Synthesis, Antimicrobial Activities, and Model of Action of Indolyl Derivatives Containing Amino-Guanidinium Moieties

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.