Fluoroquinolone Analogs, SAR Analysis, and the Antimicrobial Evaluation of 7-Benzimidazol-1-yl-fluoroquinolone in In Vitro, In Silico, and In Vivo Models

Abstract

Structure–activity relationship (SAR) studies allow the evaluation of the relationship between structural chemical changes and biological activity. Fluoroquinolones have chemical characteristics that allow their structure to be modified and new analogs with different therapeutic properties to be generated. The objective of this research is to identify and select the C-7 heterocycle fluoroquinolone analog (FQH 1–5) with antibacterial activity similar to the reference fluoroquinolone through in vitro, in silico, and in vivo evaluations. First, SAR analysis was conducted on the FQH 1–5, using an in vitro antimicrobial sensibility model in order to select the best compound. Then, an in silico model mechanism of action analysis was carried out by molecular docking. The non-bacterial cell cytotoxicity was evaluated, and finally, the antimicrobial potential was determined by an in vivo model of topical infection in mice. The results showed antimicrobial differences between the FQH 1–5 and Gram-positive and Gram-negative bacteria, identifying the 7-benzimidazol-1-yl-fluoroquinolone (FQH-2) as the most active against S. aureus. Suggesting the same mechanism of action as the other fluoroquinolones; no cytotoxic effects on non-bacterial cells were found. FQH-2 was demonstrated to decrease the amount of bacteria in infected wound tissue.

Fluoroquinolones: Action, Synthesis and Applications in Antimicrobial Therapy

“…Cross resistance is common in the case of fluoroquinolones. [12] They are also active against MRSA, multiply-antibiotic-resistant gram negative bacilli, β-lactamase-producing Neisseria gonorrhoeae. At concentrations which are one to four times the minimum inhibitory concentration, the drugs are found to be bactericidal.…”

“…These fluorine qualities influence the drug's biological activity as well as its pharmacokinetics and pharmacodynamics. [12] Following this significant discovery, SAR was investigated for the novel class of drugs known as fluoroquinolones. A variety of substituents were added to the original compounds to create new analogues with improved activity, such as antimicrobial activity, solubility, reduced side effects, improved serum half-life, favorable dosage and dosage form, etc.…”