Síntese multicomponente de hexaidroquinolinas e a formação de complexos de inclusão com ciclodextrinas

Abstract

Hexahydroquinolines (HQs) are a class of molecules that have several biological activities such as anti-inflammatory, analgesic, anticancer, antifungal, among others. And they can be produced in a single step through multicomponent reactions (RMCs). However, HQs have low solubility in water, which may reduce their bioavailability. The formation of inclusion complexes (ICs) with cyclodextrins (CDs) allows the increase of the solubility of the system, due to the internal hydrophobic cavity and the external hydrophilic one. Thus, the objective of this work was to carry out a multicomponent synthesis of comics and improve their dissolution rate through the formation of ICs with cyclodextrins. For this, the synthesis of the six hexahydroquinolines occurred through the maceration of different aromatic aldehydes, dimedone or cyclohexa-1,3-dione, ethyl acetoacetate and ammonium acetate in excess. The products were confirmed by nuclear magnetic resonance spectroscopy (1H and 13C NMR) and Fourier transform infrared spectroscopy (FTIR). Solubility isotherm experiments were carried out with one of the synthesized molecules (HQ1) and different cyclodextrins: β-CD, hydroxypropyl-β-CD (HPCD), methyl-β-CD (MeCD) and sulfobutyl ether-β-CD (SBECD). Inclusion complexes were prepared in molar ratios of 1:1 and 1:2 using SBECD (LS1 and LS2) and MeCD (LM1 and LM2). Masses of HQ1 and each cyclodextrin (SBECD and MeCD) were solubilized in acetone and ultrapure water, respectively, mixed and placed in a rotary evaporator at room temperature for two hours. After removing the solvent, the products were resuspended, frozen and lyophilized, being confirmed by means of the techniques described above, plus two-dimensional NMR (ROESY) and differential scanning calorimetry (DSC). To prove the improvement in the release rate of HQ1 in water, in vitro dissolution tests were performed. For the synthesized comics, all 1H NMR spectra showed a singlet in the region between 5.0 and 4.0 ppm, indicating that the 1,4-dihydropyridine system is present in the structures and in the non-oxidized form. Signals in the olefinic and aromatic region also confirm the substitution patterns of the substances. The solubility isotherms showed how much each CD could improve the dissolution of hexahydroquinoline in water. The FTIR showed changes in the graph profiles of the ICs compared to the pure compounds. The thermal transitions curves showed the disappearance and displacement of the signal referring to the dehydration of the cyclodextrins for the ICs with SBECD and MeCD, respectively. Variations in the chemical shifts of ICs were found in 1H NMR confirming the formation of ICs. ROESY showed correlations that confirmed the entry of HQ1 into the narrowest cavity of the SBECD and the widest one of the MeCD. The in vitro dissolution profiles showed that the solubility of the system was about three times higher than for the pure molecule. Therefore, it can be said that the formation of inclusion complexes between the cyclodextrins and the hexahydroquinoline molecule led to an increase in the dissolution of HQ1 in water, which can improve the bioavailability, release rate and stability of this molecule.