Comparing micellar, hemolytic, and antibacterial properties of di- and tricarboxyl dendritic amphiphiles

Homologous dicarboxyl dendritic amphiphiles-RCONHC(CH(3))(CH(2)CH(2)COOH)(2), 4(n); and ROCO-NHC(CH(3))(CH(2)CH(2)COOH)(2), 5(n), where R = n-C(n)H(2n+1) and n = 13-22 carbon atoms-were synthesized. Critical micelle concentrations (CMCs) in aqueous triethanolamine solutions and at pH 7.4 were measured along with hemolytic activity (effective concentrations, EC(10)) in phosphate-buffered saline (PBS). Log CMC showed a linear dependence on chain length (n); the longest chain in each series had the lowest CMC-in triethanolamine: 4(21), 180 mu M and 5(22), 74 mu M and at pH 7.4: 4(21), 78 mu M and 5(22), 33 mu M. These two series, 4(n) and 5(n), and three series of homologous tricarboxyl dendritic amphiphiles-RCONHC(CH(2)CH(2)COOH)(3), 1(n); ROCONHC(CH(2)CH(2)COOH)(3), 2(n); RNHCONHC(CH(2)CH(2)COOH)(3), 3(n), where R = n-C(n)H(2n+1) and n = 13-22 carbon atoms-were tested for growth inhibition of Staphylococcus aureus strain ATCC 6358 and methicillin-resistant S. aureus (MRSA) strain ATCC 43330 by microdilution in 0.1-strength brain heart infusion broth (BHIB). Amphiphiles 4(19), 4(21), 5(18), and 5(20) showed the strongest antibacterial activity (2.2-3.4 mu g/mL) against S. aureus (vancomycin, MIC = 0.25 mu g/mL). These four plus 1(21), 2(20), 2(22), and 3(20) exhibited the strongest antibacterial activity (1.7-6.8 mu g/mL) against MRSA (vancomycin, MIC = 0.25 mu g/mL). The MICs of these amphiphiles against six clinical MRSA were similar to those against the ATCC strain. In PBS, EC(10)s of the most active homologues ranged from 7 to 18 mu g/mL and 18 to 220 mu g/mL for di- and tricarboxyl dendritic amphiphiles, respectively. To assess the potential safety of using dendritic amphiphiles as drugs, measurements of micellar and hemolytic properties were conducted in the same medium (full-strength BHIB) that was used for antibacterial activity. The CMCs (9-36 mu g/mL, similar to 18-72 mu M) of ten amphiphiles were measured by microdilution (log 2 progression) with dye-covered beads. The EC10s were similar to those in PBS. The MICs of most amphiphiles (14-72 mu g/mL) and vancomycin (1.1-2.2 mu g/mL) against both S. aureus and MRSA increased significantly compared to the MICs measured in 0.1-strength BHIB. The one exception, 5(18), had an MIC against S. aureus of 1.1 mu g/mL compared to vancomycin (2.2 mu g/mL). With CMC (9-18 mu g/mL) and EC10 (16 mu g/mL) values higher than the MIC, 5(18) was discovered as a lead for further development. (C) 2011 Elsevier Ltd. All rights reserved.