To identify novel antimalarials from unexplored areas of chemical space, we have utilized two approaches: (a) using Torrey Pines Institute for Molecular Studies (TPIMS) proprietary high-density combinatorial libraries containing a large number of small molecule compounds residing largely in the underexplored areas of chemical space; and, (b) using novel, complexity-to-diversity/ring distortion of available natural products. The first approach involved the screening of more than 30 million compounds derived from 81 small molecule libraries, built on 81 distinct scaffolds. From this, we identified the pyrrolidine bis-cyclic guanidine library (TPI-1955) to be one of the most active and selective for antiplasmodial activity. In parallel, the synthesis of individual compounds derived from the deconvolution of the positional scanning library led to the identification of active selective antiplasmodial pyrrolidine bis cyclic guanidines. In the complexity to diversity/ring distortion approach, the indole alkaloid, yohimbine, has been re-engineered to alter the it's biological activity through a ring rearrangement synthesis pathway to develop a new series of antiplasmodial agents. One such antiplasmodial agent, Y7j, demonstrated good potency against the chloroquine-resistant Dd2 strain of parasites without eliciting cytotoxicity against human HepG2 cells. Y7j demonstrated stage specific action against plasmodium parasites in the late ring/trophozoite stage, and demonstrates the potential for ring distortion to drive new discoveries and change existing paradigms in both chemical biology and drug discovery.
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Master of Science (M.S.)
College of Medicine
Length of Campus-only Access
Masters Thesis (Open Access)
Perry, David, "Identification of Novel Antimalarials From Natural Product Inspired Libraries" (2020). Electronic Theses and Dissertations, 2020-. 397.