A mild catalyzed imino Diels-Alder reaction for the synthesis of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide derivatives as regulators of Quorum Sensing in Pseudomonas aeruginosa

Abstract

Bacterial resistance is one of the major global public health problems. In addition, virulence factors promoted multiple drug resistance through cell-to-cell communications by molecules within microbial communities, denominated Quorum Sensing (QS). The regulation of QS by small molecules appears as a therapeutic alternative through the use of synthetic analogs of agonists. The present work developed the construction of a series of derivatives of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl) formamide (1a-h) via Povarov-type sequential reactions to deliver the tetrahydroquinoline (THQ) derivatives in moderate to good yields (24–78%). To evaluate the potential in molecular diversity of THQ-type autoinducers, a study of these agents as potential inhibitors of bacterial growth and virulence factors involved in QS systems on P. aeruginosa was carried out both as antibacterial evaluation on E. coli strain. THQs showed significant activity values for molecules with halogen substituents at the C-6 position (-F, -Cl, and I), revealing at a concentration of 75 µg/mL a percentage inhibition between 27 and 40%. Furthermore, autoinducers with halogen substitutes in phenotypic studies on P. aeruginosa showed good results. Also, they exhibited weak formation of both biofilm and low pyocyanin formation, which are indicators of virulence in P. aeruginosa. Overall, the results suggest that compound N-(6-fluor-2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide (1a) stands out as the most representative within this series of THQ derivatives.

Keywords

• Antibacterial resistance
• Quorum Sensing
• Synthetic inhibitors
• Tetrahydroquinolines