Natural products have inspired chemists by their rich structural diversity and complexity while playing a pivotal role as sources for drug lead compounds during the last century. However, in order for natural products chemistry to continue to be competitive with purely synthetic based drug discovery methods, there is a need to continually improve the efficiency of the source selection, screening, dereplication, isolation and structure elucidation processes. This project aims to contribute to the emerging technological advances in this field by exploring the applicability of diffusion NMR spectroscopy as a novel characterization methodology for crude and prefractionated microbial extracts. The use of diffusion-ordered spectroscopy (DOSY) and related experiments is proposed to expedite the dereplication of known secondary metabolites present in mixtures by using the information extracted from diffusion-dependent spectra as input for database searching. Furthermore, the project aims to facilitate the direct structural elucidation of novel secondary metabolites in mixtures by the use of diffusion-edited and diffusion-encoded NMR experiments. The concepts of covariance NMR will be applied to the processing of diffusion NMR data to enhance this dereplication/elucidation process. Finally, the differential graphical comparison of DOSY plots and its quantitative multivariate statistical analysis is proposed as a novel methodology for metabolite fingerprinting/profiling usable in chemotyping-based drug discovery processes and in the annotation of crude and prefractionated natural product libraries. The newest diffusion NMR pulse sequences, processing strategies and methodologies will be explored and adapted to microbial natural product mixtures. New methods to enhance resolution of similar sized components in the diffusion dimension based on the use of matrix-assisted diffusion-ordered spectroscopy will be also investigated with the incorporation of novel resolving agents.
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