Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of <b>1</b> included removing the C2–C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to <b>1</b>. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of <b>2</b>, a structurally simplified and chemically stable analogue of <b>1</b> which retained potent antibiotic activity

Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

The X-ray structure of the previously reported PPARδ modulator <b>1</b> bound to the ligand binding domain (LBD) revealed that the amide moiety in <b>1</b> exists in the thermodynamically disfavored <i>cis</i>-amide orientation. Isosteric replacement of the <i>cis</i>-amide with five-membered heterocycles led to the identification of imidazole <b>17</b> (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested <i>in vivo</i> in mice and <i>in vitro</i> in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); <b>17</b> altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients

Antibacterial and Solubility Optimization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) provided access to analogues in the Northern region (C2–C10). Selective hydrolysis of the C10 amide of lead compound <b>2</b> and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., <b>3</b>) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster <i>C. difficile</i> models of disease. Optimal efficacy in the hamster model of <i>C. difficile</i> was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility