Medicinal Chemistry of Neglected and Tropical Diseases-Advances in the Design and Synthesis of Antimicrobial Agents PDF
Preview Medicinal Chemistry of Neglected and Tropical Diseases-Advances in the Design and Synthesis of Antimicrobial Agents
Medicinal Chemistry of Neglected and Tropical Diseases Advances in the Design and Synthesis of Antimicrobial Agents Editors Venkatesan Jayaprakash Associate Professor Department of Pharmaceutical Sciences & Technology Birla Institute of Technology, Mesra Ranchi, India Daniele Castagnolo Institute of Pharmaceutical Science King’s College London London, UK Yusuf Özkay Faculty of Pharmacy Department of Pharmaceutical Chemistry Anadolu University Eskisehir, Turkey p, p, A SCIENCE PUBLISHERS BOOK A SCIENCE PUBLISHERS BOOK Cover credit • Top right figure: Figure 6a from Chapter 4 – Reproduced by permission of the authors, Drs. J. Jonathan Harburn and G. Stuart Cockerill. • Middle left figure: Figure 1 of Chapter 14 – Curcuma Plant photograph taken from article ‘On the identity of turmeric: the typification of Curcuma longa L. (Zingiberaceae)’ published in Botanical Journal of the Linnean Society, Wiley, 2008. • Middle right figure: Figure 4c from Chapter 11. Reproduced by permission of the authors, Drs. Andrea Ilari and Gianni Colotti. • Bottom right figure: Figure 1 from Chapter 6. Reproduced by permission of the authors, Drs. D. Velmurugan, K. Manish and D. Gayathri. • Bottom left figure: Figure created by Dr. Daniele Castagnolo. CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2019 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper Version Date: 20190516 International Standard Book Number-13: 978-1-138-54124-5 (Hardback) Th is book contains information obtained from authentic and highly regarded sources. Reasonable eff orts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. 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CCC is a not-for-profi t organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identifi cation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Jayaprakash, Venkatesan, editor. Title: Medicinal chemistry of neglected and tropical diseases : advances in the design and synthesis of antimicrobial agents / editors, Venkatesan Jayaprakash, Associate Professor, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, India, Daniele Castagnolo, Institute of Pharmaceutical Science, King’s College London, London, UK, Yusuf èOzkay, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, Eskisehir, Turkey. Description: Boca Raton, FL : CRC Press, Taylor & Francis Group, [2018] | Includes bibliographical references and index. Identifiers: LCCN 2019013026 | ISBN 9781138541245 (hardback) Subjects: LCSH: Tropical medicine. | Drug development. Classification: LCC RC961 .M467 2018 | DDC 616.9/883--dc23 LC record available at https://lccn.loc.gov/2019013026 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Preface The book “Medicinal Chemistry of Neglected and Tropical Diseases: Advances in the Design and Synthesis of Antimicrobial Agents” comes as an attempt to consolidate the modern drug discovery approaches employed to date to develop effective chemotherapeutic agents for the treatment of Neglected Tropical Diseases (NTDs). According to the definition of WHO, NTDs are “a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries, affect more than one billion people and cost developing economies billions of dollars every year.” NTDs are caused by a variety of pathogens including viruses, bacteria, protozoa and helminths and are mainly common in low-income populations in developing regions of Africa, Asia, and the Americas. Currently, twenty diseases such as dengue and chikungunya infections, African and American trypanosomiasis (Sleeping sickness and Chagas disease), leishmaniasis as well as several worm infestations are listed in the WHO portfolio. Other diseases, widely spread in tropical regions, such as tuberculosis and malaria have been removed from the WHO NTDs list due to the greater treatment and research funding that they received in the last decades. However, despite the increasing investments, tuberculosis and malaria still affect millions of people worldwide and, due to the emergence of drug-resistance strains, the eradication of these diseases is still far from succeeding. Today, the majority of neglected tropical diseases are widely spread in the poorest regions of the world, where substandard housing, lack of access to safe water and sanitation, chronic hunger, filthy environments, and abundant insects and other vectors contribute to their efficient transmission. Diseases like dengue or chikungunya, and more recently zika, have been confined mainly in tropical regions since they are transmitted by mosquitoes living at these latitudes. However, due to climate changes, an increasing number of mosquitoes are adapting to live in subtropical regions, thus contributing to spread of viral infections outside their usual areas, as demonstrated by the presence of cases of chikungunya infections in southern Europe (France and Italy) in 2017–2018. Other neglected diseases, such as worm infestations (helminthiasis), are widely spread in almost any part of the world, regardless of the latitude, and currently affect more than 1 billion of people. However, despite the high number of cases, only a few drugs are available in the market to efficiently treat helminthiasis, making this a class of truly neglected diseases. The aim of this book is to highlight the progresses made to date in the field of drug design, discovery and development of novel treatments active against neglected diseases such as vector borne viral infections, trypanosomiasis, worm infections as well as those tropical diseases such as tuberculosis and malaria which, even if they are no longer considered neglected by funding investment and research, still represent a major health threat worldwide. The first three chapters of the book describe some general approaches currently used in the identification and design of novel drugs active against neglected and tropical diseases, such as fragment-based drug design and molecular hybridization of established lead molecules. Chapters 4, 5 and 6 are focused on three vector borne viral diseases, namely dengue, zika and chikungunya. Although no drugs are currently available in the market to treat these diseases, a few promising lead candidates, described in these chapters, are currently under development. In addition, the development of effective vaccine strategies as well as approaches aimed at preventing and controlling the spread of these diseases are reported. The Chapters 7, 8 and 9 will be focused on the two main non-neglected tropical diseases, tuberculosis and malaria. The most recent repositioning strategies for the treatment of tuberculosis by using non-antibiotic iv Medicinal Chemistry of Neglected and Tropical Diseases drugs are reviewed in Chapter 7 while Chapter 8 describes the recent progresses made in the synthesis of nitrogen heterocycles as antitubercular agents. Finally, Chapter 9 is focused on the recent developments made in the field of antimalarial drugs with a focus on their mechanism of action and screening of novel hit molecules. Chapters 10, 11, 12 and 13 will describe in depth all the drugs currently available for the treatment of kinetoplastid diseases, such as leishmaniasis and African and American trypanosomiasis. The Chapter 10 describes a general and comprehensive overview of the design and synthesis of currently available anti- kinetoplastid drugs, while the Chapters 11 and 12 are more focused on drugs targeting the trypanothione metabolism and on nitroaromatic drugs, respectively. Finally, Chapter 13 is specifically dedicated to anti-leishmanial drugs. The book is completed by Chapter 14 where the use of a natural product, namely curcumin, in the treatment of NTDs is presented, and by Chapter 15, which is entirely focused on the synthesis and pharmaceutical properties of currently available drugs in the treatment of worm infections. Each chapter has been designed in such a way that it caters to the need of the medicinal chemists who work in the field of the chemotherapeutics development for NTDs, as well as a guide to budding those scientists, not only chemists, who wish to work in this area of research. We believe that this book will be of interest and use for all those scientists working in the big field of NTDs and whose expertise ranges widely from chemistry to biology, pharmacology and drug development. Moreover, we hope that the book would be of inspiration for the next generation of young scientists at the beginning of their studies and careers, with the wish that they could discover novel treatments to efficiently fight neglected and tropical diseases. Finally, we want to give a special and warm thanks to all the authors who devoted themselves to this book and contributed to make it a reality. Contents Preface iii 1. Key Concepts in Assay Development, Screening and the Properties of Lead 1 and Candidate Compounds Sheraz Gul 2. The Application of Fragment-based Approaches to the Discovery of Drugs for 18 Neglected Tropical Diseases Christina Spry and Anthony G. Coyne 3. Chemical Hybridization Approaches Applied to Natural and Synthetic Compounds 48 for the Discovery of Drugs Active Against Neglected Tropical Diseases Elena Petricci, Paolo Governa and Fabrizio Manetti 4. Current Inhibitors of Dengue Virus: An Overview 76 J. Jonathan Harburn and G. Stuart Cockerill 5. Overview of Drugs used Against Zika Virus 93 Sinem Ilgın, Özlem Atlı Eklioğlu, Begüm Nurpelin Sağlık and Serkan Levent 6. Chikungunya Virus Infection: A Review of its Control and Treatment 107 D. Velmurugan, K. Manish and D. Gayathri 7. Recent Advances in Repositioning Non-Antibiotics against Tuberculosis 122 and other Neglected Tropical Diseases M.M. Dorothy Semenya 8. Prospects of Pre-clinical [6.6.0] Bicyclic Nitrogen Heterocycles in the 147 Treatment of Tuberculosis Neha P. Agre, Mariam S. Degani and Sanjib Bhakta 9. Progress in Antimalarial Drug Discovery and Development 166 Anna C.C. Aguiar, Wilian A. Cortopassi and Antoniana U. Krettli 10. Hits and Lead Discovery in the Identification of New Drugs against the 185 Trypanosomatidic Infections Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade and Maria Paola Costi 11. New Chemical Scaffolds to Selectively Target the Trypanothione Metabolism 232 Andrea Ilari and Gianni Colotti vi Medicinal Chemistry of Neglected and Tropical Diseases 12. The Renewal of Interest in Nitroaromatic Drugs: Towards New 250 Anti-Kinetoplastid Agents Nicolas Primas, Caroline Ducros, Patrice Vanelle and Pierre Verhaeghe 13. New Biological Targets for the Treatment of Leishmaniasis 281 Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran and Agostino Cilibrizzi 14. Curcumin and Neglected Infectious Diseases 310 Francesca Mazzacuva and Agostino Cilibrizzi 15. An Overview of Helminthiasis: Current State and Future Directions 337 Leyla Yurttaş, Betül Kaya Çavuşoğlu, Derya Osmaniye and Ulviye Acar Çevik Index 357 Color Plate Section 359 1 Chapter Key Concepts in Assay Development, Screening and the Properties of Lead and Candidate Compounds Sheraz Gul Introduction The drug discovery process lies at the interface of biology and chemistry and can be divided into two main phases, namely the pre-clinical and the clinical phase (Blass 2015, Ng 2015, Li and Corey 2013, Marshall et al. 2018). The former begins with the identification of a biological target that is implicated in a particular disease and ends with a candidate compound which is suitable for entering First Time in Human (FTIH) studies (Bergstrom 2017). For most drug discovery projects, it is commonplace that the duration of the pre-clinical phase is in the region of five years and costs 5–10 million Euros. The pre-clinical phase can itself be sub-divided into three stages, namely Target-to-Hit, Hit-to-Lead and Lead-to-Candidate (Mignani et al. 2018, Parker et al. 2015, Vaswani 2016). Associated with these stages are compound centric milestones such as identification of a hit compound series which will have modest potency against the biological target which it has been screened against, limited selectivity and toxicity information (Tobinaga et al. 2018, Uliassi et al. 2018, Xia et al. 2018, Yang et al. 2018, Zhang et al. 2018). Significant optimisation of a Hit compound series with respect to a number of properties is necessary, often in an iterative manner, which will yield a Lead compound series that has defined properties relating to its bio-activity, physico-chemical properties and various toxicity determinations (Chiarelli et al. 2018, Thompson et al. 2018, Xie et al. 2018). Due to the costs involved in further optimisation, the most promising Lead compound is further optimised resulting in the generation of a Candidate which has extensive data relating to its in vitro and in vivo efficacy and safety profile such that it is suitable for progression to clinical trials (Dias Viegas et al. 2018, Forkuo et al. 2018, Gao et al. 2018a, Huang et al. 2018, Wu et al. 2018). Head of Drug Discovery, Fraunhofer Institute for Molecular Biology & Applied Ecology - ScreeningPort, Schnackenburgallee 114, D-22525 Hamburg, Germany. Email: [email protected] 2 Medicinal Chemistry of Neglected and Tropical Diseases The main processes in pre-clinical drug discovery are reviewed herein and these cover target identification, assay development, compound screening, Hit identification and properties of a Lead series and Candidate compound. A summary of the key compound centric activities in the pre-clinical drug discovery value chain are shown in Figure 1. Figure 1. The milestones in pre-clinical drug discovery relating to compound progression. Target Identification Prior to initiating a drug discovery project, a biological target that is implicated in a disease needs to be selected. The success of the entire drug discovery process is dependent on choosing the right target for a particular disease, therefore, a strong biological rationale for target selection is necessary (Cowell et al. 2018, Kurata et al. 2018, Neggers et al. 2018, Storer et al. 2017). Despite all efforts and due diligence that can be taken to ensure selection of a suitable target, proof that its modulation will treat a disease will only be known during a suitably powered clinical trial (Lok et al. 2017, Shapiro et al. 2018). The sequencing of the human genome has been a major technological achievement and has led to the identification of thousands of proteins that function in concert leading to a healthy human (Venter et al. 2001). These proteins can be classified into various biological target classes; for example, there are approximately 400 GPCR, 50 nuclear receptor, 500 kinase and 400 protease targets, all of which are now well established to be tractable classes of proteins from a drug discovery perspective (Ferguson and Gray 2018, Fernandez 2018, Hauser et al. 2017, Turk 2006). A significant proportion of the human genome has therefore not been explored and it is likely that only a small fraction of these genes are actually tractable with respect to a small molecule or biologics therapeutic approach. This may be due to potential target redundancy and the existence of alternative biological pathways and it may explain the lack of efficacy that has been observed for many Candidate compounds in clinical trials (Hwang et al. 2016, Jones et al. 2017). Thus, a major challenge in drug discovery is to focus the efforts on valid targets (Floris et al. 2018, Rouillard et al. 2018, Xu et al. 2018). In light of the above challenges, target validation involves demonstrating that the target itself is directly involved in a disease process and modulation of its activity would control disease progression. For this, a comprehensive understanding of the biological pathways the target protein is involved in is necessary. However, this is usually not possible when evaluating the target in isolation or in a non-physiological environment which often occurs in the early stages of drug discovery programs. The best validated targets Key Concepts in Pre-clinical Drug Discovery 3 are generally identified as the result of extensive studies in disease biology that may have taken many years to accomplish by researchers in academia and industry. The ranking of the confidence in target validation can conveniently be classified using a score ranging from 1 (least confidence) through to 4 (most confidence), as shown in Figure 2. The ranking is also consistent with the progression of most drug discovery projects as the initial steps are biology focused and upon understanding target mechanism of action. The attention then shifts to a chemistry focus where compounds are designed, synthesised and evaluated in vitro and in vivo to confirm that they are able to modulate the activity of the biological target in a manner that could be therapeutically relevant (Bhullar et al. 2018, García-Aranda and Redondo 2017, Mohs and Greig 2017). The best assessment for validating a particular target from a drug discovery perspective would come from the existence of a therapeutic agent that has successfully been shown to yield clinical benefit. However, this scenario is not optimal when searching for novel first-in-class drugs as the existence of a competitor molecule would impact the revenue generating potential of an additional drug. The latest trends in pre-clinical drug discovery appear to emphasise the importance of developing lower-throughput but more physiologically relevant assay systems such as those that make use of patient derived cells (O’Duibhir et al. 2017), stem cells (Di Baldassarre et al. 2018, Robbins and Price 2017, Watmuff et al. 2017), complex 3D models (Miranda et al. 2018, Weeber et al. 2017), fluorescence-activated cell sorting (Fu et al. 2014), cellular thermal shift (Martinez et al. 2018, McNulty et al. 2018), high fidelity toxicity (Lin et al. 2014) and technologies such as label-free electrical impedance (Atienzar et al. 2013, Doornbos et al. 2018, Peters et al. 2015) and gene editing (Ahmad and Amiji 2018, Lino et al. 2018). A confounding aspect of target validation is when a single target is implicated in different disease processes. For example, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) is a drug target for statins (Istvan and Deisendorfer 2001) and is therefore involved in lowering blood cholesterol concentrations, but it has also been implicated in other diseases including neurodegeneration (Saravi et al. 2017), periodontal disease (Muniz et al. 2018), cancer (Zaleska et al. 2018) and Alzheimer’s disease (Daneschvar et al. 2015), albeit to varying degrees of confidence. Therefore, robust target validation relating to disease association is often lacking, especially for novel drug targets. A powerful technique that can be used to identify novel targets is Genome Wide Association Studies (GWAS) which can provide evidence for disease associated gene loci even if it often lacks detailed characterisation (Breen et al. 2016, Schunkert et al. 2001, Shu et al. 2018, Sud et al. 2017, Wijmenga and Zhernakova 2018). Although this offers the opportunity to discover first-in-class drugs, progressing small Figure 2. The criteria for ranking target validation in pre-clinical drug discovery.
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