Supramolecular interaction of ofloxacin drug with p-sulfonatocalix[6]arene: Metal-ion responsive fluorescence behavior and enhanced antibacterial activity

Abstract

The interaction of ofloxacin (OFL), a second generation fluoroquinolone antibiotic drug, with water soluble p-sulfonatocalix[6]arene (SCx6) macrocyclic host has been investigated at different pH conditions corresponding to the three different prototropic forms of the drug. Both the absorption as well as the fluorescence characteristics of different forms of OFL displayed significant changes on interacting with SCx6, in agreement to a complex formation between SCx6 and OFL. Apart from the absorption spectral shifts, the SCx6 interaction also caused strong quenching of the emission intensity of the drug with concomitant changes in the fluorescence lifetime and rotational correlation time as well. The protonated (OFLH2+) form showed 10-times higher binding interaction towards SCx6 (∼105 M−1) as compared to that of zwitterionic (OFLH(Z))/neutral (OFLH) form with SCx6 (∼104 M−1) whereas the anionic (OFL−) form, remained less interactive with SCx6. The strong binding affinity of SCx6 for the protonated form resulted in the upward shift of the OFL pKas, which shifted pKa1 from 6 to 7.4 and pKa2 from 8.5 to 9.15. The 1:1 stoichiometry, verified through Jobs plot and geometry optimization, proposed the protonated piperazinyl end of OFLH2+ as the interaction site for the anionic SCx6 moiety. The SCx6:OFLH2+ complex responded strongly, especially with trivalent metal ions such as Eu3+ and Gd3+, through a cooperative binding interaction bringing out overall quenching of the emission intensity by ∼ 90 % of that of OFL. The metal ions would cooperatively interact with the SCx6:OFLH2+ complex at the keto groups of the quinoline as well as the carboxylic moiety, providing additional non-radiative pathways for the excited state of OFLH2+. The advantageous upward pKa shift and the substantial improvement in the ambient photostability, the SCx6:OFLH2+ provided enhanced antibacterial efficacy with gram-negative bacteria S. typhimurium carried out at pH 7.4 and 8.2, promising for new generation supramolecular fluoroquinolones using non-toxic macrocycles.