UCSF

Malaria, a disease caused by infection of protozoan parasites from genus Plasmodium, claims an estimated 600,000 lives annually, with the majority of these deaths in children. The utility of artemisinin and its derivates, which constitute the foundation of modern antimalarial care, is complicated by its suboptimal pharmacological parameters and by a concerning rise in genetically driven artemisinin partial resistance phenotypes in areas of high disease burden. Following limited clinical adoption of second generation synthetic trioxolane leads arterolane and artefenomel, small molecules which retain the endoperoxide-driven antiparasitic effect of artemisinin with improved properties and streamlined synthesis, there exists an urgent and undertargeted need for improved antimalarials in this class.Herein we report the design, synthesis, and in vitro and in vivo evaluation of a library of novel trans-3” substituted 1,2,4-trioxolanes. For carbamate substituted compounds in this class, we find promising antiparasitic efficacy, excellent metabolic stability, and a superior cure rate in a 2-day dosing regimen for lead compound 9d against the rodent P. berghei model of malaria, motivating future advancement of 9d into a humanized rodent malaria model (Chapter 2). We additionally report the synthesis and evaluation of trans-3”-aryl substituted congeners of artefenomel with a focus on carbamate-linked phenols bearing basic amine or other solubilizing functionality (Chapter 3). We find this class to broadly exhibit excellent antiparasitic efficacy and improved solubility and metabolic stability relevant to the 2nd generation trioxolanes. We advance the lead analog 17, which completely eliminates K13 C580Y parasites in vitro in the ring stage survival assay (RSA) and retains potent efficacy against high-RSA Ugandan clinical isolates. We furthermore report a stereoselective route to the (R,R)- and (S,S)- forms of 17, observing increased solubility of the separated enantiomeric forms versus the racemate. We extensively profile 17S as a clinical development candidate and found the compound to exhibit a protein binding and metabolic stability profile we predict should translate to extended drug exposures in human malaria patients. We additionally explore the P. falciparum stress response as driven by PK4-mediated eIF2α phosphorylation (Chapter 4). We identify dozens of drug-like kinase inhibitors from the GSK PERK kinase set with potent antiparasitic effect. We find these inhibitors phenocopy the antiparasitic effect of bona fide PfPK4 inhibitor GSK-2606414 and plausibly retain the target profile of this comparator. We leverage our medium-throughput in vitro P. falciparum library screening pipeline to screen the SelleckChem antikinase library, reporting dozens of potent hits against the parasite and suggesting additional points of entry for targeting the P. falciparum kinome.