Vanillin Derivatives As The Selective Small Molecule Inhibitors Of FtsZ

Due to dramatically rising prevalence of multi-drug resistant Gram-positive and Gram-negative pathogen bacteria, it resulted in life-treating infectious diseases and represented the second leading cause of death, morover, it has made many of the currently available drugs ineffective. Accordingly, there is a pressing need to identify new drug targets.Recent studies have revealed FtsZ (filamentation temperature-sensitive protein Z) is one promising new target, which is a highly conserved bacterial cytoskeleton protein and a tubulin-like GTPase. FtsZ is present in almost all eubacteria and archaea and acts at an earlier stage of the division process, which plays a pivotal role in bacterial cell division. FtsZ was found to be localized specifically to the midcell, where it forms a ring-like structure known as the Z-ring. Then it recruit a diverse repertoire of accessory proteins. Following recruitment of the other cell division proteins, the Z-ring contracts, resulting in septation. Therefore, a perturbation of FtsZ function will prevent cells from dividing, leading to cell death.Vanillin (4-hydroxy-3-methoxybenzaldehyde), a dietary flavoring agent. There is a growing interest in naturally occurring compounds vanillin used as a potential source of novel preservatives because of its antimicrobial activity, moreover, vanillin has been reported to show antioxidant, antimutagenic and antifungal activities.Compounds containing azomethine group (-C=N-) in the structure are known as schiff bases, which are usually synthesized by primary amines and active carbonyl groups. It is well known schiff bases exhibit a broad range of anti-bacterial, antifungal, anti-cancer and anti-viral activities. The imine group present in such compounds has been shown to be critical to their biological activities.In view of the above mentioned findings, we combine vanillin and various aromatic amine to obtain twenty-one vanillin derivatives 4a-4u by means of computer-aided drug design (CADD). All the synthesized vanillin analogs were evaluated for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their FtsZ inhibitory activitives. Among the vanillin derivatives, compound 4u showed the most potent antibacterial activity with a MIC of 0.28 μgg/mL against E. coli strains which is superior to the positive control kanamycin with a MIC of 0.40//g/mL. Compound 4u also exhibited the most potent FtsZ inhibitory activity with polymerization IC50 of 2.1μM, the polymerization IC50 of positive control colchicine is 104.00μM.And the small-molecule docking simulations were performed using FtsZ with all the compounds to explore the binding modes of these compounds at the active site. Among the docking calculation of the synthesized compounds, compounds 4u showed the lowest interaction energy. In the binding model, compound 4u was nicely bound to the FtsZ with five interaction bonds. Moreover, the π-cation interactions were existed between benzene ring and amino acids Arg 143.