Catharanthus roseus est une plante tropicale de la famille des Apocynacées d’intérêt thérapeutique en raison de sa capacité à synthétiser des alcaloïdes indoliques monoterpéniques (AIM) utilisés en chimiothérapie anticancéreuse. La teneur en AIM in planta est très faible notamment en raison d’une haute compartimentalisation cellulaire et subcellulaire de la voie de biosynthèse. Si la compartimentalisation cellulaire était bien caractérisée, très peu de données de localisation subcellulaire in situ étaient disponibles au début de cette thèse. Une connaissance fine de cette compartimentalisation est cependant nécessaire pour identifier les transports inter-compartiment de métabolites intermédiaires, limitant potentiellement le flux métabolique, afin d’améliorer ensuite le rendement de biosynthèse des AIM par ingénierie métabolique. Dans ce contexte nous avons réalisé une étude exhaustive de la localisation subcellulaire des enzymes de cette voie par imagerie GFP dans des cellules de C. roseus transformées par biolistique permettant d’établir un nouveau modèle intégré d’organisation cellulaire et subcellulaire de la biosynthèse des AIM. / Catharanthus roseus is a tropical plant from the Apocynaceae family with a great therapeutic value due to its ability to synthesize monoterpene indole alkaloids (MIA) used in cancer treatment. The yields of these molecules in planta are very low due to a very high level of compartmentation of the biosynthetic pathway at both cellular and subcellular levels. While the cellular compartmentation was widely characterized, very few in situ subcellular localization data were available at the beginning of this PhD. An accurate knowledge of this compartmentation is necessary to identify intermediate metabolites transport events from one compartment to another one, in order to increase the MIA biosynthesis yield by metabolic engineering approaches. In this context we have proceed to the exhaustive study of the subcellular localization of these enzymes by in vivo GFP imaging in C. roseus cells transformed by biolistic. Potential interprotein interactions of these enzymes have also been studied by BiFC. Altogether, our results enabled us to draw an integrated model of the cellular and subcellular organization of MIA biosynthesis in situ.

This thesis deals with the BIM creating process with the use of laser scanning data in Revit software. It’s focusing mainly on MEP of water object. In the theoretical part of thesis there are outlined basic issues about laser scanning, informational modelling and other relating issues. In the practical part of the thesis is the summarization of procedure starting from data collecting, data processing to the procedure of creating BIM model, it’s visualisation and the use of the model. There are also mentioned useful pieces of knowledge, which I have learned during dealing with the problems related to the application of this new way of using the spatial information.

This paper investigates how virtual reality (VR) can facilitate the planning of new hospital premises from an end-user perspective and whether VR can minimize the risk of costly reconstructions close after commissioning. Currently, review of hospital premises is done in 2D based blueprints and 3D models. These blueprints and models do not always provide sufficient understanding on the hospital staff’s part. VR has been developed by suppliers to counteract this problem and to function as a design review tool for the end-users. VR is mainly used in the design phase of the building process, whereas it acts as a complementary design tool during the later phases of the building process, when the end-user participation is less tangible. Due to VR not being an established tool for all parties involved in the building process, it has consequently led to difficulties for the hospital in terms of understanding the value of said technique and knowing what set of requirements that should be taken into consideration when implementing VR into the building project. The results in this paper have shown that VR is a better tool during the design process than other available review tools. This enhanced understanding is not only limited to the end-users, but the suppliers as well have shown a better understanding of what they offer to their hospital clients. The results also show that the value of VR mainly is apparent during the design phase and less evident during the later phases of the building process due to the technical limitations VR currently faces.

The war between human and malaria has never stopped, and the development and application of antimalarial drugs has not eradicated this terrible disease. To fight drug-resistant malaria, many leads have been studied over the years. (1S,3R)-MMV008138 and MMV1803522 are two compounds that have been studied in the Carlier Group. My research focused on the structural variation of each of these compounds, in the hope that greater potency could be realized. Chapter 2 describes my work on (1S,3R)-MMV008138, which inhibits the enzyme PfIspD in the methylerythritol phosphate (MEP) pathway. This compound shows good in vitro potency against the drug resistant Dd2 strain of Plasmodium falciparum. However, this lead showed no activity in mouse models. This lack of activity may be due to poor metabolic stability of the compound. However, a significant increase in in vitro potency could also improve in vivo activity. Towards that end, I focused on further variation of the D-ring and A-rings. With the regard to the D-ring, we made five analogs of MMV008138 that replaced the 2,4-dichlorophenyl ring with dihalogenated thiophen-3-yl and thiophen-2-yl rings. We also explored the effect of installing a cyano group on the A-ring of MMV008138. Unfortunately, none of these new compounds were potent growth inhibitors of Dd2 strain P. falciparum. We conclude that the lead goes into a well-defined pocket within the PfIspD enzyme that only accommodates 2,4-dihalogenated phenyl D-rings. This pocket also cannot accept any substitution larger than F on the A-ring. Interestingly, the crystal structure of 5-cyano-substituted MMV008138 was obtained ((±)-2-50c). This is the first compound out of more than 100 analogs of MMV008138 family to be amenable to crystallization. The solid state conformation of the (±)-2-50c revealed that the C3-carboxyl group was in a pseudoequatorial orientation, and the C1-aryl group was thus in a pseudoaxial orientation. 1H NMR spectroscopic studies in CD3OD-D2O were carried out to determine the solution conformation. As expected from previous studies of ester derivatives of MMV008138, these studies indicated that in solution, 2-5 would adopt both the C3-carboxyl pseudoequatorial and pseudoaxial conformations. In Chapter 3, I describe the synthesis of analogs of the antimalarial drug candidate MMV1803522. This β-carboline-3-carboxamide shows good in vitro growth inhibition potency of Dd2 strain P. falciparum, operating by a still unknown mechanism. To investigate the pharmacophore of this lead, I first sought to determine whether the pyridine N (i.e. N2) of the β-carboline was important for in vitro potency. I prepared series of carbazole analogs of MMV1803522, which replace N2 with a CH. These compounds potently inhibited the growth of Dd2 strain P. falciparum. These results suggest that N2 of MMV1803522 is not involved in any energetically significant interactions with its target protein. To further identify the pharmacophore, we prepared truncated analogs lacking the A- and B- rings (biphenyl analogs), and tricyclic analogs that feature a reversed indole moiety. Unfortunately, the biphenyl analogs and reversed indole analogs show no growth inhibition at 10,000 nM the highest concentration tested. Lastly, I describe analogs of MMV1803522 in which the 3,4-dichlorophenyl ring of MMV1803522 was replaced with halogenated thiophene. This substitution was tolerated, but compounds were roughly half as potent as MMV1803522. / Doctor of Philosophy / Malaria, mainly caused by the infection of P. falciparum, is a serious worldwide disease. In 2020, there were 241 million cases of malaria infections and over 600,000 deaths from malaria. Combinations of commercially available antimalarial compounds, such as chloroquine, mefloquine and artemisinin, are commonly used as combination therapies to treat malaria. Since different antimalarial compounds have different mechanisms of action, this combination strategy can greatly slow down the spread of drug-resistant parasites. However, multiple drug-resistant strains of P. falciparum have been reported. Therefore, there is an urgent need for new antimalarial compounds with novel mechanisms of action. This dissertation involves my research on the investigation and optimization of two novel antimalarial compounds, MMV008138 and MMV1803522. MMV008138 is an inhibitor of the MEP pathway, which is an essential metabolic pathway and attractive target for antimalarial therapies, in malaria parasites. The parasites cannot survive, with the MEP pathway inhibited. Since the MEP pathway is not present in human, the MMV008138 molecule is unlikely to have toxicity to human. The MMV008138 molecule has been demonstrated to have great in vitro performance of inhibiting the MEP pathway in several studies, however, the in vivo performance in mouse models is yet to improve. This may be due to the poor metabolic stability of this compound. The compound decomposes in the mouse body before it takes effect. To enhance the metabolic stability and potency, I performed chemical modifications on the A- and D-rings of the MMV008138 compound. An X-ray crystal structure was obtained to help elucidate the conformer distribution of MMV008138. This crystal structure can be used to guide our understanding of the docking of this compound to the target enzyme in the future. MMV1803522 is another compound that shows great potency in vitro and in vivo. This compound is fully oxidized and contains four aromatic rings. However, the target enzyme and the mechanism of action of MMV1803522 is yet to be discovered, and the structure-activity relationship between the chemical structure and the biological activity of this molecule is still unknown. Therefore, I have developed synthetic methods to synthesize a series of compounds that are structurally similar to the MMV1803522 and found that potency of this molecule is not due to the nitrogen on the C-ring. Also, the number and size of the ring structures in the MMV1803522 may be crucial for this molecule to exhibit great potency in vitro and in vivo.

Malaria continues to threaten human beings, causing a staggering number of more than 400,000 deaths each year. Although effective treatment and prevention methods are available, rapidly emerging resistance towards existing drugs is of great concern, and the need for novel antimalarial compounds are still urgent. The Malaria Box lead molecules MMV008138 and MMV665831 are promising in this regard, due to their apparently novel antimalarial mechanisms of action. The target of MMV008138 is the PfIspD enzyme in the MEP pathway, which is absent in humans. This difference makes the PfIspD a great target. However, while MMV008138 shows potency against Plasmodium falciparum-infected human erythrocytes in vitro, no efficacy was observed in a humanized mouse model or a P. berghei infected mouse in vivo. In order to block potential metabolic spots and to probe for steric demand, a series of analogous featuring C1-deuteration, methyl substitution on B- and C-ring, and an ethylene bridge were prepared. The effect of various substitution on the tetrahydro-β-carboline conformation and D-ring orientation was studied. In the course of preparing the C1-Me analog of MMV008138 featuring 2',4'- dichloro substitution, unexpected ring-expanded azepane products were isolated. Later it was found that the desired product could be isolated when the imine formed was treated with acid at lower temperature. Other intermediates possessing a 2ʹ- substituent were also isolated under the low temperature acid treatment protocol, which upon heating in acid gave the ring-expanded azepane we initially isolated. A mechanism was proposed to account for the formation of the azepane as well as other intermediates. The driving force of the expansion reaction was explored, and the hypothesis that the steric interaction between the 2ʹ-substituent and the C1-Me was supported via DFT calculation and conformational analysis. MMV665831 is another potent hit from the Malaria Box, and it appears to inhibit the hemoglobin endocytosis process of P. falciparum. The structure–activity relationship of MMV665831 was studied with analogues featuring modifications on C2-benzamide, C3-ester, C-7 phenol, as well as the phenolic Mannich base moiety. Modifications at phenolic Mannich base moiety leads to the discovery of an analogue that is twice as potent toward cultured P. falciparum compared to MMV665831. We were worried the phenolic Mannich base moiety might act as the precursor of toxic quinone methide intermediates, and designed two analogs to block this potential toxicophore. Although the modification resulted in reduced potency, this result proved that the potency of MMV665831 does not stem from the formation of quinone methides. Unfortunately, MMV665831 did not reduce parasitemia in P. berghei- infected mice. Fast hepatocyte metabolism was observed for MMV665831, and the loss of in vivo efficacy was discussed in comparison with other phenolic Mannich bases with similar hepatocyte stability. / Doctor of Philosophy / In the fight against malaria, one concerning issue is the rapidly emerging resistance towards existing drugs. The continuous development of antimalarials with novel mechanism of action is greatly needed. To accelerate the development of novel antimalarials, an open access ensemble of 400 compounds that are toxic to the malaria parasite known as the Malaria Box, has been made available. My work involves the optimization of two compounds from this ensemble, MMV008138 and MMV665831. MMV008138 kills the malaria parasite by inhibiting an enzyme named PfIspD, which is absent in human. In the parasite an enzyme called PfIspD is responsible for the biosynthesis of IPP and DMAPP, two chemical building blocks that are essential for all cells. It is unlikely that MMV008138 will interrupt with the biosynthesis of IPP and DMAPP in human, since we use another enzyme to synthesize them. Although MMV008138 shows great in vitro potency, but did not protect a live mouse from malaria infection. The lack of in vivo efficacy could stem from the rapid metabolism of MMV008138, and analogs aimed to prevent metabolism were designed and prepared. While preparing analogs featuring 2ʹ-substitution, the desired product was not found, but other unexpected by-products were isolated. The conditions that leads to both the desired products and the by-products were found, and the mechanistics detail of this unexpected reaction were studied. During the blood-stage, which causes malaria symptoms in human, the Plasmodium falciparum parasite invades and feeds on human red blood cells (erythrocytes). The parasite destroys human hemoglobin through a multistep process that begins by transporting the hemoglobin from the red blood cell into itself, a process called endocytosis. MMV665831 appears to interfere with this endocytosis process of P. falciparum, thus starving the parasite of its food. Analogs of MMV665831 were prepared to probe for the effect on potency, and one compound that is twice as potent in cultured parasites was found. The structure of MMV665831 contains a potentially unstable moiety, which might lead to toxicity in humans. Two analogs with the problematic moiety removed were designed and prepared, and one still shows antimalarial activity, showing that the reactivity of the potentially unstable moiety is not the reason for the antimalarial activity of MMV665831. However, MMV665831did not protect P. berghei-infected mice (murine malaria) in vivo, and the reason for the loss of efficacy was discussed.

No description available.

Mycobacterium tuberculosis, the causative pathogen of tuberculosis, currently infects one-third of the world’s population, resulting in two million deaths annually. This clearly shows that tuberculosis is one of the most serious diseases of our times. The often unpleasant side effects from the current drugs, combined with the difficulty of ensuring patient compliance, and the emergence of drug-resistant and multidrug-resistant strains, makes the need for new and better drugs urgent. In this thesis, all the steps, from cloning, purification, crystallization, to activity determination, and structure determination are presented for two different M. tuberculosis enzymes. The structures, which were modeled from X-ray crystallographic data, provide the framework for structure-based drug design. Here, new potential inhibitors can be tailor-made based on the specific interactions in the enzyme’s active site. The bacteria have two different peptidyl-prolyl cis-trans isomerases that catalyze the isomerization of peptide bonds preceding proline residues, a process of high importance for correct folding. Here we present the structure of peptidyl-prolyl cis-trans isomerase A, an enzyme present inside the bacteria, and distinguish it from the B form of the enzyme, which is membrane bound, placing its active site outside the bacteria. The enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase catalyzes the second step within the non-mevalonate pathway, which leads to the production of isopentenyl diphosphate. This compound is the precursor of various isoprenoids, vital to all living organisms. In humans, isopentenyl diphosphate is produced via a different pathway, indicating that all the enzymes within the non-mevalonate pathway may be suitable drug targets in M. tuberculosis. Several structures of both wild type and mutant 1-deoxy-D-xylulose-5-phosphate reductoisomerase in complex with different substrates, and also with the known inhibitor fosmidomycin, provide valuable information not only to the field of drug design, but also, in this case, into the catalysis.

[EN] Nowadays, the improvements and developments carried out in reciprocating internal combustion engines are especially based on fuel consumption and pollutant emissions reduction. These reductions are promoted by the depletion of world fossil fuel reserves and the increase in health and environmental problems that have been reported over the years. Actual regulations are forcing manufacturers to include different technologies which lead to a reduction in harmful compounds emissions, and therefore, the pollutants emission limits can be achieved. In this regard, the aftertreatment systems located in the exhaust line in all engine architectures have become commonly used as a solution to reduce such compounds. Furthermore, the manufacturers are also developing different strategies that directly affect the combustion process such as EGR systems or exploring new combustion modes, which are focus on the reduction of pollutants. This PhD thesis has as a main objective the experimental evaluation of the pollutant emissions (CO, HC, NOx, PM and PN) obtained through the use of emerging strategies for reducing pollutant compounds in reciprocating internal combustion engines. In this context, this work also includes the development of a methodology for the evaluation and assessment of the soot concentration emitted by these engines during dynamic operating conditions. On the one hand, the strategies that are use along this work and applied to compression ignition engines have been focused on aftertreatment systems, and more precisely on the diesel oxidation catalysts and diesel particle filters. Thus, the influence of the placement of these systems in the exhaust line over pollutants emissions has been analyzed. Following in the field of diesel particle filters, the analysis of the influence of pre-DPF water injection strategy on pollutants compounds has been carried out. On the other hand, concerning spark ignition engines, the influence of low pressure EGR strategy in a turbocharged direct injection engine on pollutant emission, and the efficiency of the aftertreatment system incorporated (three way catalyst) has been studied. Through these works it has been possible to determine the effects of different emission control techniques on pollutant compounds, establishing the advantages and disadvantages of each one and, as a results, proposing how to continue the development of these strategies. / [ES] Hoy en día, el desarrollo y mejora de los MCIA está especialmente forzado por la reducción en el consumo de combustible y las emisiones contaminantes. Estas reducciones están motivadas debido al agotamiento de las reservas mundiales de combustibles fósiles y el aumento de los problemas de salud y medioambientales que se han ido reportando a lo largo de los años. Las actuales regulaciones anticontaminación están obligando a los constructores a incluir diferentes tecnologías que permitan la reducción de la emisión de compuestos nocivos y el cumplimiento de los límites máximos establecidos. En este sentido, los sistemas de post-tratamiento en la línea de gases de escape se han convertido en la solución comúnmente empleadas en todas las arquitecturas de motores existentes para la reducción de dichos compuestos; aunque también se están desarrollando diversas estrategias que afectan directamente al proceso de combustión, tales como los sistemas de recirculación de gases de escape, o nuevos modos de combustión, que buscan este fin. Esta tesis tiene como objetivo principal la evaluación experimental de las emisiones (CO, HC, NOx, PM y PN) que se obtienen a través del uso de nuevas estrategias emergentes para la reducción de contaminantes en MCIA. En este contexto, este trabajo también contempla el desarrollo de una metodología que permita la evaluación y estimación de la concentración hollín emitido durante condiciones de operación dinámicas de motor. Por un lado, las estrategias analizadas en esta tesis aplicadas a motores de encendido por compresión han estado centradas en los sistemas de post-tratamiento; concretamente, en los DOC y DPF. Así pues, se ha analizado la influencia sobre las emisiones contaminantes de la arquitectura de estos sistemas en la línea de escape, situándolos aguas arriba de la turbina de sobrealimentación, en configuración conocida como pre-turbo. Siguiendo con el campo de los DPFs, también se ha llevado a cabo el análisis de la influencia de la estrategia de inyección de agua en este sistema sobre las emisiones contaminantes con este tipo de motor. Por otro lado, y concerniente a las motorizaciones MEP, se ha estudiado la influencia de la estrategia de EGR sobre las emisiones de un motor turboalimentado y de inyección directa, así como sobre el sistema de post-tratamiento que incorpora (TWC). A través de estos trabajos se han podido evaluar los efectos de diferentes técnicas de control de emisiones, estableciendo las ventajas e inconvenientes de cada una de ellas y proponiendo finalmente como continuar el desarrollo de las mismas. / [CAT] En l'actualitat, el desenvolupament i millora dels MCIA està especialment forçat per la reducció del consum de combustible i les emissions contaminants. Aquestes reduccions estàn promogudes per l'esgotament de les reserves mundials de combustibles fòssils i l'augment dels problemes de salut i medioambientals que s'han produït durant el últims anys. Les actuals regulacions anticontaminants han fet que els fabricants incloguen distintes tecnologies que permeten la reducció de l'emissió de compostos nocius i el compliment dels límits màxims establerts. En aquest sentit, els sistemes de post-tractament en la línia dels gasos d'escapament s'han convertit en la solució més utilitzada en totes les arquitectures de motors existents per a la reducció dels compostos mencionats anteriorment; encara que també estàn desenvolupant-se diverses estratègies que afecten directament al procés de combustió, com son els sistemes de recirculació de gasos d'escapament, o nous tipus de combustió, que busquen aquest fi. Aquesta tesi té com a objetiu principal l'avaluació experimental de les emissions (CO, HC, NOx, PM y PN) que s'obtenen a través de l'ús de noves estratègies emergents per a la reducció de contaminants en MCIA. En aquest context, el treball també contempla el desenvolupament d'una metodologia que permeta l'avaluació i estimació de la concentració de sutja emés durant condicions d'operació dinàmiques del motor. Per una banda, les estratègies analitzades en aquesta tesi aplicades a motors d'encesa per compressió han estat centrades en els sistemes post-tractament; concretament, en els DOC i DPF. Així doncs, s'ha analitzat la influència sobre les emissions contaminants de l'arquitectura d'aquestos sistemes en la línia d'escapament, situant-los aigües amunt de la turbina de sobrealimentació, en configuració coneguda com pre-turbo. Seguint amb el camp dels DPF, també s'ha dut a terme l'anàlisi de la influència de la estrategia d'injeccio d'aigua en aquest sistema sobre les emissions contaminants amb aquest tipus de motor. Per altre costat, pel que concerneix a les motoritzacions MEP, s'ha estudiat la influència de l'estratègia de EGR sobre les emissions d'un motor turboalimentat i d'injecció directa, així com sobre el sistema de post-tractament que incorpora (TWC). Mitjançant aquests treballs s'han pogut avaluar els efectes de diferents tècniques de control d'emissions, establint els avantatges i inconvenients de cadascuna d'elles i propossant finalment com continuar amb el desenvolupament de les mateixes. / Campos Navarro, D. (2016). Estudio de las emisiones de escape en motores de combustión interna alternativos utilizando diferentes sistemas de control de contaminantes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/64066 / TESIS

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13159号 / 論医博第2146号 / 新制||医||1029(附属図書館) / (主査)教授 河本 宏, 教授 前川 平, 教授 髙折 晃史 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Malaria 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. / Doctor of Philosophy / The 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.