Síntese de derivados de benzo[c]acridinonas e desenvolvimento de complexos de inclusão com ciclodextrina e seu potencial biológico

Abstract

Multicomponent reactions occur by adding three or more components to one vial, without the need to purify each intermediate. One class of compounds obtained by this reaction is the benzo[c]acridinones, which have potential antimicrobial and anticancer activity. However, this compound has low solubility in water. To overcome this problem, it is proposed to obtain inclusion complexes, using cyclodextrins as host molecules. These have the shape of a conical trunk with different polarity inside and outside its structure, allowing other molecules to be housed inside. Given the above, the aim of this study was to investigate the formation of inclusion complexes between cyclodextrin and two benzo[c]acridinone derivatives. The synthesis was performed starting from three components: benzaldehyde, α-naphthylamine and dimedone (BCA1) or 5,5-cyclohexanedione (BCA2), which were later characterized by NMR and FTIR. Cyclodextrin was selected through inclusion kinetics. In addition, the formation of the inclusion complex in the liquid state was verified, in which solubility isotherm tests and one- and two-dimensional nuclear magnetic resonance spectroscopy studies were performed. In the solid state, the complex was studied using differential scanning calorimetry and infrared spectroscopy. The in vitro dissolution of molecules and inclusion complexes was verified, as well as the biological potential through assays of phospholipase A2 activity, and proteolytic and antibacterial activity. It was found that β-CD was the most efficient cyclodextrin in complexing the two molecules. This was the same cyclodextrin used in the other assays. In the study of the formation of the inclusion complex in the liquid state, it was possible to observe the formation of poorly stable complexes indicated by the association constant (BCA1 Ka= 29 M-1 and BCA Ka=68 M-1) and by the results of NMR1H. The spatial interaction between the atoms of the molecule and the β-CD was also determined by ROESY-2d, observing the formation of an inclusion complex with the BCA2 molecule and a non-inclusion complex with the BCA1 molecule. The solid complexes were characterized, and few changes were observed in the spectra and calorimetric profile, suggesting the formation of unstable systems and that the inclusion process generated unstable complexes, corroborating the results of the other experiments. It was observed in the in vitro dissolution assay that there was an increase in the intrinsic solubility of the molecule in water. Benzo[c]acrdinones and their inclusion complexes demonstrated in vitro potential to inhibit the activity of phospholipase A2 and protease enzymes, and potential to inhibit Bacillus subtilis bacteria. The presence of a contaminating molecule was observed, possibly derived from parallel reactions during the synthesis. This molecule was characterized as a xanthene, a compound that interacted with CD in the formation of the complex with derivative 1 (BCA1). In this way, it was possible to obtain the inclusion and non-inclusion complexes, with better physicochemical properties such as an increase in the dissociation of the molecule in water and potentiated its biological effects.