Synthesis and Antibacterial Activity of a Novel Series of Potent DNA Gyrase Inhibitors. Pyrazole Derivatives

Abstract

We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.

Mechanism of Inhibition of DNA Gyrase by ES‐1273, a Novel DNA Gyrase Inhibitor

“…To improve ES-0615 inhibitory activity against DNA gyrase and its antibacterial action, a series of pyrazole derivates were synthesized and ES-1273 ( Fig. 1) was finally found as the most promising compound (24). ES-1273 inhibited DNA gyrase supercoiling activity with an IC 50 value of 8 µg/ml and showed potent antibacterial activity against all the strains studied (MIC ϭ 2 µg/ml, Table 1).…”

“…Using this assay, we have identified a pyrazole derivative (ES-0615) as a DNA gyrase inhibitor. Optimization of ES-0615 led to the discovery of ES-1273, which has potent inhibitory activity against DNA gyrase and exhibits the same in vitro antibacterial activity against multi-drug resistant strains as that against susceptible strains (24).…”

Synthesis of 1-phenyl-3-(4’-nitrophenyl)-5-(3’,4’-dimethoxy-6’-nitrophenyl)-2-pyrazoline and its antibacterial activity

“…The difference of substituens affected the activity because they were the side that enabled to interact with protein target of bacteria cell. The interactions that may be occurred were hydrogen bonding, ionic and liphopilic [10]. In addition, the strains also worked on the activity due to selectivity of active compounds.…”

“…Very high rates of resistance have been observed in all WHO regions in common bacteria (for example, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus) that cause common health-care associated and community-acquired infections (urinary tract infections, wound infections, bloodstream infections and pneumonia [9]. The resistances of microbial, especially bacterial against β-lactams antibacterial have reported few decades ago [10,11]. Generally, there are mechanisms of bacterial became resistant, such as acquisition of exogenous resistance genes [11], mutations in side of drug target, over-production of drug targets, modification of cell permeability by loss or mutagenesis of porins, and drug inactivation by the enzyme degradation [12].…”

“…Tanitame et al [10] reported that the increased in lipofilicity of pyrazoline compound had role in antibacterial activity. Besides that, methoxyphenyl substituted at C5 could increase the strength of antibacterial [14].…”