The antimicrobial nalidixic acid as a probe for molecular recognition of α- and β-cyclodextrins

Abstract

The inclusion of the antibacterial drug nalidixic acid (NAL) in α- and β-cyclodextrin (CD) cavities was studied using UV–vis absorption and voltammetric methods. It was corroborated that the UV absorption bands of NAL are intensified in the presence of α- and β-CDs. A pronounced decrease in the peak currents of NAL was also noticed upon the addition of α- and β-CDs. From the changes in the peak currents, it was concluded that NAL forms 1:1 inclusion complexes with the various hosts, which is also revealed in the phase solubility profile of the NAL–β-CD system, as a representative example. From voltammetric data, the logarithm of the binding constants were calculated to be 2.60 and 3.20 for α- and β-CDs, respectively. The magnitude of the formation constants, as well as the Gibbs free energies for NAL with α- and β-CDs, shows that NAL is bound more strongly to β-CD, with a more apolar cavity, than to α-CD. These observations suggest that hydrophobic interaction is the most important recognition element in the binding process. All orientations of entering NAL into the cavity have been considered herein, with the purpose of characterizing the inclusion complex of NAL with CD. Combining the experimental results and molecular modeling and energy calculations on the inclusion complexes yielded a more detailed picture of the solution structure of the complex formed between NAL and either α-CD or β-CD. It was inferred that the inclusion process can occur through the 2-methylpyridine side. An additional hydrogen bond was also found to be formed between the carboxyl group of NAL, which remains outside the β-CD cavity, and the secondary hydroxyl group of β-CD. This hydrogen bond should, therefore, be operating as an important second recognition element in the NAL–β-CD system. Key words: cyclodextrins, host–guest association, inclusion complexes, nalidixic acid, solubility, voltammetry.