Re-evolution of the 2-Phenylquinolines: Ligand-Based Design, Synthesis, and Biological Evaluation of a Potent New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors to Combat Antimicrobial Resistance

Abstract

Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.

Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives

“…On the other hand, alterations of the basic terminus of the amide side chains at the ortho-position of the 2-phenyl group led to varying effects on antibacterial activity. Compounds 5a 4 , 5a 3 , 5a 2 and 5b 4 showed better antibacterial activity than Compounds 5a 6 , 5a 7 and 5b 6 against S. aureus and B. subtilis, indicating that rigid cyclic amino group at 2-phenyl is suitable for the anti-Gram-positive bacteria activity. On the contrary, for E. coli, Compounds 5a 6 , 5a 7 and 5b 6 exhibited stronger activity than the compounds with rigid cyclic amino substituents(5a 2 , 5a 3 , 5a 4 , 5b 4 ), suggesting that the flexible chain amino group at 2-phenyl can enhance antibacterial activity against E. coli.…”

“…Compound 4a was reacted with 3-dimethyl aminopropyl amine according to GP2 to give the desired product 5a 6 . After column chromatography with CH 2 Cl 2 /MeOH/Et 3 N (85:2:0.1) elution, a brown solid was obtained in a 55% yield.…”

“…Compound 4b was reacted with 3-dimethyl aminopropyl amine according to GP2 to give the desired product 5b 6 The in vitro antibacterial activities of newly-synthesized Compounds 5a 1 -5a 7 and 5b 1 -5b 6 were evaluated for their antibacterial activities against S. aureus (ATCC29213), B. subtilis (ATCC6633), E. coli (ATCC25922), P. aeruginosa (ATCC9027) and MRSA (ATCC43300) bacterial strains by the agar diffusion method [36]. Fifteen to twenty milliliters of agar media were poured into each petri dish.…”

“…Furthermore, many drug-resistant pathogens have emerged in recent years because of the increasing use or abuse of antibacterial agents [2,3], and antibiotic drug resistance has become a growing problem across the globe in recent years [4]. Currently, many advances for combating antimicrobial resistance have been achieved, such as modifications/improvements of existing antibiotic classes, some anti-adhesion agents against Gram-positive pathogens [5] and efflux pump inhibitors (EPIs) [6]. However, this problem has not been completely resolved.…”

“…Some quinoline-4-carboxylic acid derivatives exhibited certain antibacterial activity [20,21]. Furthermore, a literature review revealed that the presence of an aryl ring at the second position of quinoline-4-carboxylic acid derivatives exhibits good antibacterial activity for the target compound and plays a significant role in the development of new antibacterials (Figure 1) [6,15,[22][23][24][25][26][27], and they are very suitable for further modifications to obtain more effective antibacterial agents. In addition, the structure-activity relationship (SAR) studies of quinolones have indicated that the introduction of a basic group in the quinoline is useful for regulating the physicochemical property and influencing their potency, spectrum and safety [28,29].…”