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Property‐Guided Synthesis of Aza‐Tricyclic Indolines: Development of Gold Catalysis En Route
Author(s) -
Barbour Patrick M.,
Wang Wei,
Chang Le,
Pickard Kasey L.,
Rais Rana,
Slusher Barbara S.,
Wang Xiang
Publication year - 2016
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201501101
Subject(s) - chemistry , tricyclic , catalysis , combinatorial chemistry , organic chemistry , stereochemistry
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‐resistant S. 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.