Planejamento e síntese de novos derivados acridínicos por meio de simplificação molecular de um scaffold com potencial antitumoral

Abstract

Cancer is a global public health problem, whose main treatment is chemotherapy, which is linked to toxicity and drug resistance. Topoisomerases and DNA are biological targets of many antitumor drugs, including acridine compounds, and, then, are promising for the development of new drugs. Therefore, we aim to develop new acridine derivatives based on a promising scaffold, through molecular simplification, and evaluate their potential by in silico and in vitro studies, aiming for the development of a new anticancer chemotherapy drug. Five new phenylmethanimine (MAC) and three new substituted diazenylacridine (ACHZ) compounds were obtained through structural simplification of the scaffold (compound 3a), which showed promising antitumor activity in previous studies. The molecular docking study was carried out as an initial screening with topoisomerase IIα (PDB ID: 5GWK) and DNA (PDB ID: 1BNA; 1G3X), in which the molecules mostly showed similar or better free binding energy and interaction mode compared to the reference compound, with emphasis on MAC-07. In silico pharmacokinetic prediction was also performed, confirming good gastrointestinal absorption, BBB permeation and compliance with druglikeness criteria. The synthesis was carried out by linear synthetic route, where acridine aldehyde (AC-02) and hydazonomethyl-acridine were constructed, followed by condensation with different anilines and aldehydes, obtaining reaction yields ranging from 49 to 85%. A thermogravimetric analysis carried out for the MAC series showed that the molecules are stable up to 250 °C. The structural identification of the compounds was carried out using ¹H NMR and ¹³C NMR. Through in vitro studies, the molecules interacted with ssDNA, with Kb values in the typical range for intercalation complexes, highlighting the compound ACHZ-BE. They also interacted with HSA, with Kb typical of drugs capable of accommodating in this protein. In vitro antiproliferative activity studies were carried out in three tumor cell lines (MCF-7, HeLa and SKMEL-28) in which the compounds presented a level of cytotoxicity with a maximum inhibition percentage of 33.2%. In additional docking study, the molecules exhibited good interaction profile with topoisomerase I (PDB ID: 1K4T). Thus, the new molecules discovered showed potential for antitumor drugs, requiring additional studies to better understand their activity and possible mechanisms of action and cytotoxicity.