Drug Discovery in Africa Kelly Chibale • Mike Davies-Coleman • Collen Masimirembwa Editors Drug Discovery in Africa Impacts of Genomics, Natural Products, Traditional Medicines, Insights into Medicinal Chemistry, and Technology Platforms in Pursuit of New Drugs Editors Kelly Chibale Dept of Chemistry University of Cape Town Rondebosch South Africa Mike Davies-Coleman Department of Chemistry Rhodes University Grahamstown South Africa Collen Masimirembwa African Institute of Biomedical Science and Technology Harare Zimbabwe ISBN 978-3-642-28174-7 ISBN 978-3-642-28175-4 (eBook) DOI 10.1007/978-3-642-28175-4 Springer Heidelberg New York Dordrecht London Library of Congress Control Number: 2012938653 # Springer-Verlag Berlin Heidelberg 2012 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes no warranty, express or implied, with respect to the material contained herein Cover illustration: # MShep2 Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Professor Johnson Jato A Tribute On June 27, 2012, we were deeply saddened to hear of the passing in his sleep of our dear friend and colleague, Johnson Jato, at his home in Yaounde, Cameroon In Chap 2, we discuss some of the significant and novel drug leads discovered from African biodiversity in the US National Cancer Institute (NCI) program In launching the NCI plant collection program in Cameroon in 1986 through a contract with Missouri Botanical Garden (MBG), Professor Johnson Jato of the University of Yaounde proved to be the key contact for both the NCI and MBG, and prominent among the drug leads discovered were the potential anti-HIV agent, michellamine B, and the antitumor agents, the schweinfurthins Dr James Miller, who at that time was one of the main MBG investigators, now Dean and Vice President for Research at New York Botanical Garden, remarked —“Johnson was tremendously helpful in a country that is often confusing and difficult, and he helped us navigate everything from basic logistics to difficult politics My most vivid memory of Johnson was that he always did it all in a tremendously cheerful, optimistic way with a great sense of humor We could not have accomplished what we did without his help.” Regarding the michellamine B project and the cultivation of Ancistrocladus korupensis, Dr James Simon, who supervised the project while at Purdue University, noted—“Johnson did seem to be ageless with a super-sized heart of gold and always optimistic (or nearly always anyway) I remember him quite vividly and his leadership in the michellamine B project was instrumental in the ability for all of us to the work, it well and navigate it all through the complexities found out there (in Cameroon) He was a generous soul.” In the schweinfurthin project, it was the successful scale-up recollections undertaken by Professor Jato in Cameroon in 1998–1999 that permitted the ongoing preclinical studies of schweinfurthin analogues to proceed The first interaction between Johnson and the NCI was when he visited Dr Joe Mayo, Chief of the Biological Testing Branch, in the early 1980s to discuss the possibility of NCI helping with establishing some preclinical testing at the University of Yaounde While no formal collaboration was established, Johnson and Joe became close personal friends, and Joe developed a huge admiration for the level of research Johnson achieved with very limited resources Their friendship continued over the years, and in 1986, when the NCI established the plant collection contract with MBG, Joe introduced Johnson to Gordon as a possible contact in Cameroon Johnson and Gordon became firm friends and colleagues and collaborated closely in the various NCI projects in Cameroon This close relationship extended to all of us, and we kept in contact with Johnson right to the end We all remember Johnson as an ever-cheerful friend and a resourceful and reliable colleague who approached every project with a determined optimism which enabled him to overcome seemingly insurmountable challenges, and which earned him the respect and admiration of all his colleagues We can truly say we could not have accomplished what we did without his help and inspiration Thank you, Johnson We will miss you! John Beutler, Gordon Cragg, and David Newman Foreword African Drug Discovery: A Window on the World Africa is a continent of tremendous opportunity: a wealth of natural resources, people talent and energy However, there is also a great burden of neglected diseases, not only in terms of suffering and lives lost, but also as a loss of economic value Some of these diseases are shared with the Western world, but many are either especially prevalent to Africa, or even unique to the continent This book represents a ray of hope at a difficult time It is a window on the world of African science, and the perspective on the discovery and progression of new medicines to target key diseases Bringing together some of the best researchers in Africa with a common goal, to focus on how to develop new medicines in an African context Drug discovery and development requires being able to pull together people with a wide variety of expertise and background, to form teams with a common goal It means bringing together the basic science and medical research It means bridging the gap between science and technology But those who invest in new medicines must also have deep pockets, and great patience Even with the best will in the world, a new pharmaceutical can take a decade to be brought through the development pathway Traditionally, this research has largely been funded from outside Africa; what are the signs that the political will here is changing? In 2006 in the Khartoum declaration [1], members of the African Union set a target to invest 1% of their gross domestic product in R&D This target is met by three very different countries—Malawi, Uganda and South Africa—so there is every reason to hope that more will follow if there is the political will [2] There was also a call for the establishment of centres of excellence in Africa How many of those will feed into the overall objective of new medicines is not clear yet However, the establishment of ANDi (the African Network for New Drug and Diagnostic Innovation) [3] is surely an important milestone in this process The Cairo declaration of the African Ministerial Council on Science and Technology (AMCOST) [4] made two other strong recommendations: support of South-South cooperation in science, technology and innovation and the establishment of a Pan-African Intellectual vii viii Foreword Property Organization (PAIPO) This book contains many examples of the former and hopefully sows the seeds for the latter At a time when the productivity of the pharmaceutical industry is static, and its financial star is waning, it is pertinent to ask why of all technologies the countries in Africa should prioritise investments in new medicines One key to success in the identification of new medicines is the proximity to patients, having researchers who understand on a daily basis the devastating effects of the diseases they are tackling African approaches to neglected disease will not only come from the heart, but will have this insight Second, the patrimony of the continent is its natural resources, which can be used for the benefit of all Africa’s people We need to work alongside traditional healers to understand these products better [5] We need to follow the Chinese approach of dao-xing-ni-shi (acting in the reversed direction): [6] use observational clinical studies to improve our clinical understanding of how these natural products work, before becoming too reductionist These natural products have existed side by side with the population for generations, and so the information known about their clinical aspects is critical The traditional remedies of yesterday have been improved by the skills of our chemists, pharmacologists and physicians into the medicines of today [7] In a similar way, the traditional remedies of today contain the seeds of the ideas for the medicines for tomorrow The focus on natural products from Africa is clear in this book; half the chapters are dedicated to some aspect of the work We need to develop an African way forward for natural products They key here is that the way these products are moved forward must be seen from an African perspective We must avoid the tendency to ‘cut and paste’ the western experience of drug development Ultimately, science is about people, and developing a new generation of scientists Beyond funding, this requires training of the next generation of scientists, and opportunities for scientific exchange between countries [8] It is my hope that the readers of this book will benefit not only from the scientific content, but from the improved visibility and interaction with the new generation of African science leaders Ultimately, the chance to change the future of Africa is in their hands The window on African science is open; we need to all work together to keep it that way Tim Wells Chief Scientific Officer Medicines for Malaria Venture Geneva Switzerland References EX CL/Dec.254 (VIII) http://www.africa-union.org/root/au/Documents/ Decisions/com/AU6th_ord_Council_Decisions_Jan2006_Khartoum.pdf UNESCO world Science Report Foreword ix http://www.andi-africa.org/ http://www.nepadst.org/doclibrary/pdfs/cairo_declaration_2006.pdf Willcox ML, Graz B, Falquet J, Diakite C, Giani S, Diallo D (2011) A “reverse pharmacology” approach for developing an anti-malarial phytomedicine Malar J 10(Suppl 1):S8 Lei SH (1999) From Changshan to a new antimalarial drug Soc Stud Sci 29:323–358 Wells TNC (2011) Natural products as starting points for future anti-malarial therapies: going back to our roots? Malar J 10(Suppl 1):S3 Murenzi R (2011) Give the new generation a chance Nature 474:543 17 Nanomedicine in the Development of Drugs for Poverty-Related Diseases 423 Free INH SD INH Free RIF SD RIF No drug (control 1) No drug (control 2) BACTEC 460 Spray dried samples 1200 1000 GI 800 600 400 200 Day Day Day Day Day Days Day Day Day Fig 17.8 BACTEC 460 data indicating bacterial growth index of H37RV treated with encapsulated RIF and INH and unencapsulated drugs SD spray-dried Nano PLGA-INH2 Conv RIF Nano PLGA-RIF2 MIC-INH Conv INH MIC-RIF 10 Drug Conc (ug/ml) 0 20 40 60 80 100 Time (hrs) 120 140 160 Fig 17.9 In vivo release of free drugs versus spray-dried nanoparticles encapsulating RIF and INH and PZA Conv Conventional, MIC minimum inhibitory concentration 424 R Hayeshi et al M tuberculosis) was explored due to its cholesteroid properties [46], and the aptamers were prepared against the mannose receptor, which is significantly over-expressed during the activation of the macrophages in the presence of M tb Intracellular uptake of the MA PLGA nanoparticles was achieved in U937 cells However, little co-localization was observed with endocytic markers, indicating that they could be localised in the cytosol Vesicles bearing these particles were also observed in the cell membrane of the cells [47] Uptake of the aptamers into THP-1 cells was also observed, illustrating the feasibility of using the nucleic acid species for active targeted delivery of the encapsulated anti-TB drugs [47] A provisional patent application titled “High Affinity Nucleic Acid Ligands to the Mannose Receptor” has already been filed on the method The success of these two approaches of anti-TB drug targeting will greatly address the challenges of poor bioavailability, reduced efficacy and adverse side effects for diseases such as TB Research in Progress for Improving HIV and Malaria Treatment Through Nanomedicine Based on the successes and experiences obtained through the research work on nanomedicine for TB, the authors have begun on nanoencapsulation of antiretroviral and antimalarial drugs To date, efavirenz and lamivudine have been encapsulated in PCL nanoparticles with an average size of 230 nm (unpublished data) For malaria, nanocarriers are being designed to target parasites in the liver (pre-erythrocytic) and the red blood cell (erythrocytic) stage of the parasites transmission cycle Prophylactic and curative measures of the chemical agents will be investigated before and after the application of drug delivery systems Research Strategy for Improving NTDs Using Nanomedicine The parasites causing NTDs such as leishmaniasis and trypanosomiasis often disseminate throughout the RES, e.g leishmaniasis in the lymph nodes [48] and schistosomiasis in the spleen [49] Therefore, the strategy for nanomedicine for these diseases is to take advantage of the selective uptake of nanocarriers by the RES which may be further enhanced by actively targeting the nanocarriers to the parasites in the, e.g lymphatic system Activities to Build Nanomedicine Research Capacity in Africa Towards advancing nanomedicine and the benefits of the technology in Africa, the authors organised the first international sensitisation workshop on nanomedicine for infectious diseases of poverty, in South Africa on March 2011 Officially opened by the minister of the Department of Science and Technology, this workshop brought together about 90 delegates from over 20 different countries and included 17 Nanomedicine in the Development of Drugs for Poverty-Related Diseases 425 representatives from academia, the pharmaceutical industry, regulatory authorities, donor agencies, international organisations and policymakers, all interested in supporting the advancement of nanomedicine in Africa The workshop comprised a panel of highly accomplished experts in various aspects of nanomedicine and drug delivery as well as experts in drug development for poverty-related diseases Oral and poster presentations encompassed basic science through to translational efforts and addressed topics on various initiatives and funding The 4-day workshop featured plenary lectures, invited talks and round table discussions focusing on specific tenets of nanomedicine and drug development The fourth day was dedicated to discuss intellectual property rights and technology transfer, an aspect which must be kept in mind when developing new technologies Following the workshop, the authors presented a series of nanomedicine sensitisation seminars (road shows) to students and young researchers at a total of 18 institutions in Kenya, Nigeria and Ethiopia with more seminars planned for Cameroon and other African countries such as Uganda, Sudan and Tanzania These nanomedicine road shows highlight the urgent need for more in-depth training in nanomedicine for PRDs Accordingly, the authors are planning the first Pan-African summer school in nanomedicine for PRDs, in collaboration with leading nanomedicine experts that have nanomedicines on the market and also have experience in operating such nanomedicine schools and conferences in Europe and the USA annually, as well as African PRD experts The school aims to bridge the gap between the sciences, health and development in Africa, by educating young African scientists on the potential of applying nanomedicine in PRD drug development research To achieve this, the school will focus on crucial areas to build capacity in nanomedicine Furthermore, the school will assist in establishing networks and collaborations among trainees, to ensure that every trainee can confidently enhance knowledge dissemination and skills acquisition The school will also encourage the young scientists to bring with them any compound which has failed to reach the market due to the above-mentioned shortfalls In this workshop, they will have the opportunity to apply different nanocarriers to address the shortfalls 17.3.1.2 University of the Witwatersrand (Wits) The Wits Advanced Drug Delivery Platform (WAADP) is focused on advancements in polymeric science, formulation stability and drug delivery design including nanomedicine for infectious diseases such as TB In a recent publication, the group evaluated sustained release of INH and RIF from polymeric nanoparticles synthesised via four emulsion-based processing strategies, namely emulsion-solvent-surfactant-evaporation (ESSE) and emulsion-solvent-evaporation (ESE) approaches for PLGA nanoparticles and reverse-emulsion-cationic-gelification (RECG) and reverse-emulsion-surfactant-cationic-gelification (RESCG) approaches for alginate hydrogel nanoparticles [9] Encapsulation efficiencies were in the range of 73–82% The ESSE and RESCG approaches which included sorbitan 426 R Hayeshi et al monooleate as a stabiliser yielded smaller sizes of nanoparticles in the range of 200–290 nm for INH and RIF and displayed sustained release over h with zeroorder kinetics in vitro Another group at Wits, the Antiviral Gene Therapy Research Unit (AGTRU), is using nanocarriers [50] to deliver nucleic acids that are capable of silencing gene expression of viruses that are responsible for infections of serious public health importance to South Africa such as HIV infection [51] 17.3.1.3 North-West University (NWU) The Unit for Drug Research and Development at the NWU is conducting research aimed at optimising the delivery of anti-TB and antimalarial drugs using Pheroid™ technology Pheroid™ technology is a drug delivery system patented by the NWU which can be described as a colloidal system that contains stable, submicron- and micron-sized active pharmaceutical ingredient dispensing vehicles Recently, entrapment of the new artemisinin derivative, artemisone, in Pheroid™ vesicles has been shown to significantly enhance the absorption of the drug The Cmax was improved by 90%, and the T1/2 increased three times after oral administration in a mouse model [52] In addition, a Pheroid™ formulation for TB drugs is currently undergoing phase I clinical trials The CSIR and NWU research groups are now collaborating on entrapping PLGA nanoparticles in Pheroids to further improve bioavailability and achieve controlled release for TB drugs 17.3.2 Nanomedicine Research for PRDs in the Rest of Africa In the rest of sub-Saharan Africa where PRDs are endemic, there is little advancement in nanomedicine research for the treatment of these diseases A few groups exist carrying out basic research into nanomedicine-based therapies, with only two identified thus far at the University of Mauritius (UOM) and American University in Cairo, focusing on PRDs At the 4th ANDI Conference in October 2011, the Centre for Biomedical and Biomolecular Research at the UOM presented its unpublished work focusing on engineering novel block copolymer nanomicelles for the delivery of anti-TB drugs The group has engineered amphiphilic block copolymers based on poly(ester-ether)s, polyLysine-b-caprolactone and oligoagarose-g-polycaprolactone They reported loading of rifampicin up to 70% and sustained drug release over 72 h The group in Cairo is investigating nanomedicine for schistosomiasis and filariasis but has not published any data as yet In terms of non-PRD nanomedicine-based therapies, Prof Wole Soboyejo at the African University of Science and Technology (Abuja, Nigeria) is working on nanoparticles for cancer detection and treatment in collaboration with Princeton University, USA (Personal communication) In Ghana, Dr Ofori-Kwakye and 17 Nanomedicine in the Development of Drugs for Poverty-Related Diseases 427 Dr Stanley Moffat are conducting basic research in pharmaceutical nanotechnology Dr Moffat was recently appointed the African coordinator for USEACANI (US-Europe-Asia Pacific-Caribbean Nanotechnology Initiative) 17.4 Conclusions The number of discovery programmes for PRDs is too low to ensure a steady stream of treatments on to the market [53] This is mainly due to the lack of activity from the pharmaceutical industry because refinancing the high development costs will not be profitable Only 1.3 products are expected to reach the market out of 100 entering the screening phase of drug discovery [53] These figures indicate that there is an urgent need for new strategies, such as nanomedicine, in drug development programmes for PRDs Nanomedicine has been successfully applied for treatment of cancer with several products already on the market Critical properties of nanomedicine systems include protection of instable drugs, cell-adhesion properties, intracellular delivery of drugs and the ability to be surface-modified by conjugation of specific ligands, enabling targeted delivery and controlled release Thus, nanodrug delivery systems seem to be a promising and viable strategy for improving treatment of PRDs However, in Africa, there is minimal application of this technology for the treatment of PRDs with only a few groups in South Africa making significant 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27:323–329 Index A Acanthamoeba castellanii, 251 Accedine, 388 Accedinine, 388 Accedinisine, 388 Acetogenins, 223 Actinosynnema pretiosum, 40 Action TB, Activity-based protein profiling (ABPP), 120 ADME, 114, 139, 158, 411 ADMET, 285 in silico, 159 PK platforms, 151 African Institute of Biomedical Science and Technology (AiBST), 160 African Laboratory for Natural Products (ALNAP) Bibliographic Database, 109 African Malaria Network (AMANET), African Network for Drug and Diagnostic Innovation (ANDI), 6, 190, 401, 417 African Programme for Onchocerciasis Control (APOC), African trypanosomiasis, 213 AIDS, See HIV Albendazole, 129 ADME, 162 Alcyonium fauri, 338 Alkaloids, 229 6-Allyl-4,5-dimethoxy-1,3-benzodioxol (dillapiole), 225 Amaryllidaceous alkaloids, 231 American trypanosomiasis, 214 Aminomethylthiazole pyrazole carboxamide, 116 4-Aminoquinolines, 164, 303, 305 Amino steroids, 202 Amitriptyline, 278 Amodiaquine, 104, 172, 305 ADME, 162 artesunate, 293 Amprenavir, 333 Amylase inhibition, 253 Ancistrobrevines, 383 Ancistrocladine, 382 Ancistrocladus A abbreviates, 382 A barteri, 384 A heyneanus, 382 A korupensis, 45, 118, 385 ANDI (African Network for Drugs and Diagnostics Innovation), 6, 190, 401, 417 Anethum graveolens, 225 Angiotensin-converting enzyme (ACE), inhibitors, 113, 355 Angiotensinogen, 356 Antheliatin, 201 Anthelmintics, 127 Anticancer agents, 36 low dose, 294 Antifolate drugs, 313 resistance, 313 Antileishmanial activity, 225 Antimalarial activity, 4-aminoquinolines, 166 MTX, 294 Antimalarial resistance, 301 Antimalarials, 379, 396 Madagascar, 268 Anti-parasitic drugs, intrinsic clearance, 178 predicted physicochemical properties, 163 Antiplasmodial activity, 224, 269 Antiprotozoal activity, 227 Antiretroviral (ARV) drugs, 325 Anti-TB drugs, nanoencapsulation, 418 K Chibale et al (eds.), Drug Discovery in Africa, DOI 10.1007/978-3-642-28175-4, # Springer-Verlag Berlin Heidelberg 2012 431 432 Antitrypanosomal activity, 224, 227, 230 Antitumor activity, screening, 30 Antivenoms, 21 Apricitabine, 330 Argemone mexicana, 229 Artemether (ATM), 293, 302, 306, 312 Artemisia annua, 283, 311, 379 Artemisinin, 103, 129, 283, 293, 311, 379, 393 ADME, 162 combination therapies (ACTs), 293, 302 Artemisone, 426 Artesunate, 104, 162, 293, 302, 312 ADME, 162 3-Aryl-pyridobenzimidazoles, antimalarial agents, 117 Ascariasis, MDA campaigns, 129 Ascaris lumbricoides, 128 Atazanavir, 333 Avarol, 203 Axinella weltneri, 199 Azadirachta indica, 225, 392 Azithromycin, 129 B Benzo[c]phenanthridine alkaloids, 229, 391 Berchemia discolor, 45 Bioassay-guided fractionation, 106 Bioavailability, 185 Biological prioritization, 140 Biopiracy, 141, 147 Biotransformation, 111 Bis-benzylisoquinolines, 385 Bodo caudatus, 251 Botswana, 243 Bradykinin, 359 Brugia malayi, culture, 140 C Camptothecin, 37 Cancer chaperone (HSP90), 90 Cancer Chemotherapy National Service Center (CCNSC), 30 Candidate drug target profile (CDTP), 188 Captopril, 360 Carboxypeptidase, 363 Cardiovascular disease (CVD), 356 Catechin-3-O-gallate, 279 Catharanthus roseus, 37 Celastrol, 224 Index Center for Scientific Research, Indigenous Knowledge and Innovation (CesrIKi), 243 Cephalodiscus gilchristi, 47, 196 Cephalostatin, 47, 197 Chagas disease, 214 Chelerythrine, 390 Chemical prioritization, 139 Chemosensitizers, 270, 276, 304 Chloropromazine, 278 Chloroquine, 104, 110, 162, 282, 304, 379, 398 ADME, 162 dose, 294 Pfcrt/Pfmdr1, 303 resistance, 401 Chloroquine-adjuvant plants, 270 Chlorpheniramine, 278 Chlorproguanil, 313 Cinchona, 282, 379 Clausena anisata, 400 Clinical studies/trials, 15, 24 Cliona celata, 202 Clionamines, 202 Co-chaperones, 93 Combretastatins, 37 Combretum C caffrum, 37 C paniculatum, 335 Compound library characterisation, 161 Computer-aided drug design (CADD), HIV, 332, 343 Condylocarpine, 389 Conserved pathways, 85 Consortium for Advanced Research Training in Africa (CARTA), 19 Coronaridine, 386 Correlation analysis, 179 Crinum amabile, 232 Croton oil, 227 Cryptoheptine, 395 Cryptolepine, 395, 398 Cryptolepinone, 395 Cryptolepis alkaloids, 395 Cryptolepis sanguinolenta, 389, 396 Cryptospirolepine, 395, 398 Cryptotakieine, 395 Cymbopogon spp., 400 Cyproheptadine, 278 Cytochrome P450, 110, 169, 411 inhibitor, 226 Cytotoxicity, 153 Index D Dapsone, ADME, 162 Dehydroaporphines, 271, 284 15-Deoxyspergualin (DSG), 89 Derrubone, 91 Desethylamodiaquine (DEAQ), 174, 302 Desipramine, 278 Diethylcarbamazine, 129 ADME, 162 Dihydroartemisinin, 104, 311 Dihydrochelerythrine, 390 Dihydrofolate reductase (DHFR), 313 Dihydropteroate synthase (DHPS), 313 (3a,12a)-Dihydroxy-ent-8(14),15isopimaradien-18-al, 44 2,6-Dihydroxyfissinolide, 226 Dihydrousambarensine, 389 Dill oil, 225 Dillapiole, 226 Diminazene, 214 Dioncolactone A, 383 Dioncophyllines, 382, 383 Discoloranones, 44, 45 Diterpenes, 227 DNA topoisomerase inhibitors, 203 Docetaxel, 37, 41, 204, 297 Dolastatins, 47 Dollabella auricularia, 47 Dose estimation, 189 Dracunculus medinensis, 128 Drug bioavailability, 154 Drug combinations, 117 Drug delivery, nanocarriers, 415 Drug discovery, PRDs, 412 random screening, 335 Drug–drug interactions (DDI), 186 Drugs for Neglected Diseases Initiative (DNDi), 121, 219 Dual drugs, 117 E E7974, 201 Ecteinascidia turbinata, 194 Eflornithine, 214 Eleutherobia aurea, 201 Elvitegravir, 330 Emulsion-solvent-evaporation (ESE), 425 Enalaprilat, 360 Englerins, 40, 42 Entamoeba histolytica, 252 Enterobius vermicularis, 128 Enzyme identification, 175 433 Epihaemanthidine, 231 Epilgallocatechin-3-gallate (EGCG), 90, 91 8-Epixanthatin, 228 Erythromycin, 103 Erythroxylum pervillei, 43, 276 Ethambutol, 62 Euphorbiaceae, 45, 227, 250, 254, 336, 340 Euphorbia E officinarum, 340 E quinquecostata, 45 European Foundation Initiative for African Research into Neglected Tropical Diseases (EFINTD), 216 Extensively drug-resistant (XDR) M tuberculosis, 54 F Fabaceae, 249, 254, 339 Fagaramide, 390 Fagaridine, 390 Fagaronine, 390 Faith healers, 256 Farnesyl hydroquinones, 338 Fascioliasis, 21 Febrifugine, 113 Filariasis, 128, 212, 426 Financing, 120 Fissinolide, 227 Flavonoids, 220, 339, 394 FLPs, 132 FMRFamide, 132 Fosamprenavir, 333 Fund for R&D in Neglected Diseases (FRIND), 219 G Gallic acid, antiplasmodial enhancer, 279 Gambogic acid, 90, 91 Gamma-amino butyric acid (GABA), 335 Ganoderma colossum, 339 Gedunin, 225, 394, 397 Geldanamycin (GA), 88, 91 Genotoxicity, 153 Geodiamolides, 200 Ghana quinine, 396 Gigantetrocine, 224 Global Alliance for Tuberculosis Drug Development (TB Alliance), 3, 121 Global Alliance for Vaccines and Immunization (GAVI), Global health partnerships (GHPs), 434 Global Polio Eradication Programme (PEI), Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property (GSPOA), Glucohydrolase, 339 Glucosidase inhibition, 253 Glutamine synthetase, 73 Glutathione transferase, 275 Goniothalamus giganteus, 224 Gonorrhea, 251 Good clinical practice (GCP), 21 Good laboratory practice (GLP), 21 Good manufacturer practice (GMP), 21 GPCRs, 132 H Half-life, 185 Haliclona tulearensis, 200 Halitulin, 200 Halofantrine (HFT), 303, 310 Haplophyllum tuberculatum, 222 Hazomalania voyroni, 270 Heat shock elements (HSE), 86 Heat shock proteins (HSP), 85 biotechnological tools in drug discovery, 94 HSP70, 87 HSP90, 86 Heat shock transcription factors (HSF), 86 Helenalin, 229 Heligmosomoides polygyrus, culture, 140 Hemiasterella minor, 47, 200 Hemiasterlins, 47, 201 Hepatic clearance, 183 Hepatitis B, 21 Hervelines, 270, 279 Hexahydromalagashanine, 278 Highly active antiretroviral therapy (HAART), 326 High-throughput screening (HTS), 106, 112, 137, 158, 265, 281, 332 Hippadine, 231 Hirsutinolides, 104 Hit identification/evaluation, 12, 161 Hit to lead, 139 HIV/AIDS, 326, 408 Botswana, 250 drug discovery, 325 immune-enzymatic test, 21 michellamine B, 45 nanomedicine, 424 RT inhibitors, 343 HIV aspartyl protease, 333 Index HIV-1 TAT inhibitors, 345 HIV–TB co-infections, 54 HIV Vaccine Initiative (HVI), Holothin, 117, 118 Homocryptolepinone, 395 Homoharringtonine, 37 Hookworms, 128 HOP, 93 Hoslundia opposita, 339 Host-parasite coevolution, 285 Human African trypanosomiasis (HAT), 213 Hybrid compounds, 117 Hydatidosis, 21 19-Hydroxycoronaridine, 386 Hypoxia-inducible factor-1 (HIF-1), 204 Hypoxis hemerocallidea, 335 I Indigenous knowledge research, Botswana, 243 Indinavir, 333 Indole alkaloids, 232 Inequity, Integrated InnovationTM, 145 Intellectual property (IP), 14, 130, 141 International Aids Vaccine Initiative (IAVI), Irinotecan, 37 Isoannonacin, 224 Isocryptolepine, 395 Isoiguesterol, 224 Isometamidium, 214 Isoniazid, 62 16-epi-Isositsirikin, 389 Ivermectin, 129 J Jatropha curcas, 227 Justicidin A, 222 K Kallikrein-kinin system, 359 Khaya senegalensis, 225 Korundamine A, 118 Korupensamines, 385 L Lapachol derivatives, 89 Lapatinib, 41 L-Canavanine, 335 Index Lead discovery (LD), 170 Lead optimization, 12, 170, 188 Leishmaniasis, 212, 251, 409, 424 visceral, 21, 409 Leminda millecra, 205 Leptogorgia gilchristi, 203 Ligand fishing, 120 Lignans, 222 Limonoids, 225, 393 Lipophilicity, 165 Lippia javanica, 339 Lisinopril, 360 Lobostemon trigonus, 339 Lopinavir, 333 Lumefantrine (benflumetol), 302, 306 Lumefantrine (benflumetol)/ artemether, 293 Lycorine, 231 Lymphatic filariasis, 128, 129 M Macaranga schweinfurthii, 42 Madagascar, 266 malaria, 268 Malagashanine, 271, 275, 389 Malagashanol, 272 Malaria, 4-aminoquinolines, 166 hepatic stage, 274 Madagascar, 265 methotrexate, 293 tolerance, 286 Malaria Vaccine Initiative (MVI), Malonganenones, 89, 203 Managing, 120 (+)-Manool, 104 Marine bioprospecting, 193, 202 Marine resources, 47 Marketing, 16 Mass drug administration (MDA) campaigns, 129 Maytansine, 39 Maytenus M buchanii, 39 M senegalensis, 224 M serrata, 39 MDR-TB, 54 Mebendazole, 129 Mectizan Donation Programme (MDP), Medicines for Malaria Venture (MMV), 3, 76, 121 Mefloquine, 104, 310 Melarsoprol, 214 Melia azedarach, 225 435 Meliacins, 393 Metabolic stability, 168 Metabolites, identification, 171 reactive, 172 Metallopeptidases, gluzincin family, 358 Methotrexate, 293 12-Methoxy-17,18-dehyrovincamine, 389 Methyl 3b-acetoxy-6-hydroxy-1-oxomeliac14-enoate, 226 Mexicanolides, 226 Michellamines, 40, 45, 118, 384 Microsomes, 168 Modern drug discovery paradigms, 107 Molecular chaperones, 85, 87 protozoan parasites, 88 Molecular docking, 112 Molecular Mycobacteriology Research Unit (MMRU), 67 Mucobromic acid, 104 Mucochloric acid, 104 Multidrug resistance (MDR) inhibitors, 43 Multidrug resistant tuberculosis, 21, 54 Mycobacterium tuberculosis, 54, 251, 342, 408 targeted mutagenesis, 63 targets, 65 Mycothiol biosynthesis, 73 Myrtoidines, 272 N Nagana, 213 Nanocarrier, multifunctional, 418 Nanomedicine, poverty-related diseases, 407 pharmacokinetics, 413 Nanopharmacokinetics, 413 Naphthylisoquinoline alkaloids, 45, 118 Natural products, 13, 23, 92, 101, 381 databases/repositories/libraries, 108 Natural Products Research Network for East and Central Africa (NAPRECA), 108 Nauclea latifolia, 232 Nauclea pobeguinii, antimalarial activity, 110 NCI collection contractors, 31 NCI screening agreement, 36 NCP-tazopsine, 274 Neem (Azadirachta indica), 225, 392 Neglected tropical diseases (NTDs), 128, 211, 409 Neisseria gonorrhoeae, 251 Nelfinavir, 333 Nematode infections, 128 Neocryptolepine, 395 Neorautanenia mitis, 44 436 Network for Analytical and Bioassay Services in Africa (NABSA), 108 Neuropeptides, 132 New chemical entities (NCEs), 152, 330 New molecular entities (NMEs), 240 New Partnership for Africa’s Development (NEPAD), Nippostrongylus brasiliensis, culture, 140 Niprisan, 20 Nitidine, 390 Nomilin, 225 Non-nucleoside reverse transcriptase inhibitors (NNRTIs), HIV, 333 Noordwijk Medicines Agenda, Novobiocin, 90, 91 NTID609, 113 Nucleoside reverse transcriptase inhibitors (NRTIs), HIV, 333 O Oesophageal cancer, marine natural products, 204 Ombrabulin, 39 Onchocerca volvulus, 128 Onchocerciasis, MDA campaigns, 129 One Medicine Africa-UK Research Capacity Development Partnership Programme for Infectious Diseases in Southern Africa (SACIDS), 20 Oroidin, 203 Ouabain, 215 Oxynitidine, 390 P Paclitaxel, 37, 103 Pafuramidine maleate (DB289), 214 Pamianthine, 231 Pan-African Natural Products Library (pANPL), 138 Parasites, in culture, 140 Pellitorine, 390 Penicillin, 103 Pentamidine, 214 ADME, 162 Permeability, 168 Perpetrator drug, 153 Pervilleines, 40, 43, 276 Pharmaceutical Manufacturing Plan for Africa (PMPA), Pharmacokinetics (PK), 152, 154, 411 in vivo, 179 Index Pharmacology, 14 Pharmacovigilance, 16 Phenolic compounds, 220 Phorbol esters, 227 Phosphokinase C inhibitors, 203 Phyllanthus engleri, 42 Physiologically based pharmacokinetic modelling (PBPK), 160 Physostigma venosum, 215 Physostigmine, 215 Pinitol, 335 Piperaquine (PQ), 293, 314 Piperaquine (PQ)/dihydroartemisinin (DHA), 302 Piper guineense, 400 Piptadenia pervillei, 279, 284 Plant families, bioactivities, 253 Plasmodium falciparum, 113, 275, 382 HSP90 genes, 86 molecular chaperones, 88 MTX, 295 Poverty-related diseases (PRDs), 408 Praziquantel, 129 ADME, 162 Preclinical toxicology and safety, 14 Prenylated toluquinones, 205 Primaquine, 162, 178, 188, 274 ADME, 162 Pristimerin, 224, 225 Product development public-private partnerships (PDPPPs), 18 Proguanil, 313 Protein/enzyme targets, 120 Pseudomonic acid C, 117 Public–private partnerships (PPPs), 218 Pungiolides, 228 Putterlickia verrucosa, 39 Pyrantel, ADME, 162 Pyrazinamide, 62 Pyridobenzimidazoles, 116 Pyrimethamine (PM), 294 ADME, 162 sulfadoxine, 314 Pyronaridine (PRN)/artesunate (ART), 302 Q Quad, 330 Quantitative structure–activity relationship (QSAR), 333 Quercetin-3-rhamnoside/rutinoside, 394 Quinacrine, 282 Quindoline, 395 Index Quinine, 103, 215, 282, 302, 307, 379, 398 ADME, 162 Pfcrt/Pmdr1, 307 R Rabies virus, 21 Radicicol, 90, 91 Rautendiols, 44 Recombinant microbes, mechanism-based screening, 130 Regional initiatives, Regulatory expertise, 15 Reissantia buchananii, 44 Reissantins, 44 Renin-angiotensin-aldosterone system (RAAS), 356 Research, health products, 10, 22 Reverse-emulsion-cationic-gelification (RECG), 425 Reverse-emulsion-surfactant-cationicgelification (RESCG), 425 Reverse pharmacology, 240 Rifampicin, 103 Rifamycin, 103 Ritonavir, 333 Ritterazines, 198 Ritterella tokioka, 198 Roll Back Malaria (RBM), RT inhibitors, HIV, 343 Rutaevin, 225 S Safe Injection Global Network (SIGN), Sanguinarine, 230 Sansevieria ehrenbergii, 44 Sansevistatins, 44 Sarcoidosis, 364 Schistosomiasis, 21, 129 Schweinfurthins, 40, 42 Screens-to-Nature (STN) system, 244 Sesquiterpene hydroquinones, 338 Sesquiterpene lactones, 227 Sesquiterpene pyridine alkaloids, 230 Skimmianine, 390 Sleeping sickness, 213 Sodium artesunate, 104 Sodwana Bay, KwaZulu Natal, 198 Sodwanones, 199, 203 Soft tissue sarcoma (STS), trabectidin, 194 Solanaceae, 254 Solubility, 168 437 South African National Biodiversity Institute (SANBI), 108 South African Tuberculosis Research and Innovation Initiative (SATRII), 76 Southern Africa Consortium for Research Excellence (SACORE), 19 Special Programme for Research and Training in Tropical Diseases (TDR), Special Programme for Research Development and Research Training in Human Reproduction (HRP), Spiroindolone, 113 Squamous cell carcinoma (SCC), 204 Squamous cell oesophageal cancer (SCOC), 204 Stop TB Partnership (Stop TB), Strictosamide, 110 Strongyloides spp., 128 Strophanthin, 215 Structure–activity relationships (SAR), 138, 164, 175 Strychnobrasiline, 271, 276, 389 Strychnopsis thouarsii, 274 Strychnos alkaloids, Madagascar, 271 Strychnos S diplotricha, 273 S myrtoides, 270, 273, 389 S usambarensis, 389 Suramin, 214 Sutherlandia frutescens, 335 T Tabernaemontana T accedens, 386 T fuchsiafolia, 386 T glandulosa, 386 Tabernulosine, 389 Target identification, 119 Taxanes, 37 Taxoids, 3,17b-estradiol, 118 Taxol, 90 Tazopsine, 274 TDR-TB, 55 Teprotide, 360 Terpenoids, 224 Terrestrial plant collections, 31 Tetrahydroimidazo [4,5,1-jk][1,4] benzodiazepinone (TIBO), 345 Thiabendazole, ADME, 162 sites of metabolism, 172 Thiomarinol, 117 Tinidazole, ADME, 162 438 Toddalia asiatica, 390 Topotecan, 37 Totally drug-resistant (TDR)-TB, 55 Toxicity, 153 Trabectidin, 193 Trade and Related Aspects of Intellectual Property Rights (TRIPS), Traditional healers, 247 Traditional medicine, Madagascar, 266 (-)-Trans-9-acetyl-4,90-di-O-methyl-30-de-Omethyldehydrodiconiferyl alcohol, 45 Trastuzumab, 41 Trastuzumab emtansine, 41 Trichuris trichiura, 128 Trioxane, 118 Trioxaquines, 118 Triphyophyllum peltatum, 382 Triterpenoids, 224 Trypanosoma brucei, 88, 213, 252 Trypanosoma cruzi, 86, 214, 252 HSP90 genes, 86 molecular chaperones, 88 Trypanosomiasis, 18, 88, 213, 251, 297, 424 Trypsin inhibition, 253 Tuberculosis (TB), 3, 21, 53, 363, 408 drugs, delivery, 74 improved diagnostics, 73 multidrug resistant, 21 Tube worms, 196 U Uvariopsis congolana, 224 Index V Vaccines, 21 Variabilin, 203 Verapamil, 278, 304 Vernonia staehelinoides, 105 Victim drug, 153 Vinblastine/vincristine, 37, 215 Vinorelbine/vindesine, 37 Virtual screening, 112 Voacamidine, 388 Voacamine, 386 Voacangine, 386 W Wilforine, 230 X Xanthanolides, 228 Xanthipungolide, 228 Xanthium brasilicum, 227 XDR-TB, 54 Y Yaounde´ Process, Z Zahavins, 201 Zanthoxylum xanthoxyloides, 390 Zidovudine (AZT), 326 .. .Drug Discovery in Africa Kelly Chibale • Mike Davies-Coleman • Collen Masimirembwa Editors Drug Discovery in Africa Impacts of Genomics, Natural Products, Traditional Medicines, Insights into. .. into Medicinal Chemistry, and Technology Platforms in Pursuit of New Drugs Editors Kelly Chibale Dept of Chemistry University of Cape Town Rondebosch South Africa Mike Davies-Coleman Department of. .. progression of new medicines to target key diseases Bringing together some of the best researchers in Africa with a common goal, to focus on how to develop new medicines in an African context Drug discovery