Host-quest inclusion complex of quinoxaline-1,4-dioxide derivative with 2-hydroxypropyl-β-cyclodextrin: Preparation, characterization, and antibacterial activity

Abstract

Quinoxaline-1,4-dioxides (QDOs) constitute an intriguing class of heterocyclic bioactive compounds that found applications both in human and veterinary medicine. Unfortunately, the poor aqueous solubility of these analogues hampered their biological efficiency where higher doses are administered to achieve the desired clinical outcome, leading to adverse side effects. The goal of this study is to improve the aqueous solubility of QDOs via complexation with 2-hydroxypropyl-β-cyclodextrin (HPCD), a renowned functional excipient that found widespread applications in the pharmaceutical and food industries. A model QDO analogue was synthesized via the Beirut reaction, and characterized by nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), and mass spectroscopy. The inclusion of QDO in the hydrophobic cavity of HPCD was achieved via the solvent evaporation method followed by freeze-drying. The successful preparation of the QDO/HPCD was confirmed by NMR, FTIR, simultaneous Thermogravimetirc analysis /Differential thermal analysis (TGA/DTA), and X-ray powder diffraction (XRD). In addition, molecular docking studies were conducted to investigate the mechanism of inclusion complexation and the interactions of QDO with HPCD. The solubility of the prepared complex was assessed by the method of preparing saturated solution, where profound enhancement in aqueous solubility of QDO was attained. Preliminary antibacterial assessment of the QDO/HPCD inclusion complex against multiple bacterial strains showed that the complex exhibited activity against Klebsiella pneumoniae. The current study offers the first report describing the inclusion of a quinoxaline-1,4-dioxide analogue into a β-cyclodextrin derivative. Once the QDO-loaded cyclodextrin approach is validated in terms of therapeutic outcome, it will offer a universal platform that can be deployed to enhance the aqueous solubility of clinically relevant QDO derivatives.