Discovery of Benzopyrone-Based Candidates as Potential Antimicrobial and Photochemotherapeutic Agents through Inhibition of DNA Gyrase Enzyme B: Design, Synthesis, In Vitro and In Silico Evaluation

Abd El-Haleem, Akram; Ammar, Usama; Masci, Domiziana; El-Ansary, Sohair; Abdel Rahman, Doaa; Abou-Elazm, Fatma; El-Dydamony, Nehad

Abstract

Bacterial DNA gyrase is considered one of the validated targets for antibacterial drug discovery. Benzopyrones have been reported as promising derivatives that inhibit bacterial DNA gyrase B through competitive binding into the ATP binding site of the B subunit. In this study, we designed and synthesized twenty-two benzopyrone-based derivatives with different chemical features to assess their antimicrobial and photosensitizing activities. The antimicrobial activity was evaluated against B. subtilis, S. aureus, E. coli, and C. albicans. Compounds 6a and 6b (rigid tetracyclic-based derivatives), 7a-7f (flexible-linker containing benzopyrones), and 8a-8f (rigid tricyclic-based compounds) exhibited promising results against B. subtilis, S. aureus, and E. coli strains. Additionally, these compounds demonstrated photosensitizing activities against the B. subtilis strain. Both in silico molecular docking and in vitro DNA gyrase supercoiling inhibitory assays were performed to study their potential mechanisms of action. Compounds 8a-8f exhibited the most favorable binding interactions, engaging with key regions within the ATP binding site of the DNA gyrase B domain. Moreover, compound 8d displayed the most potent IC50 value (0.76 μM) compared to reference compounds (novobiocin = 0.41 μM and ciprofloxacin = 2.72 μM). These results establish a foundation for structure-based optimization targeting DNA gyrase inhibition with antibacterial activity.

Citation

Abd El-Haleem, A., Ammar, U., Masci, D., El-Ansary, S., Abdel Rahman, D., Abou-Elazm, F., & El-Dydamony, N. (2024). Discovery of Benzopyrone-Based Candidates as Potential Antimicrobial and Photochemotherapeutic Agents through Inhibition of DNA Gyrase Enzyme B: Design, Synthesis, In Vitro and In Silico Evaluation. Pharmaceuticals, 17(9), Article 1197. https://doi.org/10.3390/ph17091197

• Journal Article Type: Article
• Acceptance Date: Sep 3, 2024
• Online Publication Date: Sep 11, 2024
• Publication Date: 2024
• Deposit Date: Sep 12, 2024
• Publicly Available Date: Sep 13, 2024
• Journal: Pharmaceuticals
• Electronic ISSN: 1424-8247
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 9
• Article Number: 1197
• DOI: https://doi.org/10.3390/ph17091197
• Keywords: in silico prediction, antimicrobial activity, photosensitizing activity, furobenzopyrones, molecular docking