Synthesis, In Silico, and In Vitro Evaluation of Long Chain Alkyl Amides from 2-Amino-4-Quinolone Derivatives as Biofilm Inhibitors

Abstract

Infection from multidrug resistant bacteria has become a growing health concern worldwide, increasing the need for developing new antibacterial agents. Among the strategies that have been studied, biofilm inhibitors have acquired relevance as a potential source of drugs that could act as a complement for current and new antibacterial therapies. Based on the structure of 2-alkyl-3-hydroxy-4-quinolone and N-acylhomoserine lactone, molecules that act as mediators of quorum sensing and biofilm formation in Pseudomonas aeruginosa, we designed, prepared, and evaluated the biofilm inhibition properties of long chain amide derivatives of 2-amino-4-quinolone in Staphylococcus aureus and P. aeruginosa. All compounds had higher biofilm inhibition activity in P. aeruginosa than in S. aureus. Particularly, compounds with an alkyl chain of 12 carbons exhibited the highest inhibition of biofilm formation. Docking scores and molecular dynamics simulations of the complexes of the tested compounds within the active sites of proteins related to quorum sensing had good correlation with the experimental results, suggesting the diminution of biofilm formation induced by these compounds could be related to the inhibition of these proteins.

Heterocycles in Medicinal Chemistry

“…A series of 1-amino-2-aryliden- amine-1,2-(dicyano)ethenes as antifungal agents effective against yeasts were reported by Bettencourt et al [17]. Several synthesized long chain alkyl amides of 2-amino-4-quinolones demonstrated a high inhibition of biofilm formation of Pseudomonas aeruginosa [18].…”

Structural modification of the Pseudomonas aeruginosa alkylquinoline cell–cell communication signal, HHQ, leads to benzofuranoquinolines with anti-virulence behaviour in ESKAPE pathogens

“…On the other hand, both compounds 2 and 3 were able to suppress swarming motility in P. aeruginosa, while the full-length alkyl chain compound 1 did not. Espinosa-Valdés et al have previously shown that shortening the alkyl chain of 2-amino-4-quinolone (AQ) derivatives can lead to loss of activity against P. aeruginosa biofilms [48]. Several studies have shown that a wide range of structural modifications in AQ analogues are capable of enhancing or maintaining anti-biofilm, anti-swarming and anti-pyocyanin production activities [30,[48][49][50][51][52], suggesting promiscuity within the framework from an antagonistic perspective.…”

“…The relatively few existing studies on the interspecies activity of the AQ signalling framework and its ability to control the virulence profiles of other microbes means that there is currently no concise understanding with respect to the possible ligand–receptor interactions that underpin AQ-mediated interspecies communication. While compounds with a shorter alkyl chain have been shown to bind more effectively to the LasR quorum sensing receptor protein than even the agonist signal molecule [ 48 ], there is no evidence in this current study of receptor binding at the interspecies level [ 44, 61 ]. Co-infection between P. aeruginosa and S. aureus promotes changes in genetic regulation resulting in a conversion of essential genes to expendable genes in co-infection, as observed in a murine wound model [ 44 ].…”

Nanocatalyzed Synthetic Approach for the Quinazolinone and Quinazoline Derivatives: A Review (2015 – Present)

“…At a concentration of 20 M, the two most effective compounds (a) and (b) likewise condensed the creation of pyocyanin by between 62.6 and 68.2%. None of the investigated substances had an impact on bacterial growth, indicating that the derivatives' activity might have been modulated by QS 21 .…”