Study of acylhydrazone derivatives with deoxygenated seven-membered rings as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

Abstract

Fatty acid biosynthesis is essential for bacterial survival. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and highly conserved among Gram-positive and Gram-negative bacteria. Following previous studies, a series of acylhydrazone derivatives with deoxygenated rings were synthesized in this work. For all of the 36 analogues synthesized, studies using H NMR, C NMR, MS and elemental analyses were conducted. Their biological activities were also evaluated against two Gram-negative bacterial strains: E. coli and P. aeruginosa, and two Gram-positive bacterial strains: B. subtilis and S. aureus by the MTT method as potential FabH inhibitors. The resulting compound F18 showed the highest antibacterial activity with MIC values of 1.56–3.13 μg mL⁻¹ against the tested bacterial strains and was found to be the most potent E. coli FabH inhibitor with an IC₅₀ value of 2.0 μM. Molecular modeling simulation studies were performed in order to predict the biological activities of compound F18 into the E. coli FabH active site.