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Dissertation__Michael Berninger Development of Novel Quinolone Amides Against the African Sleeping Sickness - A Fluorine Walk Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Michael Berninger aus Eschau Würzburg 2018 Eingereicht bei der Fakultät für Chemie und Pharmazie am: Gutachter der schriftlichen Arbeit 1. Gutachter: 2. Gutachter: Prüfer des öffentlichen Promotionskolloquiums 1. Prüfer: 2. Prüfer: 3. Prüfer: Datum des öffentlichen Promotionskolloquiums: Doktorurkunde ausgehändigt am: Die vorliegende Arbeit wurde am Institut für Pharmazie und Lebensmittelchemie der Bayerischen Julius-Maximilians-Universität Würzburg auf Anregung und unter der Anleitung von Frau Prof. Dr. Ulrike Holzgrabe angefertigt. Mein herzlicher Dank gilt ihr für die Aufnahme in die Arbeitsgruppe und das Anvertrauen des spannenden Projekts. Ich bedanke mich für das in mich gesetzte Vertrauen und die gewährten wissenschaftlichen Freiräume bei der Bearbeitung des Themas. Des Weiteren bedanke ich mich beim Sonderforschungsbereich 630 für die finanzielle Unterstützung dieser Arbeit. Weiterhin möchte ich folgenden Kooperationspartnern für die erfolgreiche Zusammenarbeit danken: - Prof. Dr. Samuel Samnick, Dr. Ina Israel und Dr. Ehab Al-Momani, vom Universitätsklinikum Würzburg, Nuklearmedizin für die 18F-Fluorierung und die anschließenden PET- bzw. autoradiographischen Untersuchungen. - Antje Fuß und Dr. Joseph Skaf für die Substanztestung an Trypanosoma brucei brucei. - Dr. Christine Erk für die Bestimmung der mikrosomalen Umsetzung und Identifizierung der Metabolite. - PD Dr. Heike Bruhn und Elena Katzowitsch für die Zytotoxizitätsuntersuchungen. Dem gesamten Arbeitskreis und allen Mitarbeitern bin ich für die angenehme Arbeitsatmosphäre und die schöne gemeinsame Zeit dankbar: Lina, Ines, Flo, Anna, Regina, David, Olli, Jogi, Jan, Miri, Nils, Raphael, Jens, Nina, Lu, Johannes, Christine, Christiane, Alex, Curd, Antonio, Anja, Paul, Niclas, Flo, Nicolas, Klaus, Patrick, Markus, Jonas, Joseph. Vielen Dank an alle Menschen, die mich während dieser Zeit ein Stück begleitet haben. Teile der vorliegenden Arbeit sind Gegenstand folgender wissenschaftlichen Publikationen und Posterpräsentationen: Publikationen: Skaf, J.; Hamarsheh, O.; Berninger, M.; Balasubramanian, S.; Oelschlaeger, T. A.; Holzgrabe, U. Improving anti-trypanosomal activity of alkamides isolated from Achillea fragrantissima. Fitoterapia 2017, 125, 191-198. Pyrih, A.; Berninger, M.; Gzella, A.; Lesyk, R.; Holzgrabe, U. Synthesis and evaluation of antitrypanosomal activity of some thiosemicarbazide derivatives of 1-butyl-6-fluoro-7- morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Synth. Commun. 2018, 48, 1883-1891. Berninger, M.; Erk, C.; Fuß, A.; Skaf, J.; Al-Momani, E.; Israel, I.; Raschig, M.; Güntzel, P.; Samnick, S.; Holzgrabe, U. Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness. Eur. J. Med. Chem. 2018, 152, 377-391. Posterpräsentationen: Berninger, M.; Hiltensperger, G.; Schleier, D.; Holzgrabe, U.: “Synthesis of novel Pyrazoloquinolinones against Trypanosomoa brucei”, 8th Joint PhD Students Meeting of the SFB 630 and 766 and FOR 854, 2014, Retzbach. Berninger, M.; Güntzel, P.; Fuß, A.; Holzgrabe, U.: “4-Quinolone-3-carboxamides as active compounds against Trypanosoma brucei”, Best of SFB 630 - and Future Perspectives, 2015, Würzburg. Berninger, M.; Fuß, A.; Al-Momani, E.; Isreal, I.; Raschig, M.; Güntzel, P.; Samnick, S.; Holzgrabe, U.: “Fluorine Walk: The role of fluorine in quinolone amides active against African sleeping sickness”, XXIV EFMC International Symposium on Medicinal Chemistry, 2016, Manchester (UK) Meinen Eltern Content 1 INTRODUCTION 1 NOVEL LEAD COMPOUNDS IN PRE-CLINICAL DEVELOPMENT AGAINST AFRICAN SLEEPING SICKNESS 2 AIMS AND OBJECTIVES 39 3 SYNTHESIS OF THE FLUOROQUINOLONE AMIDES 41 3.1 DEVELOPMENT OF THE 4-QUINOLONES AS ANTIBIOTICS 41 3.2 RETROSYNTHESIS OF THE LEAD COMPOUND 42 3.3 GOULD-JACOBS PROTOCOL 43 3.4 ALKYLATION AND HYDROLYSIS TO THE 1-BUTYL-4-OXO-1,4-DIHYDROQUINOLINE-3- CARBOXYLIC ACIDS 3A-L 47 3.5 NUCLEOPHILIC AROMATIC SUBSTITUTION (SNAR) OF THE 1-ALKYL-4-OXO-1,4- DIHYDROQUINOLINE-3-CARBOXYLIC ACIDS. 54 3.6 SYNTHESIS OF THE 1-BUTYL-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDES 61 3.7 DERIVATIZATION OF THE QUINOLONE AMIDES 64 3.8 GROHE-HEITZER PROTOCOL 66 3.9 SYNTHESIS OF QUINOLONE AMIDES DERIVED FROM COMMERCIALLY AVAILABLE QUINOLONES 68 4 APPLICATION OF FLUORINE 69 4.1 ROLE OF FLUORINE IN MEDICINAL CHEMISTRY 69 4.2 FLUORINATION METHODS 70 4.3 POSITRON EMISSION TOMOGRAPHY 70 18 4.4 [ F] LABELLING 71 4.5 SMALL-ANIMAL PET 81 4.6 EX VIVO AUTORADIOGRAPHY 82 5 STRUCTURE-ACTIVITY RELATIONSHIP OF THE QUINOLONE AMIDES 82 5.1 N-1 POSITION 83 5.2 C-3 POSITION 84 5.3 C-5 POSITION 84 5.4 C-6 POSITION AND FLUORINE WALK AROUND THE QUINOLONE CORE 86 5.5 C-7 POSITION 88 5.6 N-8 AND COMMERCIALLY AVAILABLE QUINOLONES 89 Content 6 PHYSICOCHEMICAL AND PHARMACOKINETIC PROPERTIES 90 6.1 LOGP 90 6.2 METABOLISM 91 6.3 CONSIDERATION FOR AN IN VIVO STUDY 94 7 SCAFFOLD HOPPING: PYRAZOLOQUINOLIN-3-ONES 97 7.1 THE PYRAZOLOQUINOLIN-3-ONES 98 7.2 SYNTHESIS OF THE 4-CHLOROQUINOLINE 99 7.3 SYNTHESIS OF THE 2-ARYL PYRAZOLO[4,3-C]QUINOLIN-3-ONE 99 7.4 SYNTHESIS OF THE 2-BENZYL PYRAZOLO[4,3-C]QUINOLIN-3-ONE 101 7.5 SYNTHESIS OF THE ALKYLATED PYRAZOLOQUINOLIN-3-ONES 102 7.6 NUCLEOPHILIC AROMATIC SUBSTITUTION OF THE PYRAZOLOQUINOLIN-3-ONES 104 7.7 SYNTHESIS OF THE 4-THIOXO-QUINOLINE-3-CARBOXYLATE 105 7.8 BIOLOGICAL EVALUATION OF THE PYRAZOLOQUINOLIN-3-ONES 105 8 SUMMARY 107 9 ZUSAMMENFASSUNG 110 10 EXPERIMENTAL SECTION 113 10.1 GENERAL EXPERIMENTAL PROCEDURES AND EQUIPMENT 113 120 10.2 GOULD-JACOBS APPROACH 118 10.3 ALKYLATION OF THE N-H POSITION AND HYDROLYSIS TO THE 1-BUTYL-4-OXO-1,4- DIHYDROQUINOLINE-3-CARBOXYLIC ACIDS 128 10.4 SNAR OF THE 4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACIDS. 142 10.5 N-BENZYL-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDES 162 37 10.6 GROHE-HEITZER APPROACH 194 10.7 SYNTHESIS OF QUINOLONE AMIDES DERIVED FROM COMMERCIALLY AVAILABLE QUINOLONES 200 18 10.8 SYNTHESIS APPROACH FOR THE F LABELLING 204 10.9 SCAFFOLD HOPPING APPROACH: PYRAZOLO[4,3-C]QUINOLIN-3-ONE 218 10.10 CELL VIABILITY ASSAY 233 10.11 LOGP DETERMINATION 234 10.12 SOLUBILITY 235 Content 11 APPENDIX 236 12 REFERENCES 243 Introduction 1 Introduction Novel lead compounds in pre-clinical development against African sleeping sickness M. Berninger, I. Schmidt, A. Ponte-Sucre and U. Holzgrabe, Med. Chem. Commun., 2017, 8, 1872-1890. DOI: 10.1039/C7MD00280G - Reproduced by permission of The Royal Society of Chemistry. Abstract Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus Trypanosoma. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to e.g. toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development against HAT are considered, namely the target-based approach, the phenotypic high throughput screening and the drug repurposing strategy. The most promising compounds emerging from these approaches entering an in vivo evaluation are mentioned herein. Of note, it may turn out to be difficult to confirm in vitro activity in an animal model of infection; however, possible reasons for the missing efficacy in unsuccessful in vivo studies are discussed. 1. Introduction Human African trypanosomiasis (HAT) is also called sleeping sickness. The disease is mainly restricted to Africa, and depending on the affected region two types of human illness can be found: East and West African trypanosomiasis. Two species of trypanosomatides which are transmitted by the tsetse fly, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, cause the ailment. The number of cases in Africa has dropped drastically, however, approximately 3000 new infections of both East and West African trypanosomiasis have been reported to the World Health 1 Introduction Organization in 2015.1 However, underestimating the actual number of cases is a common problem due to weak health infrastructures and restricted access to medical facilities.2 HAT is mainly being spread through the bite of infected tsetse flies; infection seldomly occurs by blood transfusion or through placental transmission. Of note, the disease causes infertility and abortion in pregnant women or of childbearing age, respectively. This disease is invariably fatal if left untreated. In Africa, HAT-affected zones cover an area of about 8 million square kilometers between 14 degrees north latitude and 20 degrees south latitude.3 In the 20th century three major HAT epidemics occurred, the first one between 1896 and 1906, the second in 1920, and the most recent one in 1970 lasting until the 1990s. Between these epidemics the number of cases constantly decreased to the currently known magnitiude.4 T. brucei rhodesiense causes the more virulent form of the disease which is called East African or Rhodesian African sleeping sickness. It is zoonotic, rare, and extremely virulent; patients usually die within a few months. T. brucei gambiense causes the West African or Gambian African sleeping sickness; the gambiense type shows both long latency and chronicity, whereas in the gambiense HAT, humans only constitute the main reservoir and transmission agent within the life cycle of the parasite.1
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