Síntese multicomponente e a formação de complexos de inclusão entre dihidropirimidinona e β-ciclodextrina e avaliação do seu potencial biológico em testes in vitro

Abstract

Multicomponent reactions (MCRs) occur when three or more reactants are placed in a single reaction vessel to generate a larger molecule, without the need to purify each intermediate. An example of this is the dihydropyrimidinones (DHPMs), described by the Italian scientist Pietro Biginelli, starting from an aldehyde, urea, and ethyl acetoacetate. This class of compounds has been extensively explored due to their pharmacological activities, including antimalarial, antitubercular, and cytotoxic activities. However, these compounds often present low water solubility, which is why cyclodextrins (CDs) are used to improve this characteristic. CDs are structures with a truncated cone shape, composed of multiple glucose monomers. They are used to encapsulate various molecules in their cavity, thus forming inclusion complexes (ICs). The objective of this work is to obtain the IC between DHPM and β-cyclodextrin (β-CD) via the lyophilization method. For this, the synthesis of the molecule utilized a reflux system at 80 oC for a period of 1.5 hours. To characterize the ICs, spectroscopic techniques such as Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used. Solubility isotherm assays were used to determine the association constant (Ka), allowing the evaluation of the system's (DHPM + β-CD) solubility behavior and changes in response to increased host molecule concentration. In vitro dissolution assays were performed to establish the relationship between time and the percentage of DHPM dissolved. Additionally, this study proposed analyzing the biological potential of the ICs and the synthesized product, evaluating toxicity effects on germination using the plant model Lactuca sativa L. (lettuce). As for the results, DHPM was characterized using FTIR and 1H NMR techniques, confirming its synthesis. In the solubility assay in an aqueous solution, solubility increased by 1.73, 1.53, and 1.43 times at 25, 35, and 45 oC, respectively, with increased cyclodextrin concentration. Spectroscopic, thermal, and microscopic analyses confirmed the formation of inclusion complexes. In vitro dissolution assays showed that inclusion complexes significantly improved DHPM’s solubility in water and its dissolution rate, indicating potential benefits for controlled release and bioavailability. In the plant model assay, the ICs and the molecule showed no toxicity at the tested concentration on lettuce seeds. Additionally, studies such as Molecular Biology may be necessary to investigate potential cytogenotoxic effects and the mechanisms of action that these substances might exert on plant cells. Furthermore, as this is a compound related to the pharmaceutical field, in vivo tests are extremely important and should be conducted to confirm drug bioavailability, ensuring toxicological safety before considering clinical and therapeutic applications.