Abstract
The global spread of bacterial resistance to drugs used in therapy requires new potent and safe antimicrobial agents. DNA gyrases represent important targets in drug discovery. Schiff bases, thiazole, and triazole derivatives are considered key scaffolds in medicinal chemistry. Fifteen thiazolyl-triazole Schiff bases were evaluated for their antibacterial activity, measuring the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against Gram-positive (Staphylococcus aureus, Listeria monocytogenes) and Gram-negative (Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa) bacteria. The inhibition of S. aureus and S. typhimurium was modest. Compounds B1, B2, and B9 showed a similar effect as ciprofloxacin, the antimicrobial reference, against L. monocytogenes. B10 displayed a better effect. Derivatives B1, B5–7, B9, and B11–15 expressed MIC values lower than the reference, against L. monocytogenes. B5, B6, and B11–15 strongly inhibited the growth of P. aeruginosa. All compounds were subjected to an in silico screening of the ADMET (absorption, distribution, metabolism, elimination, toxicity) properties. Molecular docking was performed on the gyrA and gyrB from L. monocytogenes. The virtual screening concluded that thiazolyl-triazole Schiff base B8 is the best drug-like candidate, satisfying requirements for both safety and efficacy, being more potent against the bacterial gyrA than ciprofloxacin.
Highlights
The alarming worldwide spread of the bacterial resistance, to most of the drugs available nowadays in therapy [1,2,3], urgently requires the development of new effective antibacterial agents.The DNA topoisomerases manage the topological state of the DNA in the cell, being involved in replication, transcription, recombination, and chromatin remodeling
It can be observed that B5, B6, and B11–15 had minimum inhibitory concentration (MIC) lower than the antibacterial used as the reference, while B9 had the same active concentration, in agreement with the inhibitory zone diameters
The determination of the inhibitory zone diameters showed that compounds B1, B2, B9, and B10 were the most potent against Gram-positive L. monocytogenes, with an equal or a superior effect (B10), compared to ciprofloxacin
Summary
The alarming worldwide spread of the bacterial resistance, to most of the drugs available nowadays in therapy [1,2,3], urgently requires the development of new effective antibacterial agents. Quinolones are the only class of DNA gyrase inhibitors that are clinically used Their effect is based on the inhibition of the gyrA subunit, perturbing the DNA cleavage and the introduction of negative supercoils into the bacterial DNA [13]. The isosteric replacement of the quinolones’ 3-carboxyl group, essential for gyrase binding, with an amino-thiazolic fragment [27] or other azoles (thiazoles, triazoles), led to molecules with improved antimicrobial effects and a wider spectrum of activity. These compounds express fewer side effects and have a better capacity in overcoming bacterial resistance [28,29]. It can be observed that Schiff base B10 expressed the most pronounced antibacterial effect
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