Electronic Theses and Dissertations

Date of Award

1-1-2012

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Daneel Ferreira

Second Advisor

Jason Hoeksema

Third Advisor

Shabana Khan

Relational Format

dissertation/thesis

Abstract

The purpose of this study was to discover antimalarial compounds from necrotropic plant pathogenic fungi. Various phytotoxins released by necrotropic plant pathogenic fungi may inhibit the plant-like metabolic pathways in the apicoplast, a chloroplast-like organelle, essential for the survival of apicomplexan parasites, such as Plasmodium which cause malaria in humans. This dissertation describes the isolation, characterization, and biological evaluation of secondary metabolites of eight fungal strains. In addition to the antiplasmodial assay, all the extracts were subjected to phytotoxic, antimicrobial, and cytotoxic bioassays. Isolation of metabolites was performed by chromatographic methods and identification was carried out by spectroscopic and spectrometric methods. Absolute configurations of the metabolites were determined by comparing specific rotation values, ECD spectra, or X ray crystallographic analysis. The dissertation consists of seven chapters. Chapter 1 describes the overview of the current malaria situation in the world and the rationale for using necrotropic plant pathogenic fungi to discover antimalarial leads. Protocols used for isolation and fermentation of endophytic fungi from infected plant parts, as well as those used for biological activities of fungal metabolites are described in Chapter 2. Chapters 3-6 describe the isolation and identification of metabolites from the plant pathogenic fungi obtained from the American Type Culture Collection (ATCC) (Septoria pistaciarum, S. musiva, Phomopsis viticola, and Postia balsamea). Chapter 7 consists of four sections which describe the isolation and identification of active metabolites from four endophytic fungi (Xylaria sp., Alternaria sp., Botryosphaeria dothidea, and a new fungus, UM #10 M) isolated from the infected leaves and seeds of Torreya taxifolia. From these fungi, 40 compounds including 17 new natural products were isolated and identified. Thirteen compounds displayed antiplasmodial activity, 12 showed phytotoxicity, whereas all 13 exhibited weak to moderate cytotoxicity towards mammalian cells. This indicates that cytotoxicity rather than inhibition of plant-like metabolic pathways in the apicoplast was probably responsible for the observed antiplasmodial activity. The antiplasmodial compounds with high selectivity indices, septoriamycin A and 19,20-epoxycytochalasin C, were evaluated for antimalarial activity in a mouse model. Septoriamycin A showed no activity or toxicity, whereas 19,20-epoxycytochalasin C, exhibited toxicity and weak suppressive activity.

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