Design of Arylsulfonylhydrazones as Potential FabH Inhibitors: Synthesis, Antimicrobial Evaluation and Molecular Docking

Background: Antimicrobial resistance is a persistent problem regarding infection treatment and calls for developing new antimicrobial agents. Inhibition of bacterial beta-ketoacyl acyl carrier protein synthase III (FabH), which catalyzes the condensation reaction between a Co-Aattached acetyl group and an ACP-attached malonyl group in bacteria is an interesting strategy to find new antibacterial agents. Objective: The aim of this work was to design and synthesize arylsulfonylhydrazones potentially FabH inhibitors and evaluate their antimicrobial activity. Methods: MIC50 values of sulfonylhydrazones against E. coli and S. aureus were determined. Antioxidant activity was evaluated by DPPH (1-1'-diphenyl-2-picrylhydrazyl) assay and cytotoxicity against LL24 lung fibroblast cells was verified by MTT method. Principal component analysis (PCA) was performed in order to suggest a structure-activity relationship. Molecular docking allowed to propose sulfonylhydrazones interactions with FabH. Results: The most active compound showed activity against S. aureus and E. coli, with MIC50 = 0.21 and 0.44 mu M, respectively. PCA studies correlated better activity to lipophilicity and molecular docking indicated that sulfonylhydrazone moiety is important to hydrogen-bond with FabH while methylcatechol ring performs pi-pi stacking interaction. The DPPH assay revealed that some sulfonylhydrazones derived from the methylcatechol series had antioxidant activity. None of the evaluated compounds was cytotoxic to human lung fibroblast cells, suggesting that the compounds might be considered safe at the tested concentration. Conclusion: Arylsufonylhydrazones is a promising scaffold to be explored for the design of new antimicrobial agents.

Automated summary

The study designed and synthesized arylsulfonylhydrazones as potential FabH inhibitors, evaluated their antimicrobial, antioxidant activities, and cytotoxicity, with the most active compound showing activity against S. aureus and E. coli, and being non-toxic to human lung fibroblast cells. Molecular docking studies suggested that the sulfonylhydrazone moiety plays an important role in interacting with FabH, while the methylcatechol ring is involved in pi-pi stacking interaction. Overall, arylsufonylhydrazones show promise as scaffolds for the design of new antimicrobial agents.