Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: synthesis and SAR of novel analogs of MBX 1066 and MBX 1090

Abstract

The prevalence of drug-resistant bacteria in the clinic has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We have previously described a set of bisamidine antibiotics that contains a core composed of two indoles and a central linker. The first compounds of the series, MBX 1066 and MBX 1090, have potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. We have conducted a systematic exploration of the amidine functionalities, the central linker, and substituents at the indole 3-position to determine the factors involved in potent antibacterial activity. Some of the newly synthesized compounds have even more potent and broad-spectrum activity than MBX 1066 and MBX 1090.

Keywords: Amidine; Antibacterial; Antibiotic; Broad-spectrum; Cadogan–Sundberg reaction; Imidazoline; Indole; McMurry reductive homocoupling reaction; Reissert indole synthesis; Tetrahydropyrimidine.