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

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. ... mehrcoli 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,
bahaa.youssif@pharm.aun.edu.eg,
bgyoussif2@gmail.com
Stefan Bräse,
braese@kit.edu
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.