Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: synthesis and SAR of novel analogs of MBX 1066 and MBX 1090.
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.
Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA. Electronic address: jwilliams@microbiotix.com.
John D
JD
Williams
Son T
ST
Nguyen
Shen
S
Gu
Xiaoyuan
X
Ding
Michelle M
MM
Butler
Tommy F
TF
Tashjian
Timothy J
TJ
Opperman
Rekha G
RG
Panchal
Sina
S
Bavari
Norton P
NP
Peet
Donald T
DT
Moir
Terry L
TL
Bowlin
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D005663:Furans; D007093:Imidazoles; D007211:Indoles; C000591625:MBX 1066; C000591626:MBX 1090; C469777:bisamidine; C030374:indole
Amidine; Antibacterial; Antibiotic; Broad-spectrum; Cadogan–Sundberg reaction; Imidazoline; Indole; McMurry reductive homocoupling reaction; Reissert indole synthesis; Tetrahydropyrimidine