title: Property-Guided Synthesis of Aza-Tricyclic Indolines: Development of Gold Catalysis En Route.
abstract: Antibiotic resistance is a worldwide public health threat that needs to be addressed by improved antibiotic stewardship and continuing development of new chemical entities to treat resistant bacterial infections. Compounds that work alongside known antibiotics as combination therapies offer an efficient and sustainable approach to counteract antibiotic resistance in bacteria. Guided by property-based analysis, a series of aza-tricyclic indolines (ATIs) were synthesized to optimize their physiochemical properties as novel combination therapies with β-lactams to treat methicillin-resistantS. aureus(MRSA) infections. A novel and highly efficient gold-catalyzed tandem cyclization was developed to facilitate the synthesis of these ATIs. One guanidine-containing ATI was discovered to possess both improved anti-MRSA activity and lower mammalian toxicity both in vitro and in vivo. In addition, it also showed significantly enhanced aqueous solubility and metabolic stability. These results indicated that the ATIs are a novel class of anti-MRSA agents suitable for further evaluations as adjuvant therapy in animal model studies.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Barbour
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Chang
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Pickard
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
keywords: antibiotics; drug design; gold; heterocycles; homogeneous catalysis