Avaliação do perfil farmacodinâmico e farmacocinético de derivados tiossemicarbazônicos-acridínicos com potencial ação antitumoral

Abstract

Cancer is considered the main public health issue worldwide. Although there are several antineoplastic agents used clinically, they show selectivity limitations and, consequently, high toxicity. Currently, computational chemistry is essential in research and rational drug design, as it reduces unnecessary costs and research time. Acridine derivatives are important chemotherapeutic agents that contain a privileged nucleus. Based on this premise, this research aims to evaluate possible mechanisms of action of thiosemicarbazone-acridine derivatives through in silico and in vitro studies, along with the evaluation of ADMET pharmacokinetic parameters. In silico studies were performed on DNA targets, Topoisomerase II α/DNA, and bovine albumin using platforms such as AutoDock Tools, Gromacs, Discovery Studio, SwissADME, and pK-CSM. The in vitro studies on ssDNA and bovine albumin were performed using UV/visible absorption and fluorescence emission spectroscopy. To determine the ability to inhibit topoisomerase IIα, the compounds were evaluated in the plasmid DNA relaxation assay. In vitro studies for ssDNA revealed a hyperchromism of 50% for GLDL 06 and 33% for GLDL 07, in agreement with the in silico data, in which GLDL 06 presented better ΔG and Ki, in addition to being more stable on the target than GLDL 07. Furthermore, both compounds obtained typical DNA intercalator values. For topoisomerase/DNA inhibition assays, compound GLDL 07 exhibited topoisomerase inhibition of 92% and GLDL 06 inhibited the enzyme by 54%, these results corroborate the data obtained computationally. During in vitro studies with bovine albumin, the compound GLDL 07 showed a slightly greater interaction compared to GLDL 06, these results are reproduced in docking and molecular dynamics. Finally, when analyzing the in silico pharmacokinetic results, it was concluded that the thiosemicarbazone-acridine derivatives violated at most one of Lipinski's rules. However, they did not violate any of Veber's rules and are Drug Like compounds. In addition, these compounds have a higher tolerated dose in the human body than amsacrine and etoposide. Therefore, through the obtained results, it can be concluded that the compounds GLDL 06 and GLDL 07 are promising molecules for the treatment of neoplasms and, therefore, further studies and improvement of these molecules are essential.