Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers.

Lariat ethers are macrocyclic polyethers-crown ethers-to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter's potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.

Assessment of a host-guest interaction in a bilayer membrane model.

Supramolecular interactions are well recognized and many of them have been extensively studied in chemistry. The formation of supramolecular complexes that rely on weak force interactions are less well studied in bilayer membranes. Herein, a supported bilayer membrane is used to probe the penetration of a complex between tetracycline and a macrocyclic polyether. In a number of bacterial systems, the presence of the macrocycle has been found to significantly enhance the potency of the antimicrobial in vitro. The crown·tetracycline complex has been characterized in solution, neutron reflectometry has probed complex penetration, and the phenomena have been modeled by computational methods.

Group 14 Metallafluorenes as Sensitive Luminescent Probes of Surfactants in Aqueous Solution.

Sila- and germafluorenes containing alkynyl(aryl) substituents at the 2,7- position are strongly emissive with high quantum yields in organic solvents. Provided they are sufficiently soluble in water, their hydrophobic structures have the potential for many biological and industrial applications in the detection and characterization of lipophilic structures. To that end, the emission behaviors of previously synthesized 2,7- bis[alkynyl(biphenyl)]-9,9-diphenylsilafluorene (1), 2,7- bis[alkynyl(methoxynaphthyl)]-9,9-diphenylgermafluorene (2), 2,7- bis[alkynyl(p-tolyl)]-9,9-diphenylsilafluorene (3), and 2,7- bis[alkynyl(m-fluorophenyl)]-9,9-diphenylsilafluorene (4) were characterized in aqueous solution and in the presence of various surfactants. Despite a high degree of hydrophobicity, all of these metallafluorenes (MFs) are soluble in aqueous solution at low micromolar concentrations and luminesce in a common aqueous buffer. Further, the 2,7 substituent makes the emission behavior tunable (up to 30 nm). Fold emission enhancements in the presence of various surfactants are highest toward Triton X-100 and CTAB (ranging from 5 to 25 fold) and are lowest for the anionic surfactants SDS and SDBS. These enhancements are competitive with existing probes of surfactants. Quantum yields in buffer range from 0.11 to 0.34, competitive with many common fluorophores in biological use. Strikingly, MF quantum yields in the presence of TX-100 and CTAB approach 100 % quantum efficiency. MF anisotropies are dramatically increased only in the presence of TX-100, CTAB, and CHAPS. Coupled with the above data, this suggests that MFs associate with neutral and charged surfactant aggregates. Interactions with the anionic surfactants are weaker and/or leave MFs solvent exposed. These properties make metallafluorenes competitive probes for surfactants and their properties and behaviors, and thus could also have important biological applications.