7 Topics in Medicinal Chemistry Editorial Board: P. R. Bernstein · A. Buschauer · G. J. Georg · Y. Kiso · J. A. Lowe · H. U. Stilz . Third World Diseases Volume Editor: Richard L. Elliott With contributions by K. Arora Á C.E. Barry III Á H.I.M. Boshoff Á J.N. Burrows Á M. Carroll Á I. Choi Á R. Don Á R.L. Edwards Á K.D. England Á T. von Geldern Á F. Gomez de las Heras Á T.D. Gruber Á M.O. Harhay Á T.H. Keller Á J. Lee Á D. Marquess Á G.A. Marriner Á T. Mukherjee Á A. Nayyar Á S. Nilar Á I. Scandale Á P.-Y. Shi Á E. Uh Á L.E. Via Á D. Waterson Á S.Y. Wong Á Z. Yin Editor Dr. Richard L. Elliott Box P.O. 98102 Seattle Washington USA [email protected] ISSN 1862-2461 e-ISSN 1862-247X ISBN 978-3-642-23486-6 e-ISBN 978-3-642-23487-3 DOI 10.1007/978-3-642-23487-3 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011936161 # Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. 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Elliott Box P.O. 98102 Seattle Washington USA [email protected] Editorial Board Dr. Peter R. Bernstein Prof. Dr. Yoshiaki Kiso AstraZeneca Pharmaceuticals Department of Medicinal Chemistry 1800 Concord Pike Director Fairfax Research Center B313 Center for Frontier Research PO Box 15437 in Medicinal Science Wilmington, DE 19850-5437 Kyoto Pharmaceutical University USA Yamashina-ku Kyoto 607-8412 Prof. Dr. Armin Buschauer Japan Institute of Pharmacy John A. Lowe University of Regensburg Universita¨tsstr. 31 [email protected] 93053 Regensburg Germany Dr. Hans Ulrich Stilz Aventis Pharma Deutschland GmbH Prof. Dr. Gunda J. Georg Geb. G 838 University of Minnesota 65926 Frankfurt a.M. Department of Medical Chemistry Germany 8-101A Weaver Densford Hall Minneapolis, MN 55455 USA v . Topics in Medicinal Chemistry Also Available Electronically Topics in Medicinal Chemistry is included in Springer’s eBook package Chemistry and Materials Science. If a library does not opt for the whole package the book series may be bought on a subscription basis. Also, all back volumes are available electronically. For all customers who have a standing order to the print version of Topics in Medicinal Chemistry, we offer the electronic version via SpringerLink free of charge. If you do not have access, you can still view the table of contents of each volume and the abstract of each article by going to the SpringerLink home- page, clicking on ‘‘Browse by Online Libraries’’, then ‘‘Chemical Sciences,’’ and finally by selecting Topics in Medicinal Chemistry. You will find information about the – Editorial Board – Aims and Scope – Instructions for Authors – Sample Contribution at springer.com using the search function by typing in Topics in Medicinal Chemistry. Color figures are published in full color in the electronic version on SpringerLink. Aims and Scope Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the new topic-related series Topics in Medicinal Chemistry will cover all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combina- torial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug- receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. In references Topics in Medicinal Chemistry is abbreviated Top Med Chem and is cited as a journal. vii . Preface to the Series Medicinal chemistry is both science and art. The science of medicinal chem- istry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug discovery is uniquely beneficial to the field of medicinal chemistry. The series Topics in Medicinal Chemistry is designed to help both novice and experienced medicinal chemists share insights from the drug discovery process. For the novice, the introductory chapter to each volume provides background and valuable perspective on a field of medicinal chemistry not available elsewhere. Succeeding chapters then provide examples of successful drug discovery efforts that describe the most up-to-date work from this field. The editors have chosen topics from both important therapeutic areas and from work that advances the discipline of medicinal chemistry. For example, cancer, metabolic syndrome and Alzheimer’s disease are fields in which academia and industry are heavily invested to discover new drugs because of their considerable unmet medical need. The editors have therefore prior- itized covering new developments in medicinal chemistry in these fields. In addition, important advances in the discipline, such as fragment-based drug design and other aspects of new lead-seeking approaches, are also planned for early volumes in this series. Each volume thus offers a unique opportunity to capture the most up-to-date perspective in an area of medicinal chemistry. Dr. Peter R. Bernstein Prof. Dr. Armin Buschauer Prof. Dr. Gunda J. Georg Prof. Dr. Yoshiaki Kiso Dr. John Lowe Dr. Hans Ulrich Stilz ix . Preface The specter of diseases most prevalent in developing countries blatantly confronts us with one of the great ironies of the modern world, juxtaposing a tragic situation wherein rapid technological and scientific advances in biology and drug discovery have driven tremendous advances in the treat- ment of first-world diseases with a situation in the developing world wherein millions of people continue to die each year due to lack of safe and efficacious medicine, and where many of the drugs, when they are available, are ancient by modern standards and would not pass current requirements for safety and efficacy. Diseases of the developing world, often known by the moniker ‘‘neglected diseases,’’ comprise a melee of infectious and parasitic diseases that, in terms of their biology and physiopathology, defy common descrip- tion; their greatest commonality being the suffering and death they afflict on the poorest of the poor. No single volume can reasonably expect to encompass the enormity of this subject. Thus, in this volume, we have focused on a selected representative set of diseases that make major contributions to the morbidity and mortality in developing countries, with the hope of raising general awareness of these diseases and highlighting some of the recent drug-discovery advances. Following a general overview chapter, five chapters focusing on tuberculosis, malaria, kinetoplastids, dengue fever, and diarrhea provide an in-depth look at the current status of drug discovery for these diseases. Unsurprisingly, each disease is encumbered by its own unique challenges and knowledge gaps, but share commonality in that, finally, state-of-the-art drug discovery tools and approaches are being rigorously applied to discover new therapies. The picture is no longer bleak, with a number of new drug candidates under active investigation and entering clinical trials. Still, much remains to be done; with many of the more ‘‘neglected’’ diseases (e.g., filarial diseases) being so under- investigated and under-resourced that, sadly, no chapter review was war- ranted. However, the recent increase in research activity and engagement of dedicated researchers throughout the world, collaborating together in acade- mia, industry, and the nonprofit sector, is a new and uplifting trend which portends well for the future. It is with the greatest respect that I acknowledge the important contribu- tions each of the authors have made in this field, and thank them for contributing chapters to this volume. It is my hope that this volume will xi xii Preface serve to inform and guide those working on or interested in diseases that afflict the world’s poorest populations, and, more importantly, inspire a new generation of drug discoverers to devote their knowledge, skills, insight, creativity, and passion to develop new therapies for these diseases, such that we speak of these diseases as ‘‘neglected’’ no longer. Richard L. Elliott Contents Overview of Neglected Tropical Diseases ................................... 1 Federico Gomez de las Heras The Medicinal Chemistry of Tuberculosis Chemotherapy