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Malaria is caused by a protozoan parasite, Plasmodium falciparum, which is responsible for over 500,000 deaths per year worldwide. Although malaria medicines are working well in many parts of the world, antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Since the malaria parasites are once again developing widespread resistance to antimalarial drugs, this can cause the spread of malaria to new areas and the re-emergence of malaria in areas where it had already been eradicated. Therefore, the discovery and characterization of novel antimalarials is extremely urgent. A previous drug screen in Dr. Chakrabarti's lab identified several natural products (NPs) with antiplasmodial activities. The focus of this study is to characterize the hit compounds using Principal Component Analysis (PCA) to determine structural uniqueness compared to known antimalarial drugs. This study will compare multiple libraries of different compounds, such as known drugs, kinase inhibitors, macrocycles, and top antimalarial hits discovered in our lab. Prioritizing the hit compounds by their chemical uniqueness will lessen the probability of future drug resistance. This is an important step in drug discovery as this will allow us to increase the interpretability of the datasets by creating new uncorrelated variables that will successively maximize variance. Characterization of the Natural Product inspired compounds will enable us to discover potent, selective, and novel antiplasmodial scaffolds that are unique in the 3-dimensional chemical space and will provide critical information that will serve as advanced starting points for the antimalarial drug discovery pipeline.

In der vorliegenden Dissertation werden das Selbstaggregationsverhalten und die elektronischen Eigenschaften von vier expandierten pi-konjugierten Makrozyklen in geordnete supramolekulare Architekturen mit Hilfe von Rastertunnelmikroskopie (STM) und Tunnelspektroskopie (STS) an Fest-Flüssig-Grenzflächen zwischen organischen Moleküllösungen und der Basalfläche von Graphit untersucht. Zwei Makrozyklen sind die Fotoisomere Z,Z–8T6A und E,E–8T6A, in denen sechs Ethynylengruppen und zwei cis- bzw. trans-Ethylen erhalten sind. STM-Bilder zeigen 2-dimensionale hexagonale Gitter. Strom-Spannungs-Kennlinien bestätigten den erwarteten donor-artigen Charakter der Makrozyklen. Das Schalten von Z,Z–8T6A zu E,E–8T6A wird durch STS zyklische Messungen angezeigt, nachdem die stabilste kationische Spezies ausgebildet wurde. Diese Ergebnisse stellen das erste elektrochemische Schalten unter Standard STM Bedingungen dar. Außerdem wurden die Photoisomerisierungen zwischen Z,Z-8T6A und E,E-8T6A an der Fest-Flüssig-Grenzfläche beobachtet. Eine selbstorganisierte Monoschicht aus Wasserstoffbrücken-gebundenen Trimesinsäuren an der Fest-Flüssig-Grenzfläche bildet Wirtsstellen für die epitaktische Anordnung von Fullerenen mit E,E–8T6A Komplexen in Mono- und Doppelschichten aus. Mit Hilfe der STM-Tomographie wird die Bildung der Templatschicht überprüft. Die Konformationsstabilität und die Adsorptionsstellen der Monoschichten werden mit der Hilfe von Molekulardynamik-Simulation bestätigt. Die STS-Experimente zeigen die Modifikation der gleichrichtenden Eigenschaften der Makrozyklen durch die Bildung von Donor-Akzeptor-Komplexen in einer dicht gepackten, selbstorganisierten supramolekularen Nanostruktur. Die Kombination von Wirt-Gast-Komplexen mit der Schaltfähigkeit und den elektronischen Transporteigenschafte von makrozyklischen Oligothiophenen prädestinieren diese als Kandidaten für Anwendungen in supramolekular konstruierten Systemen mit gewünschten (opto)elektronischen Eigenschaften. / The present thesis concerns to the self-assembly and the electronic properties of four pi-expanded macrocycles into ordered supramolecular architectures, investigated by means of scanning tunneling microscopy (STM) and spectroscopy (STS) at the solid-liquid interface between organic solutions and the basal plane of graphite. Two macrocycles are the photoisomers Z,Z–8T6A and E,E–8T6A, which contain six ethynylenes and two cis- and trans-ethylenes in opposite positions of the ring, respectively. STM images reveal hexagonally ordered 2D-networks. Current–voltage characteristics confirm the expected donor-like character of the macrocycles. Cyclic STS measurements indicate that Z,Z–8T6A switches to E,E–8T6A after formation of a most stable cationic species. This result represents the first reported electrochemical switching experiment under standard STM conditions. Additionally, the reversible photoisomerization between Z,Z-8T6A and E,E-8T6A upon irradiation was recognized at the solid-liquid interface. Moreover, a self-assembled monolayer of hydrogen-bonded trimesic acid at the solid-liquid interface provides host-sites for the epitaxial ordering of Saturn-like complexes of fullerenes with E,E–8T6A macrocycles in mono- and bilayers. STM tomography verifies the formation of the templated layer, while molecular dynamics simulations corroborate the conformational stability and assign the adsorption sites of the adlayers. STS measurements reveal the modification of the rectifying properties of the macrocycles by the formation of donor-acceptor complexes in a densely packed all-self-assembled supramolecular nanostructure. The combination of host-guest complexation and the switching capabilities and electronics transport characteristics of cyclic oligothiophenes render them candidates for applications in the study of supramolecular engineered systems with desirable (opto)electronic properties.