The objectives of the study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-indole derivatives. Thirty-seven 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 clinical resistant Klebsiella pneumoniae (K. pneumoniae) isolates. K. pneumoniae is an important opportunistic pathogen that often threatens the health of immunocompromised people such as the elderly, children, and ICU patients. The most active compound 4P showed rapid bactericidal activity against resistant K. pneumoniae 2108 with MIC and MBC values that were 4 and 8 µg/mL, respectively. The hemolytic activity of 4P was low, with an HC₅₀ value of 123.6 µg/mL. Compound 4P induced the depolarization of the bacterial membrane and disrupted bacterial membrane integrity and was not prone to antibiotic resistance. The dihydrofolate reductase (DHFR) activity was also notably inhibited by 4P in vitro. Molecular docking revealed that the aminoguanidine moiety and indole structure of 4P played an important role in binding to the target site of the K. pneumoniae dihydrofolate reductase (DHFR) receptor. In the mouse pneumonia model caused by K. pneumoniae, 4P improved the survival rate of mice, reduced bacterial loads, and alleviated tissues’ pathological injuries at a dosage of 4 mg/kg. Therefore, compound 4P may be a promising lead compound or drug candidate for antibacterial purposes against K. pneumoniae.

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 Staphylococcus aureus (S. aureus) isolates. S. aureus is an important pathogen that has the capacity to cause a variety of diseases, including skin infections, pneumonia, and sepsis. The most active compound, 2D, showed rapid bactericidal activity against S. aureus 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 2D was low, with HC₅₀ and IC_{50(HEK 293-T)} values of 50.65 µg/mL and 13.09 µg/mL, respectively. Compound 2D 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 2D. In the mouse skin abscess model caused by MRSA-2, 2D reduced the abscess volume, decreased bacterial load, and alleviated tissue pathological damage at doses of 5 and 10 mg/kg. Therefore, compound 2D may be a promising drug candidate for antibacterial purposes against S. aureus.