Novel Pyrazoles As Potent Growth Inhibitors of Staphylococci, Enterococci and Acinetobacter Baumannii Bacteria

Abstract

Background: Methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and Acinetobacter baumannii cause serious antibiotic-resistant infections. Finding new antibiotics to treat these infections is imperative for combating this worldwide menace. Methods & Results: In this study, the authors designed and synthesized potent antimicrobial agents using 4-trifluoromethylphenyl-substituted pyrazole derivatives. In addition to their potency against planktonic bacteria, potent compounds effectively eradicated S. aureus and Enterococcus faecalis biofilms. Human cells tolerated these compounds with good selectivity factors. Furthermore, the authors provide evidence for the mode of action of compounds based on time-kill kinetics, flow cytometry analysis of propidium iodide-treated bacteria and oxygen uptake studies. Conclusion: This study demonstrated 20 novel compounds with potent antibacterial activity that are tolerated by human cell lines.

Development and Antibacterial Properties of 4-[4-(Anilinomethyl)-3-phenylpyrazol-1-yl]benzoic Acid Derivatives as Fatty Acid Biosynthesis Inhibitors

“…The Hantzsch ester in refluxing toluene without any catalyst was the best reducing agent for this reaction. In our previous studies, we found that lipophilic substituents on the aniline moiety showed potent activity against bacterial strains. − Therefore, we focused on the lipophilic substituents on the aniline moiety in this report (Scheme ).…”

“…Like monofluoro derivatives (5 and 6), difluorosubstituted compound (17) did not show any significant antibacterial activity. The chloro and fluoro derivative (18) is a moderate inhibitor of tested staphylococci strains but is not active against enterococci bacteria. 3,4-Dichloro derivative (19) is very potent against staphylococci strains with MIC values as low as 0.5 μg/mL, but this compound is not effective against enterococci strains as well.…”

“…In our effort to find potent antibacterial agents, − we have reported the synthesis of fluorophenyl-substituted pyrazole-derived hydrazones ( PH ) as potent antibacterial agents (Figure ). , Although these compounds showed good activity in vitro , most of the hydrazones are hydrolytically and metabolically unstable. , We have also found that trifluoromethylphenyl-substituted pyrazole derivatives ( TA ) are potent antibacterial agents with specific activity against Gram-positive bacteria .…”

Development of 4-[4-(Anilinomethyl)-3-phenyl-pyrazol-1-yl] Benzoic Acid Derivatives as Potent Anti-Staphylococci and Anti-Enterococci Agents

“…Membrane permeabilization using propidium iodide (PI) was further quantified using flow cytometry analysis as described previously [ 37 ]. Briefly, exponential phase S. aureus ATCC 700699 cells grown in CAMHB were harvested at 4000 rpm for 10 min, followed by washing twice with PBS, and then diluting to ~10 5 CFU/mL in the same buffer.…”

Design and Synthesis of Novel Antimicrobial Agents

“…Recently, the trifluoromethyl group (-CF3) has attracted the attention for its ability to work as a bioisostere in which it increases the lipophilicity, metabolic stability, and can alter receptor binding [ 223 ]. Alkhaibari et al [ 224 ] designed potent antimicrobial agents by using 4-trifluoromethylphenyl-substituted pyrazole derivatives and evaluated their potency against planktonic bacteria, S. aureus and Enterococcus faecalis . The starting material ( 147 , Scheme 13 ) was synthesized by reacting 4-(trifluoromethyl)phenylhydrazine ( 145 ) and 4-acetylbenzoic acid ( 146 ).…”