Design, Synthesis And Antimicrobial Activities Of Secnidazole Derivatives As Potential β-ketoacyl-acyl Carrier Protein Synthase Ⅲ (FabH) Inhibitors

Although many kinds of antibacterial agents were discovered and used for clinical treatment, the incidences of drug resistance of microorganisms to antibacterial agents were constantly reported. Therefore, the development of new types of antibacterial agents is a very important task and much of the research effort is oriented to the design of new antibacterial agents with high efficiency.In recent years, one of the most attractive biochemical pathways to be used as the target for new antibacterial agents is the fatty acid biosynthesis (FAB). This pathway has been demonstrated to be essential for bacteria cell survival. A key enzyme in this pathway is β-ketoacyl-acyl carrier protein synthase Ⅲ (FabH), which is the enzyme responsible for the first reaction in the pathway and plays an important regulatory role. The enzyme initiates the fatty acid elongation cycles, and participates in the feedback regulation of the biosynthetic pathway via product inhibition. FabH catalyzes the condensation reaction between a CoA-attached acetyl group and an ACP-attached malonyl group, yielding acetoacetyl-ACP as its final product. FabH proteins from both Gram-positive and Gram-negative bacteria are highly conserved at the sequence and structural level while there are no significantly homologous proteins in humans. Importantly, the residues that comprise the active site are essentially invariant in various bacterial FabH molecules. These facts suggest the idea that FabH can be used as an effective molecular target for the development of new antibacterial agents, since it regulates the fatty acid biosynthesis rate via an initiation pathway and its substrate specificity is a key factor in membrane fatty acid composition.Secnidazole is particularly effective in the treatment of amebiasis, giardiasis and trichomoniasis, and has a longer terminal elimination half-life than commonly used drugs in this class. So the treatment with secnidazole is shorter and more effective than the treatment using other imidazole drugs and the adverse effects are not very drastic. To sum up, secnidazole derivatives have been proved to be of great importance in pharmaceutical.In order to search for novel antibacterial agents, we designed and synthesized two series of secnidazole analogs based on oxadiazole scaffold and Schiff-Base. Herein, to keep on research on antibacterial compounds with FabH inhibitory activity, we studied their antibacterial activities against Escherichia coli (E.coli), Pseudomonas aeruginosa (P.aeruginosa), Bacillus Subtilis (B. Subtilis) and Staphylococcus aureus (S. aureus) and E.coli FabH inhibitory activities. Docking simulation was performed using the X-ray crystallographic structure of the FabH of E.coli in complex with the most potent inhibitor to explore the binding mode of the compound at the active site. In this sturdy, compound F8, F9and H20showed the most potent antibacterial activity with MIC values of1.56-6.25μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC5o of2.3-5.1μM. This demonstrated that that F8, F9and H20are novel compounds that can be potent antimicrobial inhibitors of FabH and provide valuable information for the design of antibacterial agents.