Design, synthesis, molecular docking, and dynamics studies of novel thiazole-Schiff base derivatives containing a fluorene moiety and the assessment of their antimicrobial and antioxidant activity

Abstract

In this study, a series of eighteen fluorene-containing substituted thiazole derivatives were synthesized and characterized via spectral analyses. The proposed compounds were screened for their in vitro antimicrobial activity, and it was found that compound 2a displayed a significant zone of inhibition (20.3 ± 0.6 mm) against B. subtilis and compound 2b exhibited inhibitory activity (30.3 ± 0.6 mm) against a C. albicans fungal strain. Furthermore, antioxidant activity was evaluated for all analogues, where 2f exhibited a four-fold higher antioxidant capability (11.73 ± 1.22 μg mL^-1) than the standard ascorbic acid. Oral bioavailability and toxicological parameters were considered, and most of the compounds satisfied Lipinski's rule of five and Veber's rule, except for one violation by a few derivatives. Molecular docking and molecular dynamics simulation were performed, providing more explicit ideas on the binding interaction and stability of compounds that exhibited wet lab activity. Average RMSD and RMSF values ranged between 0.5 Å and 2.5 Å, which indicated the stability of ligands inside the complex, yielding some engrossing insights.

Fig. 1. Chemical structures of several fluorene (blue), thiazole (pink) and Schiff base (red) bearing biologically active compounds.

Scheme 1. Synthetic routes to the target derivatives 2a–2r.

Fig. 2. Comparison of inhibition (%) of DPPH radicals at various concentrations of ascorbic acid (AA) and synthesized compounds 2a–2r. Data are expressed as mean ± SD of three experiments.

Fig. 3. Optimized molecular structures of compounds 2a, 2b, and 2f on the basis of DFT/B3LYP/6-31+G(d,p).

Fig. 4. The molecular docking studies of 2a against 6JHK, 5H1N, and 2b against 5AEZ protein receptors. (A) 3D interaction profiles. (B) 2D docking simulations.

Fig. 5. The molecular docking studies of 2f against the human antioxidant enzyme receptor 3MNG. (A) 3D interaction profile. (B) 2D docking simulation.

Fig. 6. Predicted drug-score of synthesized compounds 2a–2m, ceftriaxone (Cf), amphotericin B (Am), and ascorbic acid (AA).

Fig. 7. (A) Initial and (B) final snapshots of four different complexes during the 100 ns MD trajectory for 2a+6JHK, 2a+5H1N, and 2b+5AEZ complexes for antimicrobial studies and the 2f+3MNG complex for antioxidant studies.

Fig. 8. 2D amino acid interaction profile of four protein–ligands complexes after 100 ns of simulation.

Fig. 9. RMSD plot of protein–ligands complexes: (A) bacterial and fungal protein receptors and (B) antioxidant enzyme receptor.

Fig. 10. Radius of gyration (R_g) plot for the four complexes.

Fig. 11. Root mean square fluctuation (RMSF) analysis for the four protein–ligand systems.

Fig. 12. Binding free energy of four protein–ligand complexes over 100 ns of simulation.