1. Novel quinazoline sulfonamide-based scaffolds modulate methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in immunodeficient irradiated model: Regulatory role of TGF-β.
- Author
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Soliman AM, Ghorab WM, Ghorab MM, ElKenawy NM, El-Sabbagh WA, and Ramadan LA
- Subjects
- Animals, Mice, Molecular Structure, Structure-Activity Relationship, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta antagonists & inhibitors, Dose-Response Relationship, Drug, Humans, Molecular Docking Simulation, Pneumonia, Staphylococcal drug therapy, Methicillin-Resistant Staphylococcus aureus drug effects, Sulfonamides chemistry, Sulfonamides pharmacology, Sulfonamides chemical synthesis, Quinazolines pharmacology, Quinazolines chemistry, Quinazolines chemical synthesis, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents chemical synthesis
- Abstract
A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-β (TGF-β). Compound 3n showed a non-significant deviation of lung TGF-β1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-β and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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