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 (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h 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 S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC 50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i 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 OPEN ACCESS EDITED BY Anton V. Dolzhenko, Monash University, Australia REVIEWED BY Juliana Amorim, Catholic University of Cuenca, Ecuador Vijaya Bhaskar Baki, University of California, Riverside, United States Chunli Wu, Zhengzhou University, China *CORRESPONDENCE Bahaa G. M. Youssif, [email protected], [email protected] Stefan Bräse, [email protected] RECEIVED 17 April 2024 ACCEPTED 24 May 2024 PUBLISHED 07 June 2024 CITATION Al-Wahaibi LH, Mahmoud MA, Alzahrani HA, Abou-Zied HA, Gomaa HAM, Youssif BGM, Bräse S and Rabea SM (2024), Discovery of new Schiff bases of the disalicylic acid scaffold as DNA gyrase and topoisomerase IV inhibitors endowed with antibacterial properties. Front. Chem. 12:1419242. doi: 10.3389/fchem.2024.1419242 COPYRIGHT © 2024 Al-Wahaibi, Mahmoud, Alzahrani, Abou-Zied, Gomaa, Youssif, Bräse and Rabea. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Chemistry frontiersin.org01 TYPE Original Research PUBLISHED 07 June 2024 DOI 10.3389/fchem.2024.1419242 compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development