Broad-spectrum cyclic boronate β-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability. (15th May 2022)

• Record Type: Journal Article
• Authors: Raja Reddy, K.; Totrov, Maxim; Lomovskaya, Olga; Griffith, David C.; Tarazi, Ziad; Clifton, Matthew C.; Hecker, Scott J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 62(2022)
• Publication Date: 2022-05-15
• Subjects: BLI β-lactamase inhibitor -- KPC Klebsiella pneumoniae carbapenemase -- Leu leucine -- Trp tryptophan -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- HOBt hydroxybenzotriazole -- TBSOTf tert-butyldimethylsilyl triflate -- DIPEA diisopropylethylamine -- HATU hexafluorophosphate azabenzotriazole tetramethyluronium; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116722
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Early efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important β-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52–69%) compared to the ring-opened carboxylate salt (9%).