Physicochemical interpretation, with qsar/sar analysis, of how the barriers of pseudomonas aeruginosa bacteria were penetrated by parasubstituted n-arylbenzylimines: Synthesis, characterization, and in vitro antibacterial effect

Resistance to antibiotics is a growing problem that imposes limitations on current therapy around the world. The World Health Organization (WHO) recommends creating new antibacterial molecules to inhibit the most harmful bacteria by aiming at specific targets. Among such bacteria is multi-drug resistant Pseudomonas aeruginosa, a Gram-negative bacterium responsible for 70% of invasive infections worldwide. The aim of this investigation was to synthesize N-arylbenzylimines, examine their antibacterial activity against P. aeruginosa ATCC 27853, and determine their physicochemical properties by quantitative structure-activity relationship (QSAR/SAR) analysis. Seven N-arylbenzylimines were synthesized with yields ≥50%, all with the Econfiguration (as shown by NMR spectra and confirmed with X-ray diffraction). The in vitro microbiological evaluations were carried out with the Kirby-Bauer method, following the guidelines of the Clinical & Laboratory Standards Institute (CLSI). The N-arylbenzylimines produced a very good antibacterial effect on P. aeruginosa, with minimum inhibitory concentration (MIC) values ranging from 198.47-790.10 µM, calculated by the Hill method. Based on the slopes of the concentration-response curves, the mechanism of action is different between the test compounds and aztreonam, the reference drug. The QSAR study performed with in vitro experimental data found that biological activity correlates most significantly with molecular size, followed by lipophilicity and electronic effects. According to the SAR analysis of antibacterial activity, molecules cross bacterial barriers differently if they bear substituents with resonance versus inductive electronic effects. The physicochemical data presently described are of utmost importance for designing and developing new molecules to combat the pathogenicity and resistance of P. aeruginosa.