Antibacterial and Solubility Optimization of Thiomuracin A

Synthetic
studies of the antimicrobial secondary metabolite thiomuracin
A (1) provided access to analogues in the Northern region
(C2–C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked
analogues (e.g., 3) 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 C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed
both potent antibacterial activity and high aqueous solubility.