Synthesis of Pyrrolo[3,2-c]quinolin-4-one Structure For Development of Antivirulence Pro-Quorum Sensing LuxO Inhibitors of V. cholerae

Abstract

Antibiotic resistance is a growing problem in the treatment of cholera outbreaks. One way to address this challenge is by decreasing virulence factor production in V. cholerae through activation of its quorum sensing system. In this work, several approaches are explored for the synthesis of a pyrrolo[3,2-c]quinolin-4-one heterocyclic core structure for a potential small-molecule inhibitor of LuxO. LuxO is a transcriptional regulator involved in the quorum sensing response of V. cholerae, and ultimately affects the production of cholera toxin (CT) and toxin coregulated pilus (TCP). Inhibition of LuxO via this small-molecule is expected to lead to attenuated virulence and provide a potential therapeutic alternative that is less likely to stimulate the emergence of resistant cholera strains. Four synthetic routes for the production of this three-ring heterocyclic core were studied and evaluated in terms of practicality for the synthesis of the target molecule and related structures. The ring-forming reactions use 1) an azide intermediate and subsequent pyrolysis, 2) aldol intramolecular reactions, 3) a Pd-catalyzed cross-coupling reaction, and 4) CuI catalyzed ring-formation. The route employing CuI was found to be the most successful for synthesis of the desired heterocycle, and enables the creation of a focused library of potential LuxO inhibitors.