Literature data indicate that some calixarene derivatives with antimicrobial activities may be useful as drugs; one of the aspects of the biological activity of different classes of antibiotics concerns interactions with lipid membranes. Here, the possibility of incorporation and/or translocation of three amphiphilic p-tert-butylcalix[4]arene derivatives across membranes was studied using lipid monolayers. The derivatives used have 6-aminopenicillanic acid or benzylpenicillin moieties grafted in alternate positions at the calixarene lower rim; 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), a model bacterial membrane lipid, was used to prepare the monolayers. The miscibility of calixarene-antibiotic conjugates with lipid films was studied using surface pressure and surface potential measurements, as well as Brewster angle microscopy. The results obtained show that the miscibility is significantly different for the 6-aminopenicillanic acid and the two benzylpenicillin derivatives. Molecular modeling allowed the assessment of the lowest energy conformations of the calixarene derivatives and gave more insight into the interactions with the DMPE films.
The two new p-tert-butylcalix[4]arene derivatives described here bear one or two nalidixic acid arms linked to the lower calixarene rim via the quinolone carboxylate moiety. These derivatives were synthesized in order to investigate two important features of molecules conceived as potential antibiotics, namely, metal cation complexation and interfacial properties, and the way in which they interrelate. The properties of the calixarene derivatives were studied in monomolecular films spread on pure water and on aqueous subphases containing biologically relevant mono- and divalent metal cations. These systems were examined via surface pressure and surface electrical potential measurements, polarization modulation infrared reflection absorption spectroscopy, and molecular modeling. Molecular modeling shows that important differences exist, first, between the structure and stability of the complexes formed with the two derivatives and, second, between their mono- and dication complexes. Correlating the properties of the monolayers with those of the modeled molecules lets us propose that the derivatives bearing one or two nalidixic pending arms form preferentially inter- and intramolecular complexes, respectively. The results obtained in this study indicate that a possible biological role of the nalidixic arms grafted on the calixarene crown may be revealed upon cation complexation.
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