UC San Diego

This dissertation is divided into three chapters that cover various topics in medicinal chemistry. Chapter 1 focuses on the design, synthesis, and physicochemical evaluation of a series of N-acylsulfonamides and related bioisosteres. The N-acylsulfonamide is a feature of the pharmacophore of many biologically active molecules, and several bioisosteres have been developed over the years that provide opportunities to modulate both structure and physicochemical properties. A structure-property relationship study was conducted based on matched molecule pairs, in which the N-acylsulfonamide moiety of template structure is replaced with a series of bioisosteres. The data presented, which include an assessment of relative changes in acidity, permeability, lipophilicity, and intrinsic solubility, provide a basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design. Chapter 2 focuses on the development of inhibitors of the HEG1-KRIT1 protein-protein interaction (PPI) as candidate pharmacological probes and therapeutics. In endothelial cells (ECs), the HEG1-KRIT1 PPI has been implicated in vascular disease and development. Inhibitors of this PPI may be desirable as research tools and/or candidate therapeutics. Through high-throughput screening and structure-based design, small molecules belonging to the 2-hydroxy-1-naphthaldehyde (HNA) class were identified as bona fide inhibitors of HEG1-KRIT1. The mode of action of the HNA was further elucidated by assessing its binding mode, specificity and selectivity, and inhibition kinetics. Through structure-based design, >50 HNA analogs were designed, and several improved inhibitors were identified. HNA analogs led to upregulation of blood flow responsive genes Krüppel-like factors KLF2 and KLF4, which are transcriptional regulators linked to anti-inflammatory, anti-thrombotic, and anti-proliferative effects in ECs. Chapter 3 focuses on the structure-activity relationship (SAR) of candidate therapeutics for schistosomiasis, a neglected tropical disease caused by parasite Schistosoma mansoni. Prior studies identified a series of thiophenyl phenylpyrimidines (TPPs) as promising candidates against schistosomiasis due to a long-lasting, paralytic effect against S. mansoni. To further elucidate the SAR and identify preferred candidate anti-schistosomiasis agents, a set of >30 TPPs were designed, synthesized, and evaluated against S. mansoni. These studies resulted in the identification of more potent TPP analogs with improved drug-like properties.