Studies in organic and medicinal chemistry: Treatment of malaria and cytomegalovirus

Despite advances in disease therapy, several diseases continue to affect large numbers of human populations due to lack of an effective therapy or drug resistance. These diseases include but are not limited to malaria and cytomegalovirus (CMV). Novel therapies are urgently needed for these diseases, and organic synthesis of biologically active molecules can be harnessed to accomplish such a task. The research presented here is a combination of detailed organic chemistry on both natural product derivatives and previously established bioactive molecules and application of chemical biology to establish novel therapies.;Novel artemisinin-derived compounds (monomers and dimers) and an amodiaquine-furoxan hybrid were synthesized, and their biological activities were established both in vitro and in vivo. The artemisinin-derived dimers of varied linker lengths are exceptionally active in treating both P. berghei infected mice and CMV in vitro. Amodiaquine, from the quinoline class of antimalarial drugs, was functionalized with a reactive group that is known to release nitric oxide. The 3-cyano-4-phenyl-1,2,5-oxadiazole-2-oxide (reduced to the common name, furoxan) can react with nucleophiles (in vivo, thiols from cysteine-containing proteins) to release nitric oxide, and this process alters redox metabolism. The group was tethered to amodiquine to create a dual-action hybrid molecule that is active against several parasitic diseases.;Additionally, novel drug combinations for the treatment of malaria are also explored via high throughput matrix combination studies to identify synergy, additivity or antagonism between two therapeutics. High-throughput combination studies revealed two distinct classes of synergistic interactions - those involving drugs thought to target the parasite mitochondria, and interactions between known antimalarial drugs (whose mechanism of action is either unclear or is thought to generate reactive oxygen or carbon centered radical species) and ion homeostasis modulators. The novel compounds that were synthesized and the drug combinations that were uncovered represent promising new candidates for novel antimalarial and anti-CMV treatments.