33 KJEMI 4 2025 compounds or the development of new drugs and inhibitors. Alternative strategies are also being explored, including novel drug delivery systems. Recently, an approach based on exploiting the ability of MBLs to hydrolyze β-lactams has been investigated using cephalosporin prodrugs. The reported conjugates consisted of aromatic thiol-based MBL inhibitors linked to a cephalosporin scaffold that was designed to release the inhibitors upon enzymatic hydrolysis.The goal of the current work was to extend the concept of thiol-releasing conjugates to aliphatic thiolbased MBL inhibitors, as aliphatic thiols have been described to lack the required leaving group properties. The work is based on the hypothesis that fluorination in the vicinity of the thiol moiety can be used as a tool in the design of aliphatic thiol-releasing conjugates. Thus, the initial focus was on designing fluorinated captopril analogues, exhibiting inhibitory activity against relevant MBLs, and investigating the influence of fluorination on their inhibitory effect. A library of fluorinated thiols, of which several exhibited IC50 values in the low micromolar region against NDM-1, was developed. Furthermore, the use of fluorinated inhibitors as probes for NMR-based binding studies was demonstrated on a representative compound. Universitet og dato: UiT, Kjemisk institutt, 25. oktober, 2024 Navn: Sahil Gahlawat Veiledere: Hovedveileder: Professor Kathrin H. Hopmann, Co-veiledere: Principal scientist Per-Ola Norrby, AstraZeneca og Forsker Abril C. Castro, UiO Opponenter: First opponent: Professor Vidar Remi Jensen - Department of Chemistry, University of Bergen Second opponent: Researcher Dr. Cristina Trujillo - Computational Organic Chemistry Group, University of Manchester, UK Committee coordinator: Researcher Dr. Bin Gao, Department. of Chemistry, UiT Tittel på prøveforelesning: In Silico Catalyst Design: History, State of the Art, and Perspectives Tittel på avhandling: Computational Approach to Molecular Reactivity of Transition Metal Complexes Sammendrag: Transition metal (TM) catalysts are indispensable in industrial operations and organic synthesis due to their unique properties, such as variable oxidation states, rich coordination chemistry, and ability to enable electron transfer processes. These properties allow them to activate a diverse range of substrates by lowering activation energies, and the catalysts can be fine-tuned to enhance chemo-, regio-, and stereoselectivities for desired products. One of the prominent and requisite uses of TM catalysts is in the conversion of CO2 to higher-value products.With the advent of climate change, scientists are looking for renewable carbon sources to replace fossil fuels. One promising option is CO2, a non-toxic and highly abundant greenhouse gas. However, the use of CO2 in chemical synthesis is limited due to its kinetic and thermodynamic stability. TM catalysts have the potential to address these challenges, making the study of these catalysts vital for developing effective CO2 activation processes. Nonetheless, their complex electronic structures, ligand coordination dynamics, assorted reaction pathways, broad spectroscopic signals, and environmental sensitivity make it difficult to study them experimentally. Computational chemistry, with its explanatory and predictive power, can help elucidate their intricate behaviors and interactions.In this thesis, I examined TM-mediated processes using computational chemistry techniques, particularly density functional theory (DFT), to identify transient species like intermediates and transition states, and to understand their nuclear and electronic structures. My research included an analysis of the factors leading to enantioenriched carbamate formation from CO2, catalyzed by an Ir-based complex (Paper I). Another study investigated the CO2-insertion mechanism into diverse Pd-alkyl complexes and its relationship with the experimentally observed reaction kinetics, in close collaboration with an experimental group from Yale University (Paper II). I also collaborated with Aarhus University to examine diverse mechanistic pathways for a Nicatalyzed aryl-alkyl cross-coupling reaction with CO (originating from CO2) insertion (Paper III). Additionally, I employed state-of-the-art computational techniques, involving ab initio molecular dynamics simulations (AIMD), to precisely predict 19F nuclear magnetic resonance (NMR) chemical shifts in a Ni-fluoride complex (Paper IV).
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