Morita-Baylis-Hillman em síntese: diversidade estrutural e avaliação biológica de espiro-hexadienonas

Based on a methodology of synthesis for spirohexadienones preparation, recently developed in our lab, this work was done aiming to increase spirohexadienones' structural diversity and to make an antimicrobial and antitumor biological analysis of these molecules. This way, a series of spiros was synthesized with different substituents, optimizing the previous strategy developed, aiming to improve global yields. Two sequences of analogs were prepared through bromination of phenolic rings of the intermediary 'alpha'-(4-hydroxybenzyl)-'beta'-ketoesters, which were later cyclized to afford the corresponding spirohexadienones. The spiro di- and mono-brominated were obtained through this method. The structures of the di-brominated spiros were confirmed by X-ray diffraction analysis. Also oximes were prepared from the 'alpha'-(4-hydroxybenzyl)-'beta'-ketoesters that enabled access to aza-spiros, containing nitrones. These aza-compounds structures were also confirmed by X-ray diffraction analysis. The evaluation of the biological profile of the synthesized compounds library demonstrated that these molecules are highly cytotoxic and that they exhibit antibacterial activity against Gram positive bacteria, including strains of S. aureus resistant to Methycillin. In order to evaluate the relation structure-activity, the reduction of the intermediary 'alpha'-(4-hydroxybenzyl)-'beta'-ketoesters was made to obtain a spiro with the saturated ring of five members. The spiro obtained employing this reduction completely lost the antibacterial activity. The antitumor activity of the synthesized spirohexadienones was also tested, demonstrating an excellent antiproliferative profile. Some of these molecules inhibited tubulin, apparently in the binding site of colchicine. Lastly, it is possible to affirm that this work provided the synthesis and biological evaluation of new spiro molecules, which hereafter may serve as prototype for the design of new antibacterial and/or antitumor drugs (AU)