. These are responsible for a high degree of morbidity, mortality and socio-economic under-development in these regions. According to WHO estimates the annual death toll due to parasitic diseases is nearly 2.5 million throughout the world [1,2]. The biggest killers of these are malaria, amoebiasis and hookworm infections responsible for killing 1,000,000-2,000,000; 40,000-110,000 and 50.000-60,000 patients, respectively, every year [2]. In view of the detrimental impact of parasitoses on human health and resulting economic losses, WHO has included five parasitic diseases, viz. filariasis, schistosomiasis, malaria, trypanosomiasis and leishmaniasis and one mycobacterial disease, viz. leprosy, amongst its priority research areas.

Parasitic infections are distributed world-wide but they are particularly endemic in the tropical zones of the globe. The main cause of the widespread prevalence of parasitic infections in the tropics is the climate; high temperature and humidity are ideal for parasite growth. This when combined with low standards of living, poor sanitation, lack of personal hygiene, inadequate prophylactic measures and abundance of disease carriers provide ideal situation for survival, dissemination and propagation of the parasites. Although most parasitic infections can be effectively prevented by proper prophylaxis, strict sanitary regulations and vector control, the implementation of these measures, pose practical problems in developing countries due to climatic factors and economic constraints. Immunotherapy and vaccination may emerge as useful tools to control and eradicate parasitic infections, but these are still in their early stages of development. Therefore, chemotherapy is the main tool available to combat parasitic diseases in humans and domestic animals.

Parasitic diseases are caused by the invasion of humans and animals by several species of protozoans and helminths. The pathogenic protozoans may invade the blood circulation, liver, spleen, or external organs such as mouth, gastrointestinal tract and vagina. A major population of the helminths, on the other hand, parasitize the gastrointestinal tract while some live in the blood circulation, lymphatics, connective and subcutaneous tissues, eyes, lungs, and liver. Most of the extra-intestinal protozoal infections are acquired by the bites of an insect vector which injects infective larvae of the parasite while feeding on the blood of the victim. The intestinal protozoal diseases are contracted by ingesting protozoal cysts through food, drink and faecal contact. The helminth diseases in man may be acquired either by ingestion of helminth eggs through food, drinks or soiled hands or penetration of infective larvae through skin. The latter mode of infection may occur either by the bites of an arthropod vector or exposure of legs and arms to soil and water contaminated with infective larvae [3–6].

2 THE HELMINTH INFECTIONS

A variety of helminths belonging to the class nematoda (roundworms), trematoda (flatworms or flukes) and cestoda (tapeworms) are known to infect humans and domestic animals. The diseases caused by these worms are not only responsible for occasional deaths and wide range of health problems in man, but also exert detrimental effect on the nutritional and immune status of the host resulting in low resistance against other infections. The presence of helminth infections in livestock leads to decrease in output of animal products (milk, fat, butter, meat, eggs, wool and leather etc.) and has, therefore, strong socio-economic impact in countries with agro-and dairy-based industries [7].

The economic losses incurred by helminth infections have been assessed in several ways. In ascariasis the loss is due to the carbohydrate depletion by Ascaris worms in the patients. It has been estimated that a patient with 20 adult worms of Ascaris lumbricoides may lose 2.8 g of carbohydrate daily [8] which amounts to 2800 kg of carbohydrate per 1 million cases per day. Thus the world-wide loss of carbohydrate for 1100 million patients carrying ascariasis would be nearly 3080 tonnes per day. Stephenson and coworkers [9] have shown that ascariasis is not only associated with poor growth and protein-caloric malnutrition in pre-school children, but also reduces absorption of macronutrients and vitamin A. The authors also showed that economic loss due to ascariasis in Kenya in 1976 was about US$ 5 million which could have been saved by the use of an anthelmintic costing about US$ 1 million only.

The hookworms are other important human parasites which cause high degree of economic losses among the victims. An early estimate [10] showed that Japan suffered an economic loss of US$ 60 million per year due to hookworm infections that could have been prevented by treating the patients with anthelmintics costing only US$ 7 million. Since hookworms survive on the direct blood feed from the hosts, their presence in human leads to heavy blood loss resulting in hypochromic anaemia. It has been estimated [11,12] that one Ancylostoma duodenale sucks 0.15-0.23 ml of blood per day. Thus, for 1 million patients carrying an average of 100 hookworms, the total blood loss would be 15,000-23,000 liter per day. In case of Necator americanus which consumes about 0.03 ml of blood daily from its host, the total blood loss for 1 million cases with an average of 400 hookworms would be nearly 12,000 liter daily.

The high degree of physical deformity (hydrocoele and elephantiasis of legs and arms) caused as a result of lymphatic filariasis and blindness due to onchocerciasis still pose major medical challenge in different countries of Asia, Africa and Latin America. Similarly, the grave clinical manifestations produced by tapeworm infections, schistosomiasis, trichinosis and hydatidosis continue to be major health problem for millions of people living both in the developing and developed nations of the world. Recent studies carried out by Stephenson and coworkers [13,14] in Kenyan subjects show that by deworming the infected population, it is possible to improve the growth and physical fitness in children and productivity in adults.

Worm infections are also known to exert detrimental effect on the health and productivity of cattle, equines, sheep, goats, pigs and fowls, thereby considerably hampering the yield of various animal products like milk, eggs and wool etc. Urquhart [15] has earlier estimated that the potential loss due to uncontrolled nematode parasites in ruminants was nearly US$ 160 million. By treating the infected ruminants with anthelmintics costing US$ 20,000, this loss was reduced to around US$ 30 million. In Great Britain, about US$ 100 million is lost annually due to liverfluke infections in sheep and cattle [16]. Similarly, in Florida, USA, the economic loss from liver condemnation was more than US$ 500,000 per year which was due to liver fluke infections in cattle [17]. Stephenson et al. [18] have shown that pigs infected with Ascaris spp. and on low protein diet consumed 6.8 kg of food to gain 1 kg as compared to control pigs which needed only 3.3 kg of food to gain 1 kg of weight. It has been estimated that the total loss due to parasitic infections in livestock in USA is more than US $ 3 billion per year [19]. Thus eradication of parasitoses from livestock is economical as it increases the productivity of the animals [20].

These are only a few examples which clearly demonstrate that treatment of helminth diseases in man and domestic animals is not only essential to have a healthier society but also to raise the living standards by boosting socio-economic status of the people living in the tropics. A brief outline of the helminth diseases occurring in man and animals is given below.

2.1 Helminth diseases of human

Worm infections are amongst the earliest diseases known to mankind. Their impact on human health and its serious dimension was highlighted in the classical paper of Stoll “This Wormy World” published in 1947 [21]. Estimating the world population at that time as 2.1 billion, Stoll reported that nearly 650 million people were infected with the intestinal roundworm, Ascaris lumbricoides. The incidence (in million) of other intestinal nematode infections was as follows: hookworm disease (450), trichuriasis (350) and strongyloidiasis (35). With the increase in world population the prevalence of these worm infestations has proportionally increased. According to recent estimates [22,23] in a global population of 4.3 billion there are 1100-1300 million cases of ascariasis while the incidence of hookworm infection may touch the 1000 million mark. Similarly the number of cases suffering from trichuriasis, enterobiasis and strongyloidiasis may range from 500-1000, 300-500 and 50-100 million, respectively. In addition, nearly 400 million people around the world are known to suffer from the debilitating effects of filariasis, while there are 130 million cases of tapeworm infections and nearly 200 million people are...

Produkt-Details

• Erscheint lt. Verlag: 10.7.1997
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Mikrobiologie / Infektologie / Reisemedizin
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Pharmazie
• Themenwelt: Naturwissenschaften ► Chemie
• Themenwelt: Technik
• Themenwelt: Wirtschaft
• ISBN-10: 0-08-052752-3 / 0080527523
• ISBN-13: 978-0-08-052752-9 / 9780080527529