Discovery and Development of Therapeutics from Natural Products Against Neglected Tropical Diseases

Goutam Brahmachari

• Publisher: Elsevier
• Year: 2019
• Print ISBN: 9780128157237
• eBook ISBN: 9780128157244
• Topic: Physical Sciences
• Subtopic: Pharmacology

Discovery and Development of Therapeutics from Natural Products against Neglected Tropical Diseases draws together research on medicinal agents from natural sources as starting points for the design of drugs against Neglected Tropical Diseases (NTDs). From the prediction of promising leads and identification of active agents, to the extraction of complex molecules, the book explores novel, economical and efficacious therapeutics for these diseases. It describes current research and the role of natural products, antimalarial compounds from marine natural products and sesquiterpene lactones, natural antileprotic agents, natural products with potential against Leishmaniasis, Trypanosomiasis and Dengue, and more.In addition, Quinoline and Isoquinoline alkaloids for developing new antiprotozoal agents are discussed, alongside anti-trypanosomatid heterocyclic compounds as structures for development. Combining the expertise of specialists from around the world, this volume aims to support and encourage researchers in the investigation of natural sources as starting points for the development of novel, safe and effective agents for use against neglected tropical diseases.- Includes chapters written by active researchers and leading global experts deeply engaged in the research field of natural product chemistry for drug discovery- Draws together cutting-edge research advances in natural product chemistry that are targeted at neglected tropical diseases- Highlights the future potential of natural products as sources of novel medicinal compounds against neglected tropical diseases

1

Therapeutics from natural products against neglected tropical diseases: an overview

Goutam Brahmachari, Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan, India

Abstract

This chapter provides an overview of the book ‘Discovery and Development of Therapeutics from Natural Products Against Neglected Tropical Diseases’ and summarizes the contents and subject matter of each chapter by highlighting certain glimpses of the coverage to the readers before they go in-depth.

Keywords

Neglected tropical diseases (NTDs); natural products with anti-NTD potential; natural sources and isolation; chemical and pharmacological aspects; structure–activity relationships; clinical aspects; modes of action; biosynthesis; total synthesis; overview

Chapter Outline

• 1.1 Introduction 1
• 1.2 An overview of the book 2
• 1.3 Concluding remarks 6

1.1 Introduction

Therapeutics From Natural Products against Neglected Tropical Diseases under the book series Natural Product Drug Discovery is an endeavor to access the ongoing developments and recent cutting-edge research advances in the field of natural products against neglected tropical diseases with regard to their identification, isolation, and overall chemistry and pharmacology, as well as to underline how natural product research continues to make significant contributions in the domains of discovery and development of new medicinal entities. The book is intended for phytochemists, synthetic chemists, combinatorial chemists, biologists, pharmacologists, clinicians, as well as other practitioners and advanced students in related fields. This book, comprising of 11 technical chapters, offers recent updates on these areas of natural product research with an intention to unravel their pharmaceutical applicability in modern drug discovery processes in the field of neglected tropical diseases (NTDs).

NTDs, a diverse group of infectious diseases primarily caused by parasitic organisms, prevail in tropical and subtropical conditions in 149 countries and remain a leading cause of morbidity and mortality among the world’s poorest populations. Collectively, it is estimated that these diseases afflict more than 1 billion of the world’s poorest 2.7 billion people living below the poverty line. These diseases are termed neglected because they primarily affect poor people and are often hidden as they are concentrated in remote rural areas or urban slums and shantytowns. NTDs inflict massive suffering, with many causing life-long disability and death, stigma, mental distress, and discrimination, especially of girls and women. The World Health Organization (WHO) enlists 17 medical conditions as NTDs. These include: dengue fever, rabies, trachoma, buruli ulcer (BU), endemic treponematoses, leprosy, Chagas disease, human African trypanosomiasis (HAT), leishmaniases, taeniasis/cystercercosis, guinea-worm disease, echinococcosis, foodborne trematodiases, lymphatic filariasis, onchocerciasis, schistosomiasis, and soil-transmitted helminthiases. Historically, they have collectively attracted much less research investment than so-called first-world diseases. The situation has, however, been gradually changing during the past decade. To improve drug development for neglected diseases, there needs to be better coordination of community efforts, a significant increase in medicinal chemistry personnel, and extensive investment in the downstream steps of the drug development pipeline.

Nature has provided an innumerable wealth of drugs for the treatment of many serious diseases. Natural products continue to provide useful drugs in their own right, but also provide templates for the development of other compounds. Secondary metabolites of natural sources from an immense diversity of living organisms, including plants, marine, animals and microbes, thus, represent a huge repository of chemical structures which has been, and will continue to be, a source of new drugs, directly in their native form or after optimization by synthetic medicinal chemistry. This book is an endeavor to access the recent cutting-edge research advances in the field of bioactive natural products and natural drug formulations to combat these destructive diseases. The volume focuses on molecules of natural origin and their synthetic analogues that show promising potential to act against the pathogens responsible for NTDs, with a motto to support the discovery and further development of natural products against NTDs.

This introductory chapter (Chapter 1) summarizes the contents and subject matter of each chapter so as to offer certain glimpses of the coverage of discussion to the readers before they go for detailed study.

1.2 An overview of the book

The book contains a total of 11 technical chapters (Chapters 2–12). This section summarizes the contents and subject matter of each chapter.

In Chapter 2, Marine natural products as strategic prototypes in the development of a new generation of antimalarial agents, Fotie offers a comprehensive overview on marine natural products as strategic prototypes in the development of a new generation of antimalarial agents. It is the high time to take proper initiatives in developing new antimalarial treatments that should give critical consideration to marine natural products, not only from the preliminary growth inhibition perspective, but also of the mechanisms by which these compounds achieve their antimalarial activity. The chapter covers almost 200 potentially significant antimalarial marine natural products and their analogues. The author also discusses the mechanism of action of these molecules by focusing on their structural diversity coupled with their potential antimalarial activity. This illuminating review would boost the ongoing research in antimalarial drug development.

Chapter 3, Sesquiterpene lactones: a versatile class of structurally diverse natural products and their semisynthetic analogs as potential antimalarials, by Chaturvedi categorically offers the antimalarial potential of naturally occurring sesquiterpene lactones (SLs) and their semisynthetic analogues. This class of compounds are well-known for their wide range of pharmaceutical properties including antimalarial activity. Chaturvedi provides an up-to-date development on various kinds of structurally diverse antimalarial SLs of natural origin and their semisynthetic derivatives. Some SLs such as artemisinin and their potential analogues have emerged as antimalarial drugs. This chapter is anticipated to be useful to chemists/pharmacologists working in the area of antimalarial drug discovery research.

Kouznetsov and his group offer a thorough account on the natural and synthetic quinoline compounds against tropical parasitic pathologies such as Chagas disease, African sleeping sickness (HAT), and leishmaniasis in Chapter 4, Natural and synthetic quinoline molecules against tropical parasitic pathologies: an analysis of activity and structural evolution for developing new quinoline-based antiprotozoal agents, by focusing on the analysis of such activities and structural evolution in developing new quinoline-based antiprotozoal agents. New treatments and drugs for antiparasitic agents to treat these diseases are now urgently needed as some current medicines have impractical treatment regimens, emerging drug resistance, or are unaffordable. Under this purview, simple or complex natural or synthetic quinolines are suitable and promising models for developing new and more effective candidates as affordable chemotherapies for these devastating diseases. The authors address all these issues in their comprehensive review by focusing on medicinal chemistry research with natural and synthetic quinoline molecules as antitrypanosomal agents against parasitic infections. Carefully selected examples are discussed to underline the progress made in the development of natural and synthetic quinolines for potential therapeutic applications against these diseases. This illustrative review on such potentially important quinolines of both natural and synthetic origins would really create an enthusiasm among the readers.

Chapter 5, Promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogs, presents a comprehensive overview on promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogues by da Silva-Júnior and coauthors. The available pharmacotherapies to combat trypanosomiasis infections are limited and associated with strong side effects, and moreover, resistance has developed against most drugs. New drugs are now urgently needed. In the past decade, a huge number of trypanocidal natural compounds have been isolated and characterized. In this chapter, the authors summarize the state-of-the-art concerning current therapy of trypanosomiasis and address well-screened antiparasitic heterocyclic compounds identified by bioactivity-guided fractionation of active herbal or microbial extracts along with their semisynthetic derivatives. In addition, the authors also discuss the mechanism of action where available. Actually, a better understanding of such trypanocidal potential must be investigated to allow researchers to design more potent and selective antitrypanosomiasis agents for clinical purposes. This exhaustive review offers hugely relevant information to both natural and synthetic chemists.

Sil and coauthors offer an enlightened overview of the role of oxidative stress in the pathogenesis of Schistosomiasis, Echinococcosis, and Trypanosomiasis as part of the therapeutic approach against some deadly diseases in Chapter 6, Oxidative stress in Schistosomiasis, Echinococcosis, and Trypanosomiasis: a therapeutic approach. The protective role of various bioactive compounds against these diseases is exhibited through their antioxidant properties or by oxidative insult which evades the antioxidant defense of the parasites within the host body. Treatment with natural compounds, herbal extracts, and nanoparticles exhibiting antioxidant properties can, thus, be considered as a possible therapeutic approach owing to their cost effectiveness, easy availability, and minimal side-effects. The antioxidant mechanisms, in general, involve the activation of antioxidant enzymes. Some bioactive compounds induce oxidative insult to overcome the antioxidant defense of the parasites, thereby preventing progression of the disease. Owing to the fact that the parasites involved in these diseases can evade the immune system of the host body by their own antioxidant defense, various natural compounds can also evade the parasitic defense by eliciting oxidative insult through the inhibition of antioxidant enzymes. These bioactive compounds exhibit their activities at various stages of the lifecycle of the parasites. However, further investigation of such protective effects needs to be addressed. This chapter focuses on the protective effects of natural antioxidants and herbal extracts in controlling infections and would satisfy readers in understanding certain types of mechanistic aspects of the drug molecules holding promise.

The plant kingdom contributes a vast structural diversity of bioactive compounds that provide unique and myriad opportunities for discovering new drugs. Traditional as well as ethno-medicinal usage together with extensive basic laboratory findings has depicted the important role of plants in the prevention and treatment of protozoan neglected diseases. In Chapter 7, Plant-derived compounds against protozoan neglected diseases: toward sustainable drug development, Mathew and Negi review the current status of plant-derived antiprotozoal products against three major NTDs, Chagas disease, Sleeping sickness, and Leishmaniasis, based on the functional and structural diversity of plant extracts for efficient drug development against them. The challenges associated with current therapeutic drugs as well as potent plant-derived natural products possessing in vivo and in silico antiparasitic activities which can further be developed into useful therapeutics to combat these diseases are discussed in detail. This informative review would act as a stimulus in this direction.

Chapter 8, Leishmaniasis control: limitations of current drugs and prospects of natural products, by Singh and his group is dedicated to the prospects of natural products in controlling leishmaniasis, which is endemic in 98 countries and a serious threat to approximately 310 million people living in endemic regions of the affected countries. Limited therapeutic options and growing incidences of drug resistance are continuously posing serious threats. Current treatment strategies have also failed to produce a sterile cure leaving behind a potential source of parasitic reservoirs. In lieu of unavailability of a vaccine and lacuna in the current therapeutic strategies, new therapeutic strategies or drugs are essentially required to curb the growth of leishmaniasis. It has been demonstrated that natural products such as alkaloids, chalcones, triterpenoids, naphthoquinones, quinones, steroids, lignans, saponins, and flavonoids offer an excellent opportunity to identify new drug/s to combat leishmaniasis. In this chapter, the authors summarize a wide range of compounds isolated from various natural sources that are worth screening to develop new antileishmanial drugs. This information would be very beneficial to the readers at large.

Leprosy is a chronic infectious disease primarily producing skin lesions and nerve damage caused by Mycobacterium leprae bacillus. India bears 60% of the global caseload of leprosy, followed by Brazil and Indonesia. In Chapter 9, Natural antileprotic agents: a boon for the management of leprosy, Ali and coauthors present an excellent overview on the current status of leprosy treatment by focusing on the needs to develop new therapies against this disease utilizing antileprotic naturally occurring agents. Extensive studies should be carried out to investigate the potential remedies in order to decrease the global burden of leprosy. In this chapter, the authors focus on antileprotic natural agents of both plant and animal origins along with the scientific evidence backing up the use of such agents against leprosy, with an intention to boost ongoing research in this area in order to assist the development of future drugs for mitigating leprosy.

BU, a deadly infectious disease caused by the human pathogen Mycobacterium ulcerans is emerging as the third most-common type of mycobacterial infection in the world, after tuberculosis and leprosy, for which current treatments are very limited. In Chapter 10, Aloe vera: a promising hope against buruli ulcer, Brahmachari highlights the future prospects of the valuable medicinal plant, Aloe vera, in search of potential leads against BU. A. vera is one of the most beautiful and efficacious gifts to mankind by nature and has been in use for millennia in beauty and healthcares. A preliminary experiment with the plant against buruli ulcer infection has just geared the path. The plant may offer some potential lead molecules against the infection in the near future once the task is taken on by researchers in a proactive way. This chapter has been designed with this motto so as to boost and motivate young researchers working in the challenging field of medicinal and pharmaceutical chemistry.

Chapter 11, Plant and marine products: a promising hope in search of therapeutics against dengue, is devoted to the promising role of natural products against dengue infection by Jena and her coauthors. Dengue is the leading cause for death where it is endemic. Despite certain advances in early detection and efforts to establish new therapies for various diseases, there is no clinically approved drug available in the market for treating dengue. Recently, one vaccine ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Editor Biography
• Foreword
• Preface
• 1. Therapeutics from natural products against neglected tropical diseases: an overview
• 2. Marine natural products as strategic prototypes in the development of a new generation of antimalarial agents
• 3. Sesquiterpene lactones: a versatile class of structurally diverse natural products and their semisynthetic analogs as potential antimalarials
• 4. Natural and synthetic quinoline molecules against tropical parasitic pathologies: an analysis of activity and structural evolution for developing new quinoline-based antiprotozoal agents
• 5. Promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogs
• 6. Oxidative stress in schistosomiasis, echinococcosis, and trypanosomiasis: a therapeutic approach
• 7. Plant-derived compounds against protozoan neglected diseases: toward sustainable drug development
• 8. Leishmaniasis control: limitations of current drugs and prospects of natural products
• 9. Natural antileprotic agents: a boon for the management of leprosy
• 10. Aloe vera: a promising hope against Buruli ulcer
• 11. Plant and marine products: a promising hope in the search of therapeutics against dengue
• 12. Total synthetic approaches for lucidone: a promising natural lead candidate against dengue infection
• Index