Carla Brown Phd Thesis V5

DESIGN AND SYNTHESIS OF NOVEL SMALL-MOLECULE ANTIMICROBIALS DESIGN AND SYNTHESIS OF NOVEL SMALL-MOLECULE ANTIMICROBIALS By CARLA E. BROWN, B. Art. Sc., M. Sc. A Thesis Submitted to the School of Graduate Studies in Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy McMaster University © Copyright by Carla E. Brown, June 2017 Ph.D. Thesis – C. Brown; McMaster University – Chemistry and Chemical Biology McMaster University DOCTOR OF PHILOSOPHY (2017) Hamilton, Ontario (Chemical Biology) TITLE: Design and Synthesis of Novel Small-molecule Antimicrobials AUTHOR: Carla E. Brown, BArtSc. (McMaster University), M.Sc. (University of Toronto) SUPERVISOR: Professor James McNulty NUMBER OF PAGES: xiii, 281 ii Ph.D. Thesis – C. Brown; McMaster University – Chemistry and Chemical Biology There is a need to discover new antimicrobial drugs to combat drug-resistant infections. We are trying to find new molecules that can prevent the growth of parasites and viruses by developing and using novel chemical reactions, as well as by isolating new products from plants and fungi. This text describes a new way to make quinolines, a type of molecule found in many drugs. A molecule prepared by this method inhibited the parasite T. gondii at low concentrations. We have also identified quinazolinones, molecules that can be rapidly assembled by combining three components, which inhibit parasites and viruses. The thesis also includes a faster way to make derivatives of an antiviral molecule from daffodils, which can help determine which parts of the molecule are important for antiviral activity. We have also identified new molecules from the fungus Xylaria polymorpha and an antiviral compound from the Ficus benjamina tree. iii Ph.D. Thesis – C. Brown; McMaster University – Chemistry and Chemical Biology Antimicrobial resistance is a significant threat to global health, and it is necessary to identify new drugs and drug targets for pathogenic bacteria, parasites, viruses, and fungi. Novel small molecules with antimicrobial activity may be discovered in the lab through chemical synthesis or from nature as secondary metabolites. This thesis describes our efforts to synthesize and identify antiparasitic and antiviral small molecules. The preparation of 3-diarylether quinolines with 5 µM activity against the parasite T. gondii, through a novel TFA-catalysed Povarov reaction using enol ethers as carbonyl surrogates is described. Libraries of quinazolinone and dihydroquinazolinone derivatives have been prepared through a multicomponent synthetic route. Structure activity relationship analysis allowed for differentiation of the antiparasitic pharmacophore from the antiviral pharmacophore, as well as the identification of compounds with single digit micromolar activity against both T. gondii and Herpes Simplex Virus 1. This work also details the design and synthesis of B-ring aza-analogs of bioactive Amaryllidaceae alkaloids in just 5 steps from chiral pool reagents. Aza-substitution of the B-ring eliminated antiviral activity, and this modification may also affect anticancer activity. Analysis of several natural product sources has also identified novel small molecules. Isolation of metabolites from Xylaria polymorpha identified three novel polyketide derivatives with unknown biological activity. The alkaloid candicine was found to be the primary polar metabolite from Ficus benjamina latex, as well as a potent inhibitor of murine cytomegalovirus. By identifying the mechanisms of action of these bioactive small molecules, we may identify targets for further drug development. iv Ph.D. Thesis – C. Brown; McMaster University – Chemistry and Chemical Biology Firstly, I would like to sincerely thank my supervisor, Dr. Jim McNulty, for his thoughtful guidance, criticism, and encouragement. Jim: thank you for giving me so many opportunities to learn inside and outside the lab, for pushing me to be a better chemist, and for always finding time to talk to through an idea on the board. To my committee members, Dr. Nathan Magarvey and Dr. John Valliant, thank you for your helpful feedback and suggestions. I also want to thank our research collaborators at Johns Hopkins University (Dr. Lori Jones-Brando, Claudia Bordon, Dr. Bob Yolken) and the University of Pittsburgh (Dr. Dino D’Aiuto, Dr. Vish Nimgaonkar, Matt Demers, and Dr. Lora McClain) who performed all biological testing. I would also like to thank all of my colleagues in the McNulty lab: Dave McLeod, Janice Calzvara, Alex Nielsen, Carlos Zepeda, Kunal Keskar, Sean van den Berg, Chanti Dokuburra, Arkesh Narayanapappa, Omkar Revu, Dave Hurem, and Suresh Borra. I am especially grateful to Alex Nielsen and Dave McLeod for their encouragement and commiseration during long days in the lab and Friday nights at the Phoenix. I also want to thank Tiffany Kong, our fantastic undergraduate student who helped me prepare our quinazolinone library. I’m extremely grateful to my family and friends that have supported me throughout graduate school. To my parents, Grace and Peter: thank you for your endless love and support. To my sister, Anita: thank you for always cheering me up when my chemistry went wrong. Finally, I want to thank my husband Kenwrick. Kenwrick, thank you for sharing every day of this process with me. You have made the difficult times bearable and the good times wonderful. v Ph.D. Thesis – C. Brown; McMaster University – Chemistry and Chemical Biology Table of Contents 1 Introduction to antimicrobial chemotherapy ....................... xi 1.1 The origins of antimicrobial drug discovery ........................................................... 1 1.2 Parasitic diseases have a global impact .................................................................. 3 1.3 Antiparasitics target different functions in the apicomplexan lifestyle .................. 7 1.4 Human viruses with neurological implications .................................................... 10 1.5 Herpesvirideae and Flavivirideae are viruses with neurological outcomes .......... 12 1.6 Antiviral therapy: reviewing the approved treatments and mechanisms of action of antiviral drugs ............................................................................................................ 13 1.7 A strategy for identifying novel small molecules with activity against parasites and viruses ...................................................................................................................... 20 1.8 References ............................................................................................................. 21 2 Synthesis of antiparasitic quinolines ..................................... 32 2.1 Classical quinoline synthesis ................................................................................ 32 2.2 Quinolines with activity against T. gondii ............................................................ 33 2.3 Enol ethers as carbonyl surrogates in a modification of the Povarov synthesis of 3-arylquinolines and their anti-Toxoplasma activity ..................................................... 34 2.4 Conclusion and future work .................................................................................. 48 2.5 Experimental ......................................................................................................... 49 2.6 References ............................................................................................................. 60 3 Design and synthesis of bioactive quinazolinones ............... 64 3.1 Introduction to quinazolinone heterocycles .......................................................... 64 3.2 Synthesis of substituted quinazolinones in the literature ...................................... 66 3.3 Preparation of the initial quinazolinone library .................................................... 68 3.4 Quinazolinones with activity against T. gondii ..................................................... 71 3.5 Quinazolinones with activity against HSV-1 ........................................................ 76 3.6 Design and synthesis of second generation quinazolinones ................................. 80 3.7 Second generation quinazolinones – T. gondii SAR ............................................ 84 3.8 Second generation quinazolinones – HSV-1 SAR ............................................... 88 3.9 Conclusions and future work ................................................................................ 92 3.10 Experimental ....................................................................................................... 93 3.11 References ........................................................................................................ 114 4 Design and synthesis of quinazolinone alkaloids ............... 120 4.1 Amaryllidaceae alkaloids have potent bioactivity .............................................. 120 4.2 Phenanthridone quinazolinone hybrids ............................................................... 122 4.3 Synthetic route from D-ribose: ........................................................................... 124 4.4 Synthetic route from L-arabinose: ...................................................................... 126 4.5 Biological activity of quinazolinone alkaloids ................................................... 132 4.6 Conclusion and future work ................................................................................ 135 4.7 Experimental ......................................................................................................

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