Design, Synthesis and Antibacterial Activities of Novel Amide Derivatives Bearing Dioxygenated Rings as Potential β-Ketoacyl-acyl Carrier Protein Synthase III (FabH) Inhibitors

Abstract

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. FabH would trigger the initiation of fatty acid biosynthesis and it is highly conserved among Gram-positive and -negative bacteria. A series of novel amide derivatives bearing dioxygenated rings were synthesized and developed as potent inhibitors of FabH. These compounds were determined by 1 H-NMR, 13 C-NMR, MS and further confirmed by crystallographic diffraction study for compound 19. Furthermore, these compounds were evaluated strong broad-spectrum antibacterial activity. Some compounds with potent antibacterial activities were tested for their Escherichia coli (E. coli) FabH inhibitory activity. Especially, compound 19 showed the most potent antibacterial activity with minimum inhibitory concentration (MIC) values of 1.56-3.13 mg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC 50 of 2.4 µM. Docking simulation was performed to position compound 19 into the E. coli FabH active site to determine the probable binding conformation.

Design, Synthesis and Molecular Docking of 1,3,4‐Oxadiazole‐2(3H)‐thione Derivatives Containing 1,4‐Benzodioxane Skeleton as Potential FabH Inhibitors

“…To sum up, as shown in Figure 1, we extracted the structures of 1,4‐benzodioxane and 1,3,4‐oxadiazole‐2(3 H )‐thiones, and then introduced a synergistic group ArCO‐. The introduction of ArCO‐ group can improve the antibacterial activity to a certain extent, [24] and the introduction of benzene ring can also increase the interaction with the active site of the target protein amino acids to a certain extent, thus improving the antibacterial ability [25] . A series of new (5‐(2,3‐dihydrobenzo[ b ][1,4]dioxin‐6‐yl)‐2‐thioxo‐1,3,4‐oxadiazol‐3(2 H )‐yl)(phenyl)methanone derivatives were designed and synthesized.…”

“…The introduction of ArCO-group can improve the antibacterial activity to a certain extent, [24] and the introduction of benzene ring can also increase the interaction with the active site of the target protein amino acids to a certain extent, thus improving the antibacterial ability. [25] A series of new (5-(2,3dihydrobenzo[b] [1,4]dioxin-6-yl)-2-thioxo-1,3,4-oxadiazol-3(2H)-yl)(phenyl)methanone derivatives were designed and synthesized. To verify whether these designed compounds can target FabH, molecular docking was performed by fitting these designed compounds to the active binding sites of FabH (PDB code: 5BNM).…”