Malaria is a severe and deadly mosquito-borne disease. Although treatable, the continuous emergence of multi-drug resistant parasite strains urgently calls for the development of novel antimalarial agents. P. falciparum parasites synthesize essential isoprenoid precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), via a non-mevalonate pathway: the methylerythritol phosphate (MEP) pathway. This pathway is not utilized by humans. Thus, compounds that target the MEP pathway and disrupt isoprenoid biosynthesis in P. falciparum hold promise as potent and safe new antimalarial agents, that engage new targets.
Previously, we and others identified MMV008138 from the Malaria Box as a MEP pathway targeting compound. Later work revealed that it targets the IspD enzyme within the MEP pathway. Work in the Carlier group has established preliminary structure-activity relationship (SAR) of MMV008138: 1) (1R,3S)-configuration is required; 2) 2', 4'-disubstitution of the D-ring with small, electronegative substituents; 3) functional importance of carboxylate acid at C3.
In this work, I aim to gain further insight into the C3 SAR and A-ring SAR of lead compound MMV008138. Synthesized acid bioisosteres and A-ring analogs of MMV008138 were evaluated in their ability to inhibit P. falciparum parasite growth. We showed that the C3 substituent of MMV008138 has a very tight SAR, and likely interacts with a very constricted pocket within the PfIspD enzyme. A-ring modifications are limited to certain positions of MMV001838 and need to be sterically small. However, we have yet to identify a modification that significantly improves drug lead potency.
Future work will continue towards understanding the A-ring SAR of MMV008138, as well as D-ring SAR and C1-SAR. Efforts will also be directed towards finding analogs with improved potency, transport and metabolic stability. / MS / Malaria is a severe and deadly mosquito-borne disease, caused by malaria parasites. Although treatable, the continuous emergence of drug resistance urgently calls for the development of novel antimalarial agents. Research in the Carlier group is aimed at finding drug molecules that can selectively target and kill the malarial parasite, and at the same time be safe to humans. The Carlier group has identified MMV008138 from the Malaria Box as a promising drug lead. In this work, I aim to understand the how the structure of MMV008138 play a role in its ability to kill malaria parasites. These results will help identify modification strategies that may significantly improve drug lead potency.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/95315 |
| Date | 15 May 2018 |
| Creators | Liu, Lixuan |
| Contributors | Chemistry, Carlier, Paul R., Tanko, James M., Kingston, David G. I. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Thesis |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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