1,3-Disubstituted-tetrahydro-β-carbolines: A New Method for Stereochemical Assignment and Synthesis of Potential Antimalarial Agents

dc.contributor.authorCagasova, Kristynaen
dc.contributor.committeechairCarlier, Paul R.en
dc.contributor.committeememberSantos, Webster L.en
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberEtzkorn, Felicia A.en
dc.description.abstractMalaria is a serious mosquito-borne disease affecting the majority of Earth's southern hemisphere. While consistent efforts to curb malaria spread throughout 20th and early 21st century were largely successful, the recent rise in resistance to antimalarial treatments resulted in an increasing incidence rate and stalling mortality rate. This trend clearly signifies the need for the development of novel antimalarial agents able to circumvent current drug-resistance mechanisms. In 2014, in collaboration with Prof. Maria Belen Cassera from the University of Georgia, our group found that compound 1a (1R,3S-MMV008138), discovered from the publicly available Malaria Box, targets an essential biosynthetic pathway (MEP pathway) of malaria-causing parasite Plasmodium falciparum. Analogs of 1a synthesized in our laboratory were found effective against multi-resistant Dd2 strain of P. falciparum which, together with an absence of MEP pathway in humans, suggests that potent analogs of 1a may be safe and efficient antimalarial drug candidates. The initial bioassay studies determined that only one of four possible MMV008138 stereoisomers satisfactorily inhibits the target PfIspD enzyme. Thus a secure determination of stereochemistry in 1a analogs was of utmost importance to the structure-activity relationship studies performed in our group. The second chapter of this work discusses the validation of the previously known empirical stereoassignment method based on analysis of relative shift of 13C NMR resonances between cis and trans diastereomers and compares it to a new method based on 3JHH coupling constants developed in our laboratory. We demonstrate that the new method relying on the analysis of 1H-1H coupling is reliable over large samples of experimental data and suitable even when only a single diastereomer is produced in the synthetic process. Importantly, the origin of 3JHH coupling constants is well understood, unlike the source of relative differences in 13C NMR shifts observed in the older method. The empirical observations for both stereoassignment methods are supported by extensive density-functional theory calculations, which validate the new 1H-1H coupling-based assignment but do not provide a conclusive explanation for the origin of the 13C NMR-based method. In the third chapter, we discuss the replacement of the carboxylic acid moiety in 1a by alternative functional groups promising improved toxicity and bioavailability profile. The total synthesis of tetrazole (trans-23a) and phosphonic acid ((±)-62a) derivatives of 1a is discussed in detail. The tetrazole analog 23a was previously synthesized in the Carlier group as a diastereomeric mixture of cis and trans isomers (dr = 3:7), and it was tested for growth inhibition of multi-resistant P. falciparum with promising results. Later, the synthesis was revisited to obtain a stereochemically pure sample of trans-23a, which was expected to show improved potency compared to the original sample. Furthermore, the synthesis of pure trans-23a confirmed the accuracy of the previous assignment of cis and trans diastereomers in the mixture. Unfortunately, neither analog showed an improvement in potency relative to 1a.en
dc.description.abstractgeneralThe most severe form of malaria disease is caused by the parasite, Plasmodium falciparum, which gives rise to over 200 million infections and more than 400 thousand deaths every year, the majority of which affect young children. In recent years, the effectiveness of clinically used antimalarial medicines decreased due to an increase in drug-resistant strains of P. falciparum. Therefore, there is an urgent need for new antimalarial agents that could bypass the emerging resistance. A promising candidate for a new antimalarial drug is a molecule named MMV008138. This molecule exists in four distinct forms called stereoisomers. Stereoisomers are molecules with the same chemical formula, but the atoms in each molecule are positioned differently. Only one of MMV008138's four stereoisomers (1a) was effective in killing the P. falciparum. The second chapter of this work discusses a new method for identifying stereoisomers in molecules like MMV008138. We demonstrate that the new method is both reliable and simpler than the previously used procedures. The third chapter of this dissertation discusses the preparation of two new compounds based on the structure of 1a that contain modifications promising improved biological activity. Unfortunately, neither of these two molecules was able to kill the P. falciparum efficiently.en
dc.description.degreeDoctor of Philosophyen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.subjectMEP pathwayen
dc.subjectPictet-Spengler reactionen
dc.subjectγ-gauche effecten
dc.subject1H-1H couplingen
dc.subjectbioisostere synthesisen
dc.subjectphosphonic aciden
dc.title1,3-Disubstituted-tetrahydro-β-carbolines: A New Method for Stereochemical Assignment and Synthesis of Potential Antimalarial Agentsen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.nameDoctor of Philosophyen
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