Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

作者：Basarab Gregory S^*; Brassil Patrick; Doig Peter; Galullo Vincent; Haimes Howard B; Kern Gunther; Kutschke Amy; McNulty John; Schuck Virna J A; Stone Gregory; Gowravaram Madhusudhan

来源：Journal of Medicinal Chemistry, 2014, 57(21): 9078-9095.

DOI：10.1021/jm501174m

The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.

• 出版日期2014-11-13