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 () isolates. 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 showed rapid bactericidal activity against resistant 2108 with MIC and MBC values that were 4 and 8 µg/mL, respectively. The hemolytic activity of was low, with an HC value of 123.6 µg/mL. Compound 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 in vitro. Molecular docking revealed that the aminoguanidine moiety and indole structure of played an important role in binding to the target site of the dihydrofolate reductase (DHFR) receptor. In the mouse pneumonia model caused by , improved the survival rate of mice, reduced bacterial loads, and alleviated tissues' pathological injuries at a dosage of 4 mg/kg. Therefore, compound may be a promising lead compound or drug candidate for antibacterial purposes against .