Nijhawan, Deepak2023-06-072023-06-072021-052021-05-01May 2021https://hdl.handle.net/2152.5/10062Emerging resistance of the malaria causing Plasmodium parasite to current first-line therapies underscores the need for new antimalarial agents with broad ranging activity against multiple stages of the parasite. No new chemical class of antimalarials has been introduced into clinical practice since 1996. Overcoming emerging drug resistance requires new drugs with novel modes of action. With the aim of identifying new classes of antimalarials, I completed a phenotypic high throughput screen of two synthetic chemistry libraries against erythrocytic stage P. falciparum and compiled a portfolio of chemically novel validated antiplasmodials (ALCHM1 - 18). Herein I describe the discovery and characterization of three prioritized scaffolds: a tetrazole-based ALCHM3 series, an azetidine amide ALCHM17 series and a piperidine carboxamide ALCHM18 series. I report here on the biological profiling, mechanistic characterization and potential as next-generation anti-malarial agents of these three previously unreported scaffolds. ALCHM3 is a novel chemical series, with fast kill kinetics that targets the historically druggable heme polymerization pathway. The fast kill azetidine amide ALCHM17 series, is a novel scaffold with inhibitory activity in the pre-erythrocytic and erythrocytic stages, and the first azetidine scaffold with Pfcarl associated resistance. The piperidine carboxamide ALCHM18 is a proteasome β5 subunit-selective inhibitor, with a moderate rate of kill, species selectivity, strong starting in vitro and in vivo ADME properties, and potential to become the first proteasome inhibiting preclinical candidate for malaria treatment.application/pdfenAmidesAntimalarialsHemoglobinsPlasmodium falciparumTetrazolesThesis2023-06-071381370397