Journal
NEW JOURNAL OF CHEMISTRY
Volume 45, Issue 18, Pages 8166-8177Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1nj00150g
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Funding
- Research Foundation of Erciyes University [FBA-2017-7340]
- Sonnenfeld Foundation
- Ministry of Education, Science and Technological Development of the Republic of Serbia [451-03-9/2021-14/200042]
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Sulfonamides, as the oldest synthetic antibacterial agents, have been compromised due to widespread resistance. Research on modified sulfathiazole derivatives has shown new compounds with better antibacterial activities against Staphylococcus aureus, particularly when introducing bulky lipophilic substituents. However, the mechanisms behind these antibacterial activities are still not completely understood.
Sulfonamides represent the oldest synthetic antibacterial agents; however, their central position in controlling bacterial diseases has been seriously damaged by the development of widespread resistance. Herein, we revisited sulfathiazole, a commercial member of antibacterial sulfa drugs, intending to overcome sulfonamide resistance and identify new drug candidates through molecular modifications. We synthesized twelve sulfonamides (SA1-SA12) by replacing the amino group on the phenyl ring with various substituents and introducing a thiophene ring on the core scaffold of sulfathiazole. The obtained compounds and additionally two commercial sulfonamides, sulfathiazole and sulfadiazine, were extensively screened for their antimicrobial activities. The results indicated that new sulfonamides, unlike traditional ones, were selectively effective against various Staphylococcus aureus strains. Introducing a bulky lipophilic substituent at the para position of the phenyl ring significantly increased the antibacterial activities of the compounds against Staphylococcus aureus. The compounds demonstrating favourable selectivity indices were further evaluated for their membrane potential perturbation and DNA interaction properties. The obtained data showed that these are not supporting mechanisms for the antibacterial activities of the modified sulfathiazole derivatives. In order to rationalize the activity of the three most active compounds, SA7, SA11 and SA12, against S. aureus ATCC 25923, their binding hypotheses within the catalytic site of Staphylococcus aureus dihydropteroate synthase, the validated target enzyme of sulfonamides, were generated via molecular docking and further dissected using molecular dynamics simulations and dynamic 3D pharmacophores (dynophores).
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