Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria

Abstract A series of novel diamidines with N -substituents on an amidine N -atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N -substituents with a branched chain and a shorter carbon chain on the amidine N -atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2–16  μ g/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae , Acinetobacter calcoaceticus , Enterobacter cloacae , and Proteus mirabilis was observed for 5i in comparison with 5c . Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2–4  μ g/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED 50 values of 2.62 mg/kg.