Marine natural products biodiscovery continues to evolve into an increasingly more sophisticated and multidisciplinary field. Since the first reported marine compound in the 1970’s, there have been more than 33,000 marine natural products reported in the literature with seventeen marine-derived drugs currently approved for therapeutic use worldwide. Despite this, how much do we really know about marine natural product chemical space with respect to biological activity, and are we examining these precious resources against suitable disease targets that aim to maximise their potentials for drug discovery? Currently, most marine drugs are approved for the treatment of cancer, however, because most marine natural products are inactive in these assays, should this continue to be the main emphasis for exploration of their potential bioactivity? Instead, should we be placing a larger emphasis on leveraging these precious natural resources against more suitable disease and infection targets? This thesis attempts to answer the aforementioned questions using multidisciplinary approaches toward marine natural products biodiscovery that aim to maximise the bioactivity ascribed to marine derived and/or inspired compounds for drug discovery. The introduction to the thesis presented in Chapter 1.0 provides an informative overview focused on the history of marine natural products and their roles in modern drug discovery and development. Chapter 2.0 explores a meta-analysis of the biological activities reported for marine indole alkaloids, a diverse and increasing sub-class of marine natural products represented across most marine phyla. Our analyses found that the biological potentials for 85% of marine indole alkaloid chemical space is unexplored or undefined. Further, most marine indoles are continuing to be examined for cytotoxicity and antimicrobial activities despite the fact that they are unlikely to display meaningful activities in these assays. Using cheminformatics analyses, we have clustered the chemical diversity of marine indoles based on both, the potency of their activities in specific disease areas, and with a dataset of indole drugs and drug-leads from non-natural sources, to predict underexplored areas of potential new activity for future testing. Our findings clearly suggest that the testing of marine indoles, and marine natural products in general, continue to be conducted on a narrow breadth of bioassays and we recommend the diversification of their future testing to include non-toxic disease targets to maximise the potential of these precious resources for future drug discovery. Using the findings from our meta-analysis of marine indole bioactivities presented in Chapter 2.0 to direct biological testing, we undertook the chemical investigation of two Australian marine invertebrates for new marine natural products. Chapter 3.0 describes the chemical re-investigation of the colonial Australian ascidian Synoicum prunum for minor components, including indole alkaloids, that remained unidentified. This resulted in the isolation and structure elucidation of eight new marine natural products, including seven prunolides and a β-carboline sulfamate, alongside the previously reported prunolides A-C. The prunolides were found to bind and inhibit the aggregation of the Parkinson’s disease implicated amyloid protein, α-synuclein. Further, prunolide B was found to contain significant inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model at 0.5 μM, suggesting the prunolides, and perhaps other butenolide natural products, provide interesting scaffolds for the potential treatment of amyloidosis. Chapter 4.0 reports six new thiazole-homologated cyclic peptides, the cyclotheonellazoles D-I, isolated and identified from a Theonella sponge species collected from the Coral Sea, Northern Australia. The type 2 azole-homologated peptides reported herein each contained up to five non-proteinogenic amino acids including the α-keto-β-amino acid protease transition state mimic, 3-amino-4-methyl-2-oxohexanoic acid (Amoha). Further, the known cyclic anabaenopeptins, the keramamides A and L, were also reisolated in this investigation affording further investigation of their biological activities. The marine peptides were examined for inhibition of SARS-CoV-2 3CL protease, an attractive antiviral therapeutic target for COVID-19. The keramamides A and L displayed the highest inhibition of the protease (IC50 1.1 and 4.6 μM, respectively), with the leucine containing cyclotheonellazoles D and H the most potent of the new peptides tested (IC50 16.1 and 6.1 μM, respectively). All of the peptides examined for cytotoxicity against human breast, ovarian, and prostate cancer cell lines were inactive up to 20 μM. Chapter 5.0 describes the synthesis of 32 ascidian-inspired brominated indol-3-yl-glyoxylamide analogues and the exploration of their potential bioactivities against SARS-CoV-2 3CL protease, inhibition of the amyloid protein implicated in Parkinson’s disease, α-synuclein, and their effect on the cell viability of 3 human cancer cell lines (breast, prostate and ovarian cancer). Consistent with our findings in Chapter 2.0, the marine-inspired synthetic indoles had no effect on the cell viability of three cancer cell lines, but displayed interesting non-toxic activities, including promising inhibition of SARS-CoV-2 3CLpro and α-synuclein aggregation. Chapter 6.0 reports the structure revision of a series of sponge-derived bis-indole sulfamates, echinosulfone A and the echinosulfonic acids A-D. The total synthesis of echinosulfone A, alongside reanalysis of the reported NMR spectroscopic and MS spectrometric data for the echinosulfonic acids A-D, resulted in the reassignment of their structures from sulfone and α-sulfonic acid carbamates to carbon-bridged bis-indole sulfamates. In Chapter 7.0 we report the synthesis of the non-sulfonated scaffolds of the echinosulfonic acids C and D, alongside a series of echinosulfonic acid D and echinosulfone A inspired bis-indoles. The synthesis of the non-sulfonated echinosulfonic acids C and D, in tandem with comparative DFT NMR analysis, confirms undoubtedly our recent structure revisions published for this series of bis-indoles. The potential biological activities of the synthesised bis-indoles reported herein were explored by predictive cheminformatic cluster analyses using the results of our meta-analysis of marine indole alkaloids in Chapter 2.0. Findings from our cheminformatic analysis suggest that an interesting starting point for their future biological evaluation should examine their potential antibacterial activities, alongside unexplored areas of non-toxic activity associated with mode of action disease targets.