Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety

The objectives of this study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-tetralone derivatives. Thirty-four new compounds were effectively synthesized through nucleophilic substitution reaction and guanidinylation reaction. Chemical structures of all the desired compounds were identified by NMR and HR-MS spectroscopy. Most of the synthesized compounds showed significant antibacterial activity against ESKAPE pathogens and clinically resistant <i>Staphylococcus aureus</i> (<i>S. aureus</i>) isolates. <i>S. aureus</i> is an important pathogen that has the capacity to cause a variety of diseases, including skin infections, pneumonia, and sepsis. The most active compound, <b>2D</b>, showed rapid bactericidal activity against <i>S. aureus</i> ATCC 29213 and MRSA-2 with MIC/MBC values of 0.5/4 µg/mL and 1/4 µg/mL, respectively. The hemolytic activity and cytotoxicity of <b>2D</b> was low, with HC₅₀ and IC_{50(HEK 293-T)} values of 50.65 µg/mL and 13.09 µg/mL, respectively. Compound <b>2D</b> induced the depolarization of the bacterial membrane and disrupted bacterial membrane integrity, ultimately leading to death. Molecular docking revealed that dihydrofolate reductase (DHFR) may be a potential target for <b>2D</b>. In the mouse skin abscess model caused by MRSA-2, <b>2D</b> reduced the abscess volume, decreased bacterial load, and alleviated tissue pathological damage at doses of 5 and 10 mg/kg. Therefore, compound <b>2D</b> may be a promising drug candidate for antibacterial purposes against <i>S. aureus</i>.