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Synthesis and Biological Evaluation of Trisindolyl-Cycloalkanes and Bis- Indolyl Naphthalene Small Molecules As Potent Antibacterial and Antifungal Agents

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Synthesis and Biological Evaluation of Trisindolyl-Cycloalkanes and Bis- Indolyl Naphthalene Small Molecules As Potent Antibacterial and Antifungal Agents Synthesis and Biological Evaluation of Trisindolyl-Cycloalkanes and Bis- Indolyl Naphthalene Small Molecules as Potent Antibacterial and Antifungal Agents Dissertation Zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) Vorgelegt der Naturwissenschaftlichen Fakultät I Institut für Pharmazie Fachbereich für Pharmazeutische Chemie der Martin-Luther-Universität Halle-Wittenberg von Kaveh Yasrebi Geboren am 09.14.1987 in Teheran/Iran (Islamische Republik) Gutachter: 1. Prof. Dr. Andreas Hilgeroth (Martin-Luther-Universität Halle-Wittenberg, Germany) 2. Prof. Dr. Sibel Süzen (Ankara Üniversitesi, Turkey) 3. Prof. Dr. Michael Lalk (Ernst-Moritz-Arndt-Universität Greifswald, Germany) Halle (Saale), den 21. Juli 2020 Selbstständigkeitserklärung Hiermit erkläre ich gemäß § 5 (2) b der Promotionsordnung der Naturwissenschaftlichen Fakultät I – Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, dass ich die vorliegende Arbeit selbstständig und ohne Benutzung anderer als der angegebenen Hilfsmittel und Quellen angefertigt habe. Alle Stellen, die wörtlich oder sinngemäß aus Veröffentlichungen entnommen sind, habe ich als solche kenntlich gemacht. Ich erkläre ferner, dass diese Arbeit in gleicher oder ähnlicher Form bisher keiner anderen Prüfbehörde zur Erlangung des Doktorgrades vorgelegt wurde. Halle (Saale), den 21. Juli 2020 Kaveh Yasrebi Acknowledgement This study was carried out from June 2015 to July 2017 in the Research Group of Drug Development and Analysis led by Prof. Dr. Andreas Hilgeroth at the Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg. I would like to thank all the people for their participation who supported my work in this way and helped me obtain good results. First of all, I would like to express my gratitude to Prof. Dr. Andreas Hilgeroth for providing me with opportunity to carry out my Ph.D. studies, supervising adequately, and motivating me to work independently in order to develop myself and accomplish my project. I would also like to thank Dr. Dieter Ströhl at the Institute of Chemistry for measuring the 1D-1HNMR, 2D-1HNMR, and APT spectra and his useful consultations within NMR spectra interpretation, Prof. Dr. Wolfgang Sippl, PD. Dr. habil. Matthias Schmidt and Dr. Tino Heimburg from the Research Group of Medicinal Chemistry for RP-HPLC results, Mrs. Manuela Woigk for Mass spectrometry data, Mrs. Heike Rudolph for IR measurements, Mrs. Monika Lunow and Mr. Dirk Stolzenhain for providing chemicals and glasswares at the Institute of Pharmacy. Many thanks to Pharmacy Diploma Student Kerolos Ashraf for synthesizing the compounds 23-40 as his diploma project and other colleagues Fabian Lentz, Tim Fischer, Nico Schade, Cornelius Hempel, Tobias Mohs, Ansgar Opitz, Marius Seethaler, and Robin Gehrmann for their supports and helps and providing appropriate atmosphere in the laboratory. I would appreciate the chance to thank Prof. Dr. Sibel Süzen from Department of Pharmaceutical Chemistry, Ankara University, Prof. Dr. Michael Lalk from Institute of Biochemistry, Ernst-Moritz-Arndt-Universität Greifswald, PD. Dr. Knut Ohlsen, Dr. Tobias Hertlein, Mr. Emmanuel Tola Adeniyi from Institute of Molecular Infection Biology, Julius Maximillians Universität, Würzburg, and PD. Dr. Frank Erdmann from Institute of Pharmaceutical Biology and Pharmacology, Martin-Luther-Universität Halle- Wittenberg for carrying out the Bioassy part of this project. At the end, I would like to sincerely thank my mother for her supports and encouragements within these four years. Table of Contents 1. Introduction ............................................................................................................................ 1 1.1 Chemistry of indole .............................................................................................................. 1 1.1.1 The structure and reactivity of indole ............................................................................... 1 1.1.2 Electrophilic substitution reactions by indoles ................................................................. 6 1.1.2.1 Michael addition of indoles ........................................................................................... 6 1.1.2.1.2 The factors affecting the Michael Addition of indoles to various α,β unsaturated compounds ................................................................................................................................. 9 1.1.2.2 Anti-Michael addition of indoles ................................................................................. 10 1.1.2.3 Friedel-Crafts (F-C) reactions of indoles to epoxides .................................................. 10 1.1.2.4 Electrophilic substitution reaction of indoles to carbonyl compounds such as aldehydes and ketones .............................................................................................................. 12 1.1.2.4.1 The factors affecting the electrophilic substitution reactions of indoles to aldehydes and ketones ............................................................................................................................... 14 1.1.2.5 The electrophilic substitution reactions of indoles to isatins ....................................... 15 1.2 Indoles in nature ................................................................................................................. 16 1.2.1 Naturally occurring indole-containing compounds in marines and plants ..................... 16 1.2.2 Naturally occurring indole-containing compounds in microorganisms .......................... 19 1.3 Bacteria, cell growth mechanisms, and modes of action of some commercial antibacterial agents ....................................................................................................................................... 20 1.3.1 Inhibition of cell metabolism (antimetabolites) .............................................................. 20 1.3.2 Inhibition of cell wall biosynthesis ................................................................................. 20 1.3.3 Impairing the protein synthesis translation ..................................................................... 23 1.3.4 Inhibition of nucleic acid transcription and replication .................................................. 23 1.3.5 Fatty acid biosynthesis inhibition (FabI) ........................................................................ 24 1.4 Drug resistance, the possible mechanisms, and examples ................................................. 25 1.5 The infections and diseases caused by bacteria ................................................................. 27 1.5.1 Skin infection .................................................................................................................. 27 1.5.2 Urinary tract infection ..................................................................................................... 27 1.5.3 Otitis media ..................................................................................................................... 27 1.5.4 Brain infection ................................................................................................................ 27 1.5.5 Respiratory infections ..................................................................................................... 27 1.6 Structure-Activity Relationship (SAR) .............................................................................. 27 1.7 A review to bioactivities of synthetic indole-containing compounds and their SARs ...... 28 1.7.1 Antibacterial and antifungal activities ............................................................................ 28 1.7.1.1 The Structure-Activity Relationships (SARs) of the above indole-containing compounds ............................................................................................................................... 43 1.7.2 Anti-cancer activity ......................................................................................................... 45 1.7.2.1 The Structure-Activity Relationship (SAR) of the above indolyl-derived compounds as Anti-cancer agent ................................................................................................................. 46 1.7.3 Other biological activities of some indolyl-derived compounds .................................... 47 2. Results and Discussion ....................................................................................................... 48 2.1 Synthesis part ..................................................................................................................... 48 2.1.1 The reactions of indoles with glutaric dialdehyde and malondialdehyde ....................... 48 2.1.2 The formation of (Z)-3,3',3'' tris products ....................................................................... 55 2.1.2.1 The spectral data confirming the formation of (Z)-3,3',3'' tris products ...................... 59 2.1.2.2 The possible stereochemistry of chiral centres in hexahydrocyclohepta[b]indoles and tetrahydrocyclopenta[b]indoles................................................................................................ 61 2.1.3 The electrophilic substitution reactions of indoles to o-phthaldialdehyde ..................... 64 2.1.3.1 The spectral data confirming the structures of 11- and 6-indolylbenzocarbazole compounds (compounds 23-37) ..............................................................................................
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