Síntese e avaliação de atividades biológicas de novas drimanamidas e tetronamidas

Abstract

The chemical unit of drimanes and butenolides is present in a wide variety of natural products (NPs) with a wide spectrum of bioactivity and, therefore, are units of great academic and industrial interest. In chapter 1 of this thesis, the synthesis, characterization, and evaluation of the biological activity of 25 drimanamides (15 unpublished) derived from the natural product (3aR)-(+)-sclareolide are approached. The derivatives were synthesized by aminolysis of the lactone portion of NP using trimethylaluminum and different aliphatic and aromatic amines (yield 56-98%). From the substituted N-propargyl derivative (J-1.7), with the use of benzyl azides, 5 new triazoles were prepared (yield 70-81%). The synthesized compounds were evaluated for their anticholinesterase and antitumor activities. The best enzymatic inhibition results were achieved for compounds J-1.12 (p-substituted trifluoromethylphenyl) (AChE = 78%) and J-1.9 (m-substituted bromophenyl) (AChE = 77% and BuChE = 73%), being the last, for BuChE, more active than the standard drug galantamine (BuChE = 43%). Furthermore, interesting correlations were observed between enzymatic tests and molecular docking studies, which suggested that the activities observed in vitro occur due to important interactions with the enzymatic active site. The evaluation of the antitumor potential of these compounds revealed a new class of cytotoxic substances. In particular, J-1.1 (substituted N-(2-(piperidin-1-yl)ethyl) exhibited considerable antitumor action against HT29 with EC50 = 9.2 µM. Analysis of antitumor activity revealed that the presence of the triazole ring did not cause a great difference in the cytotoxicity against the A2780 tumor cell line when compared to the respective N-aryl substituted drimanamide. In short, the changes made to the structure of (3aR)-(+)-sclareolide led to the obtaining of new bioactive molecules. In the second chapter of this thesis, the synthesis, characterization, and evaluation of the cyanobactericidal, herbicide activities are described and inhibitor of photosynthesis of new β-amino-substituted butenolides (tetronamides). These products are inspired by rubrolides, a class of PNs isolated from marine sponges. The synthesis of these analogues had three main steps, which were: (i) a Suzuki cross-coupling between bromobenzaldehyde and different boronic acids to give biphenyl aldehydes (88-94%, 4 substances); (ii) a vinylologous addition/elimination between different 2,4-dialofuran 2(5H)ones and aromatic and aliphatic amines (33-98%, 9 substances) and (iii) an aldol condensation between the biphenyl aldehydes (i) and the tetronamides that were obtained through vinylic addition/elimination (ii) (19-85%, 20 substances, 18 unpublished). The final substances (the aldol adducts J-2.16 to J-2.35) were evaluated for their cyanobactericidal activities, with the 5 most toxic compounds in the series having an IC50 close to 2 µM. The photosynthesis inhibition assays revealed that the mechanism of action of these substances, in the cyanobactericidal action, should not occur via inhibition of the photosynthetic electron transport system. The herbicidal activity assays showed that the obtained tetronamides do not exert great influence on the development of plants, which suggests the selectivity of the substances for action against cyanobacteria. Furthermore, QSAR studies were carried out to rationalize the relationships between bioactivities and chemical structures of tetronamides. These studies showed the great relevance of biphenyl and N-aryl units for bioactivity against cyanobacteria. Given the context of the diseases that affect the human population and the consequent search for new drugs, as well as the need to develop new agrochemical agents, the data presented and discussed in the present work thus contribute to the discovery of new structural skeletons of interest scientific and social.