Development of new spiro[1,3]dithiine-4,11′-indeno[1,2-b]quinoxaline derivatives as S. aureus Sortase A inhibitors and radiosterilization with molecular modeling simulation

• Published in: Bioorganic chemistry 2023-02, Vol.131, p.106307-106307, Article 106307
• Main Authors: Ragab, Ahmed, Abusaif, Moustafa S., Gohar, Nirvana A., Aboul-Magd, Dina S., Fayed, Eman A., Ammar, Yousry A.
• Format: Article
• Language: English
• Subjects: 7-Flouro-indenoquinoxaline; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-microbial activity; Bacterial Proteins; Biofilm; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular docking and quantum studies; Molecular Docking Simulation; Quinoxalines - pharmacology; Sortase A inhibitors; Staphylococcus aureus; Sterilization
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.106307

[Display omitted] •New spiro-1,3-dithiinoindenoquinoxaline derivatives were efficiently synthesized.•The structures of all obtained products were elucidated by spectroscopic techniques (FT-IR, 1H NMR, and 13C NMR).•Most active derivative 4b exhibited the highest MIC value ranging between 0.06 and 0.25 µg/mL (64–133 folds) against bacteria and with MIC = 0.25 µg/mL (16 folds) with the Candida strain.•The synthesized spiro-1,3-ditiino-indenoquinoxaline derivatives are relatively strong candidates as SrtA inhibitors by decreasing the fluorescence signal in a dose-dependent manner and reducing the adherence of S. aureus to fibrinogen as SrtA inhibitors.•The spiro-1,3-dithiinoindenoquinoxalines eradicate the biofilm biomass of S. aureus nearly-four-folds than control via expression of SrtA activity.•The FMOs of most active derivatives were calculated to predict the most reactive regions in molecular systems and specify the importance of charge transfer, as well as describe the different types of reactions with the binding site in biological targets. Multi-drug resistant microbes have become a severe threat to human health and arise a worldwide concern. A total of fifteen spiro-1,3-dithiinoindenoquinoxaline derivatives 2–7 were synthesized and evaluated for their biological activities against five standard and MDRB pathogens. The MIC and MBC/MFC for the most active derivatives were determined in vitro via broth microdilution assay. These derivatives showed significant activity against the tested strains with microbicidal behavior, with compound 4b as the most active compound (MIC range between 0.06 and 0.25 µg/mL for bacteria strains and MIC = 0.25 µg/mL for C. albicans). The most active spiro-1,3-dithiinoindenoquinoxaline derivatives were able to inhibit the activity of SrtA with IC50 values ranging from 22.15 ± 0.4 µM to 37.12 ± 1.4 µM. In addition, the active spiro-1,3-dithiinoindenoquinoxaline attenuated the in vitro virulence-related phenotype of SrtA by weakening the adherence of S. aureus to fibrinogen and reducing the biofilm formation. Surprisingly, compound 4b revealed potent SrtA inhibitory activity with IC50 = 22.15 µM, inhibiting the adhesion of S. aureus with 39.22 ± 0.15 % compared with untreated 9.43 ± 1.52 %, and showed a reduction in the biofilm biomass of S. aureus with 32.27 ± 0.52 %. We further investigated the effect of gamma radiation as a sterilization method on the microbial load and found that a dose of 5 kGy was sufficient to eradicate