Doctor of Philosophy (Ph.D.)
Degree Granting Department
James W. Leahy, Ph.D.
Bill Baker, Ph.D.
Jianfeng Cai, Ph.D.
Sandy Westerheide, Ph.D.
Infectious diseases, Leishmania donovani, promastigotes, amastigotes, radicicol, Plasmodium, xanthurenic acid, gametogenesis
Infectious diseases continue to be a major concern worldwide. They are the second leading cause of death after heart disease. Factors such as an increasing global population, travel, urbanization, global climate change and evolution of pathogens have made infectious diseases more common. Infectious diseases, particularly neglected tropical diseases (NTDs) result in many deaths worldwide. Malaria and leishmaniasis are two common (NTDs) which affect low income countries around the globe. Low cost drugs with novel mechanism of action are required to tackle the growing resistances of parasites against current drugs used in the developing world, where most of the cases occur. The first part of this manuscript (chapters 1 - 3) describes the synthesis of novel analogs active against Leishmania donovani parasite which causes leishmaniasis. Leishmaniasis is a vector-borne complex group of diseases transmitted through the bite of an infected female sand-fly. Its clinical manifestations range from the less severe (cutaneous) to fatal (visceral) forms depending upon infecting species, immunity of host and the environment. Reports have suggested the role of Heat shock protein 90 (Hsp 90) in the differentiation of the Leishmania parasite from the promastigote stage to the pathogenic amastigote stage inside the host. A series of tetrahydro-indazole, tetrahydro-pyrazolo pyridine and radicicol hybrid compounds were prepared based on known Hsp 90 inhibitors, SNX2112 and NVP-AUY922. The synthetic approach allowed us to generate a diverse library of analogs which were used to probe the hydrophobic pocket of Hsp 90 active site. The most active compound, was found to be twice more active as the clinically used drug, Miltefosine, in an infected macrophage assay with an IC50 = 0.88 µM.
The second part of this manuscript (chapters 4 - 5) describes the synthesis of xanthurenic acid analogs as antimalarial drugs. Xanthurenic acid (XA) is a vital component for the gametogenesis of the Plasmodium inside the mosquito’s gut. Gametogenesis plays an important part in the continuation of the parasite’s life cycle. A series of xanthurenic acid analogs were synthesized with the aim of inducing premature exflagellation of the microgametes, thus blocking the key step required for the transmission of parasites from humans to the mosquito. A biotinylated xanthurenic acid analog and a clickable xanthurenic acid analog were also synthesized which will help us investigate the mechanism of action of xanthurenic acid in inducing gametogenesis in mosquito. In the preliminary screening efforts in an exflagellation assay, analog 4.40 showed promising activity and was more active in inducing exflagellation than xanthurenic acid. An exflagellation assay of other analogs is currently being pursued. Further investigations into the molecular target and mechanism of action are underway with the biotinylated xanthurenic acid analog.
Scholar Commons Citation
Kanwar, Ankush, "Studies Aimed at the Synthesis of Anti-Infective Agents" (2018). Graduate Theses and Dissertations.