Malaria is caused by five species of the Plasmodium group of protists. The deadliest cases are often the result of infection by the species Plasmodium falciparum which is,, coincidentally, the most drug resistant. The looming threat of spreading antimalarial resistance in this species could destabilize widespread treatment of malaria in the developing world. As such, efforts to develop novel chemical therapies must strive not only for effectivity and economy but to address the growing problem of antimalarial resistance. Bifunctional inhibitors of cancer and HIV have shown promise as being more resilient to resistance conferred by mutagenesis than their one target counterparts and have therapeutic value for antimalarial development. Past work in our group on substituted triazine scaffolds has led to the development of a triazine-based N-hydroxyacetamide as a bifunctional inhibitor of histone deacetylase (HDAC) and dihydrofolate reductase (DHFR) in P. falciparum and this work will focus on its synthesis, homologation, and biological evaluation. The lead compound contains hydroxamic acid and diamino triazine moieties, known to target HDAC and DHFR in P. falciparum, respectively. Compounds were synthesized, purified, and characterized using common synthetic and organic laboratory methods. Homologation of the triazine carbon-2 locus was achieved via a key synthetic step. The homologs having propyl, butyl, and pentyl substituents will be synthesized and tested in vitro and in vivo against DHFR and HDAC. These short carbon chains will increase the hydrophobicity and optimally facilitate transport of the inhibitor through the cell membrane and towards the molecular targets. A QSAR approach will be utilized in determining the optimum effect of extending the carbon chain at this locus and what this could mean for the design of future inhibitors.

Homologation of a proposed bifunctional inhibitor of HDAC and DHFR in Plasmodium falciparum

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.