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-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.

Tetracyclic indolines as a novel class of β-lactam-selective resistance-modifying agent for MRSA

“…Further biological profiling studies showed that some hits from the screens, such as the ring-opened fused indoline Of1 ( 1 , Figure 1) and tetracyclic indolenine 2, selectively re-sensitizes MRSA to β-lactam antibiotics [33]. Aza-tricyclic indoline 3 (Figure 1) was developed to optimize the physiochemical properties Of1 [39]. Herein, we report the antibiotic profiling and structure-activity relationship (SAR) studies of alkylated fused indoline Kf18 ( 4 , Figure 1), another hit compound from our previous screens [33], with a distinct tetracyclic indoline scaffold.…”

Heteroarene‐tethered Functionalized Alkyne Metamorphosis

“…The rationalized mechanism of this tandem cyclization process involves π‐activation, nucleophilic indole addition in 6‐ exo‐dig mode and second nucleophilic amine addition to the iminium intermediate followed by subsequent protodeauration (Scheme 83). [97] …”

“…The rationalized mechanism of this tandemc yclization process involves p-activation, nucleophilic indole addition in 6-exo-dig mode and second nucleophilic amine additiont ot he iminium intermediate followed by subsequentprotodeauration (Scheme 83). [97] In 2018, Maestri and co-workers developed ap rotocol for the synthesis of tetrahydro-b-carbolines from the corresponding N-propargyl tryptamines jointly catalyzed by Pd 0 and benzoic acid. Treatment of tryptamined erivative 332 with 5mol % Pd(PPh 3 ) 4 and 30 mol %b enzoic acid furnished the desired carboline derivatives 334 in good yields.…”

Bioinspired Discovery of Chemical Reactions and Biological Probes

“…24,25 It is worth mentioning that another gold-catalyzed cyclization was developed to facilitate the synthesis of the aza-tricyclic indoline core structure of 1 for further inquiry. 26 This study yielded compound 2, which had greatly improved pharmacokinetic properties and water solubility compared to 1. 26 These properties were desired because the biological profile and poor water solubility of 1 had prevented it from use in animal studies.…”

“…26 This study yielded compound 2, which had greatly improved pharmacokinetic properties and water solubility compared to 1. 26 These properties were desired because the biological profile and poor water solubility of 1 had prevented it from use in animal studies. Ongoing synthesis and testing of indole alkaloid-like compounds revealed other structures that exhibited RMA activity against MRSA, such as compound 3, which was discovered from a collection of bridged tetracyclic indolenines.…”