Comparing anti-HIV, antibacterial, antifungal, micellar, and cytotoxic properties of tricarboxylato dendritic amphiphiles

Three series of homologous dendritic amphiphiles—RCONHC(CH 2CH 2COOH) 3, 1( n); ROCONHC(CH 2CH 2COOH) 3, 2( n); RNHCONHC(CH 2CH 2COOH) 3, 3( n), where R = n-C nH 2n+1 and n = 13–22 carbon atoms—were assayed for their potential to serve as antimicrobial components in a topical vaginal formulation. Comparing epithelial cytotoxicities to the ability of these homologues to inhibit HIV, Neisseria gonorrhoeae, and Candida albicans provided a measure of their prophylactic/therapeutic potential. Measurements of the ability to inhibit Lactobacillus plantarum, a beneficial bacterium in the vagina, and critical micelle concentrations (CMCs), an indicator of the potential detergency of these amphiphiles, provided additional assessments of safety. Several amphiphiles from each homologous series had modest anti-HIV activity (EC 50 = 110–130 μM). Amphiphile 2( 18) had the best anti- Neisseria activity (MIC = 65 μM), while 1( 19) and 1( 21) had MICs against C. albicans of 16 and 7.7 μM, respectively. Two measures of safety showed promise as all compounds had relatively low cytotoxic activity (EC 50 = 210–940 μM) against epithelial cells and low activity against L. plantarum, 1( n), 2( n), and 3( n) had MICs ⩾ 490, 1300, and 940 μM, respectively. CMCs measured in aqueous triethanolamine and in aqueous potassium hydroxide showed linear dependences on chain length. As expected, the longest chain in each series had the lowest CMC—in triethanolamine: 1( 21), 1500 μM; 2( 22), 320 μM; 3( 22), 340 μM, and in potassium hydroxide: 1( 21), 130 μM; 3( 22), 40 μM. The CMC in triethanolamine adjusted to pH 7.4 was 400 μM for 1( 21) and 3900 μM for 3( 16). The promising antifungal activity, low activity against L. plantarum, relatively high CMCs, and modest epithelial cytotoxicity in addition to their anti- Neisseria properties warrant further design studies with dendritic amphiphiles to improve their safety indices to produce suitable candidates for antimicrobial vaginal products.