Design and Evaluation of Vanillin Derivatives as Dual Inhibitors of Neuraminidase of Streptococcus pneumoniae and FtsZ of Staphylococcus aureus
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UNIVERSITI MALAYSIA SARAWAK
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Majority pneumonia cases were caused by two types of bacterial strains: Streptococcus pneumoniae and Staphylococcus aureus. Despite the fact that vaccines and antibiotics were available, the problem continue to arise due to the increasing emergence of strains that exhibit significant resistance to the available drugs. Based on reported research, neuraminidase of S. pneumoniae and FtsZ of S. aureus played imperative role in facilitating the pneumococcal infection. Schiff base vanillin derivatives were reported to exhibit wide range of biological activity, including antibacterial activity against various bacterial strains. As a whole, this research study focuses on the study of Schiff base vanillin derivatives targeting neuraminidase of S. pneumoniae and FtsZ of S. aureus by performing computational methods and antibacterial assay. A total of 21 vanillin derivatives were evaluated. Based on the results of the study as potential S. pneumoniae neuraminidase inhibitors, all 21 vanillin derivatives were able to show pharmacophore fit values and matching features more than half of the training sets. The fit values ranged from 64.25 to 81.50, together with 6 to 8 matching features in ligand-based pharmacophore modelling. In structure-based pharmacophore modelling and molecular docking, 15 out of 21 derivatives were successfully aligned with the 4 out of 6 key active site residues of oseltamivir carboxylate ligand of 2YA8, including ARG332, ARG648, ARG706 and ASP357. Simultaneously, the derivatives were able to show binding affinity values lower than –6.00 kcal/mol, indicating strong docking interaction to the protein pocket of 2YA8. For analysis as potential inhibitors of S. aureus FtsZ, the 21 derivatives showed pharmacophore fit values ranging from 66.45 to 104.06, depicting 6 to 10 out of 17 pharmacophore features. Only 17 out of 21 showed fit values more than half of the training sets. In structure-based pharmacophore modelling and molecular docking, 19 out of 21 derivatives were able to iv matched with 4 to 6 out of 6 key active site residues of the PC190723 ligand of 3VOB, including VAL297, VAL203, THR309, LEU200, LEU209 and ASN263. Similarly, the derivatives possessed strong binding affinity values less than –6.00 kcal/mol in the protein pocket of 3VOB, suggesting strong interaction to the active site. In combination of the all results, 10 out of 21 vanillin derivatives showed satisfactory results as potential inhibitors of both S. pneumoniae and S. aureus, which were compounds (5), (8), (9), (10), (12), (15), (16), (17), (19) and (21). By fulfilling all rules in Lipinski’s Rule of 5, this provided further support to their role as orally active drugs. A total of 6 out of 10 vanillin derivatives were successfully synthesized and characterized by Fourier-Transform-Infrared spectroscopy (FT-IR) and Nuclear Magnetic Resonance Spectroscopy (NMR). On top of that, the derivatives also depicted significant antibacterial activity against Gram-positive bacteria by agar diffusion antibacterial assay. Average diameter of inhibition zone ranging from 9.78 mm to 20.40 mm were shown in comparison with the controls. Schiff base vanillin derivatives were concluded to possess potential dual inhibitory activity against both neuraminidase of S. pneumoniae and FtsZ of S. aureus via in silico. With support from their druglikeness in Lipinski’s Rule of 5, and their agar diffusion antibacterial activity against Gram-positive bacteria, the derivatives serve as promising drug candidates for futuristic development via in vivo or in vitro.