Síntesis sostenible y evaluación biológica de derivados de quinolina

Abstract

[EN] The pharmaceutical industry is considered one of the industries with the largest carbon footprint. Concern about the impact of the chemical industry on the environment gave rise to a movement now known as Green Chemistry or Sustainable Chemistry. Its goal is to move from traditional methods, which focus on chemical yields, to cleaner methods and alternatives. Many of the chemical processes used to produce pharmaceuticals still rely on traditional synthetic methods. The application of more sustainable methods is of particular interest for the synthesis of structures with bioactivity, such as quinolines. Quinoline is a structural unit present in natural and pharmaceutical products. Since its discovery in the 19th century, numerous medicinal properties have been described for compounds with a quinoline skeleton. First against malaria and then against many other diseases, such as other parasitic and bacterial infections, HIV and cancer. Consequently, many synthetic methods have been developed to obtain the quinoline ring as well as its subsequent application in other strategies to improve its biological activity, such as hybridization. Hybridization, used in medicinal chemistry, allows combining several bioactive chemical structures by means of connectors or spacers in a single molecule and is used with the aim of improving their pharmacological properties. In previous projects, the research group applied this strategy in the synthesis of hybrid compounds of naphthohydroquinones and podophyllotoxin. The subsequent biological evaluation of these compounds showed good results against cancer. In this thesis the synthesis of quinolines, such as 4-carboxyquinolines, with possible bioactivity against diseases like cancer, was proposed using methods that are in accordance with the principles of green chemistry. Thus, this project focused on the following aspects of green chemistry: use of less toxic solvents and reagents, atomic efficiency, multicomponent synthesis and use of catalysts. The obtained quinoline compounds were used to prepare new hybrid-type compounds with a naphthohydroquinone. The naphthohydroquinone moiety was synthesized based on the method previously optimized by the group from myrcene and p-benzoquinone. The two moieties were then linked through several linkers with ester bonds using a,w-dibromo-reagents or with amide bonds using diamines. Aiming to obtain new hybrid compounds, it was also explored the synthesis of bisquinolines, both symmetrical and asymmetrical. In addition, in this work, a new research line was opened in the group with the long-term objective of a possible application of dextran-quinoline conjugates in controlled and targeted drug delivery systems. Different binding methods between the obtained quinolines and dextran were evaluated, and it was obtained one of these quinoline-dextran conjugates. The obtained hybrid compounds and their precursors were further evaluated considering their biological activity. Antioxidant properties were evaluated using the DPPH method, where one hybrid compound showed better results than its precursors. Cytotoxic activity was carried out using MTT method against HT-29, H460 and MCF-7 cell lines. It was observed that hybridization improves the compounds activity, since all compounds showed cytotoxicity in the order of μM for at least one cell line. ADME prediction of the most promising compounds allowed to conclude that, in general, compounds from the same family present the same pharmaceutical characteristics. In summary, in this thesis it has been possible to obtain 4-carboxyquinolines by a new method. The obtained quinolines were used to synthesize quinoline-naphthohydroquinone hybrid compounds and bisquinolines, as well as, for exploring the possibility of dextranquinolines conjugates. In the subsequent biological evaluation, hybrid compounds have presented not only better antioxidant capacity but also an improvement in activity against the tested cell lines, showing hybridization as a good strategy to improve pharmacological properties.