The long held goal of malaria eradication faces increasing adversity due to limited treatment options and growing drug resistance. New drug scaffolds are needed to both improve treatment outcomes, and expand our knowledge of parasite-drug interaction. In the following dissertation, we utilize fungi as a chemical source for antiplasmodial screening. Through these endeavors, over 6,000 fungal extracts have been screened, and more than 100 compounds with antiplasmodial activity have been identified. In the coming pages, we outline the work performed on two prominent compound classes identified: cyclic tetrapeptide HDAC inhibitors and peptaibols. Our investigation of a potent cyclic tetrapeptide scaffold developed the structure activity relationship of 24 inhibitors that show markedly improved selectivity for the malaria parasite over previous analogs. These new inhibitors demonstrated nanomolar potency against the plasmodial class I HDAC, PfHDAC1, and caused hyperacetylation of histone H4 in vitro. Semi-synthetic modifications to the zinc binding group resulted in a dramatic change in killing permeance, potentially linked to early life cycle inhibition. While chemical optimization is needed for in vivo implementation, this analysis generated valuable data regarding the class as a whole, and the factors that govern their killing profile. In our work with peptaibols, we break ground on a completely unexplored class in the malaria field. These inhibitors show incredible antiplasmodial potency, and more than two hundred fold selectivity. Additionally, they demonstrate potential as dual stage inhibitors for both prophylaxis and treatment. Their blood stage activity appears linked to a change in membrane permeability, specifically at the level of the parasites digestive vacuole. This finding is further supported by an in-depth transcriptome analysis and resistance generation. In summary, the original research produced as part of this dissertation expands the current boundaries of knowledge in the field of malaria therapeutics, furthering drug discovery and development efforts.


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Graduation Date





Chakrabarti, Debopam


Doctor of Philosophy (Ph.D.)


College of Medicine


Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences




CFE0009646; DP0027505





Release Date

February 2028

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Campus-only Access)

Restricted to the UCF community until February 2028; it will then be open access.