β-Cyclodextrin Inclusion Complex to Improve Physicochemical Properties of Pipemidic Acid: Characterization and Bioactivity Evaluation

Rosa Iacovino,Marina Isidori,Agostino Russo,Gaetano Malgieri,Filomena Rapuano,Chiara Russo,Luigi Russo,Carla Isernia,Jolanda Caso,Margherita Lavorgna

doi:10.3390/ijms140713022

Abstract

The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native β-CD were prepared in solid state by kneading method and confirmed by FT-IR and 1H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC50s and EC90s. The results showed that the antibacterial activity of HPPA:β-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:β-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of β-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity.

Highlights

Pipemidic acid (HPPA), 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido[2,3-d]pyrimidine-6carboxylic acid [1,2] shown in Figure 1, is a therapeutic agent for urinary tract infections because of its antibacterial activity against gram-negative as well as some gram-positive bacteria [3,4]
In the Fourier Transform Infrared (FT-IR) spectrum of HPPA, one prominent characteristic peak was found at 3046 cm−1, which was assigned to stretching vibration of the –OH group and intramolecular hydrogen bonding
The formation of the inclusion complex was confirmed by FT-IR spectroscopy

Summary

Introduction

Pipemidic acid (HPPA), 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido[2,3-d]pyrimidine-6carboxylic acid [1,2] shown in Figure 1, is a therapeutic agent for urinary tract infections because of its antibacterial activity against gram-negative as well as some gram-positive bacteria [3,4]. In the HPPA molecule, a quinolone derivate, the carboxylic group at C6-position makes this compound acidic while the piperazine in position 2 includes an amine group, which is basic. For these reasons, in aqueous solution, 2-piperazinyl quinolone exists in three different species: acidic for pH values under pKa1 = 5.4, neutral for pH value closely to isoelectric point (pH = 6.8) and alkaline for pH values higher pKa2 = 8.2 [5]. Pseudomonas aeruginosa than piromidic and nalidixic acids, structurally related to it [6] This drug severely damages DNA in the absence of an exogenous metabolizing system and it may act as a multidentate ligand to coordinate with metal ions [7,8]. Its very low aqueous solubility [9,10]

Methods

Results

Conclusion