Synthesis and Antibacterial Activity of Cinnamaldehyde Acylhydrazone with a 1,4-Benzodioxan Fragment as a Novel Class of Potent β-Ketoacyl–Acyl Carrier Protein Synthase III (FabH) Inhibitor

Abstract

Fatty acid biosynthesis is essential for bacterial survival. β-Ketoacyl-acyl carrier protein (ACP) synthase III (FabH), is a particularly attractive antibacterial target, since it is central to the initiation of fatty acid biosynthesis. Three series of 21 cinnamaldehyde acylhydrazone derivatives, A3-9, B3-9, and C3-9, were synthesized and evaluated for FabH-inhibitory activity. Compound B6 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis (minimum inhibitory concentrations (MICs) values: 1.56-3.13 µg/mL) and was comparable with the positive control. Docking simulation by positioning compound B6 in the FabH structure active site was performed to explore the possible binding model. Key words cinnamaldehyde; acylhydrazone; benzodioxan; antibacterial; structure-activity relationship; FabH inhibitor Bactria has become a greater threat to human beings as antibiotic resistance sweeps the world.1) Fatty acid biosynthesis (FAB) is an essential metabolic process for prokaryotic organisms and is required for cell viability and growth.2) The significant differences between human and prokaryotic FAB systems render prokaryotic FAB to be an attractive target.3)The β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) has no homologs in human and is one of essential functional enzymes in bacterial FAB system. FabH initiates the FAB cycle by catalyzing the first condensation step between acetylCoA and malonyl-ACP, playing a key regulatory role in the bacterial FAB cycle.4) Many kinds of compounds harbored Schiff base motif or hydrozone motif was screened for antimicrobial activity, some of which are potent inhibitors of FabH. 5)For example, compounds 1-8 (Fig. 1A) reported as inhibitors of Escherichia coli FabH showed the most potent FabH inhibitory activity in each article respectively. [6][7][8][9][10][11][12] 1,4-Benzodioxan is an important frame for medicine and widely found in natural products, e.g. silybin, purpurenol, 3,4-dihydroxystyrene dimmers (shown in Fig. 1B). It can also be acquired from more common natural sources. [13][14][15][16][17] It was reported that various derivatives of 1,4-benzodioxan show biological activities, [18][19][20] some of which are anticancer agents 21) or new anti-inflammatory compounds.18) The aim of this study is to design a series of hydrazide-Schiff bases with a spectrum of antibactrial applications. In view of the findings mentioned above, we report in this present work the synthesis of a series of 1,4-benzodioxan acylhydrazone derivatives (showed in Fig. 1C) to achieve new potential antibacterial FabH inhibitors. Results and DiscussionChemistry In this study, twenty-one cinnamaldehydeacylhydrazone derivatives were designed and synthesized. The synthesis of compounds A3-9; B3-9 and C3-9 followed the general pathway outlined in Chart 1. All of them were prepared in three steps, which is based on our previous research. with 85% hydrazine monohydrate in ethanol. The synthesis of compounds A3-9, B3-9...

Non-invasive 19F NMR analysis of a protein-templated N-acylhydrazone dynamic combinatorial library

“…Since each molecule was composed of A-B ring systems joined by an NAH linker it provided the basis around which our dynamic library was designed. [37][38][39][40][41] The 5-membered proof-of-concept library was based around commercially available fluoro-aromatic aldehyde A as the central core along with five commercially available aromatic hydrazides 1-5 with differing chemical and physical properties (Fig. 2).…”

PENHASCOS DE ATIVIDADE BIOLÓGICA COMO FERRAMENTA NA ANÁLISE DA RELAÇÃO ESTRUTURA ATIVIDADE EM UMA SÉRIE DE INIBIDORES DA ENZIMA Β-Cetoacil-Acp SINTASEIII

“…Após realizar uma análise preliminar na literatura, foram escolhidas 233 moléculas de 16 artigos ((LI et al, 2009;LI et al, 2010;LI et al, 2012;LI et al, 2013;LI et al, 2014;ALHAMADSHEH et al, 2007;ALHAMADSHEH et al, 2008;LV et al, 2010;YANG et al,2012;SONG et al, 2014;WANG et al, 2012;LI et al, 2014;MCKINNEY et al, 2016;CHENG et al, 2009;CHENG et al, 2010;CHENG et al, 2013;ZHANG et al, 2011) para compor o grupo de moléculas para estudo dos AC. Cada uma das 233 moléculas foi desenhada com o software livre MarvinSketch versão 15.9 (ChemAxon, 2017).…”

New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors

“…The most active compound of their series exhibited potent E. coli activity by inhibiting the catalytic activity of FabH. Additionally, Song et al 12 also described cinnamaldehyde acylhydrazone derivatives as a novel class of effective E. coli FabH inhibitors, suggesting the relevance of this group to exert interactions in the receptor binding site ( Fig. 2E).…”

“…Many different compounds with good antibacterial profiles and capable of selectively inhibiting FabH have been described in the literature. [8][9][10][11][12][13] These compounds have been obtained through structure-based drug design (SBDD) or by high-throughput screening (HTS) of natural products and small libraries of molecules (Fig. 2).…”

“…13 To achieve a better understanding of the interactions at molecular level, we selected 10 residues located in the FabH binding site, including the catalytic triad, and evaluated the interatomic distances using the LPC/CSU server (Supplementary information). [11][12][13] The results showed several putative interactions between all compounds and the enzyme-binding site. Those interactions include hydrogen bonding, p-p stacking (aromatic interactions), hydrophobic and van der Waals bonding, according to the classification of ligand-protein contacts by the server.…”