Discovery of new Schiff bases of the disalicylic acid scaffold as DNA gyrase and topoisomerase IV inhibitors endowed with antibacterial properties

Abstract

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (<b>5a-k</b>) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets <b>5f-k</b> exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound <b>5h</b> demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against <i>S. aureus</i>, <i>E. coli</i>, and <i>P. aeruginosa</i>. <b>5h</b> had a MIC value of 0.050 μg/mL against <i>B. subtilis</i>, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives <b>5f</b>, <b>5h</b>, <b>5i</b>, and <b>5k</b> against <i>E. coli</i> DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on <i>E. coli</i> DNA gyrase, with IC₅₀ values ranging from 92 to 112 nM. These results indicate that <b>5f</b>, <b>5h</b>, <b>5i</b>, and <b>5k</b> are more effective than the reference novobiocin, which had an IC₅₀ value of 170 nM. Compounds <b>5f</b>, <b>5h</b>, <b>5i</b>, and <b>5k</b> were subjected to additional assessment against <i>E. coli</i> topoisomerase IV. Compounds <b>5h</b> and <b>5i</b>, which have the highest efficacy in inhibiting <i>E. coli</i> gyrase, also demonstrated promising effects on topoisomerase IV. Compounds <b>5h</b> and <b>5i</b> exhibit IC₅₀ values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC₅₀ value of 11 µM. Docking studies demonstrate the potential of compound <b>5h</b> as an effective dual inhibitor against <i>E. coli</i> DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.