RESUMEN
Some lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural ß-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-ß-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT-IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with ß-CD and HP-ß-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Flúor/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Simulación por Computador , Excipientes/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Solubilidad , Relación Estructura-ActividadRESUMEN
Lithiooxiranes 3a and 3b, generated by deprotonation of oxiranes 2a and 2b with s-BuLi at -100 degrees C in Et(2)O, were found to be chemically very stable. trans-Lithiooxirane 3a was also configurationally stable and reacted stereospecifically with electrophiles to give 4a--k. In contrast, cis-lithiooxirane 3b was found to be configurationally much less stable and reacted with electrophiles affording mixtures of diastereomers 4, 7, and 8. After only a very short reaction time, 3b too reacted with electrophiles highly stereospecifically. Deprotonation--deuteration and deprotonation--alkylation of chiral oxazolinyloxiranes 12a and 12b to give oxiranes 12c and 12d were also examined. Semiempirical and ab initio calculations were carried out in an effort to explain the observed stereochemistry.