Design, organocatalytic synthesis, and bioactivity evaluation of enantiopure fluorinated LpxC inhibitors

• Published in: Organic & biomolecular chemistry Vol. 18; no. 3; pp. 5867 - 5878
• Main Authors: Rodríguez-Alvarado, Melanie, Russo, Riccardo, Connell, Nancy D, Brenner-Moyer, Stacey E
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 05.08.2020; Royal Society of Chemistry
• Subjects: Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biological activity; Catalysis; Chemistry; Chemistry, Organic; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorination; Fluorine; Halogenation; High-performance liquid chromatography; Inhibitors; Liquid chromatography; Low molecular weights; Microbial Sensitivity Tests; Molecular Structure; Molecular weight; Physical Sciences; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ZINC-DEPENDENT DEACETYLASE; ANALOGS; PSEUDOMONAS-AERUGINOSA; BIOSYNTHESIS; ESCHERICHIA-COLI; CONSTRUCTION; CHALLENGES
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d0ob01125h

Enantiopure compounds with a strategically incorporated fluorine atom intended to enhance LpxC inhibition have been synthesized using an organocascade fluorination reaction as the key step. These are the first low molecular weight LpxC inhibitors to contain a fluorine atom on a critically important chiral center that is substituted with two pharmacophoric moieties, and were thusly designed to provide new SAR data for this class of compounds. Fluorinated compounds were evaluated against ESKAPE pathogens and exhibited MICs of ≤12.5 μg mL −1 against Pseudomonas aeruginosa . Enantiopure compounds designed to enhance LpxC inhibition via strategic incorporation of a fluorine atom were synthesized using an organocascade fluorination reaction as the key step.