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. / Thesis / Doctor of Philosophy (PhD) / 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.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22000 |
| Date | January 2017 |
| Creators | Brown, Carla |
| Contributors | McNulty, James, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0291 seconds