Isoíndigos e azaisoíndigos: síntese, caracterização, formação de análogos funcionalizados e avaliação de atividade biológica contra SARS-CoV-2.

Abstract

This doctoral thesis is an approach of the synthesis of heterocyclic substances such as derivatives of isoindigo and azaisoindigo with potential biological activity against SARS-CoV-2. The work was divided into three main parts: the first consisted of synthesizing 21 isatin derivatives from bromination, chlorination, nitration, N- acetylation and sodium borohydride reduction reactions. The second aspect, in turn, was the synthesis of 16 compounds 3’-hydroxy-bis-oxindoles and isoindigos via coupling methodologies described in the literature. The corresponding isatin derivatives were synthesized by coupling conditions with ZrCl4/EtOH/reflux or with HCl/AcOH/reflux, and the use of oxindole and functionalized isatins, obtaining 3’- hydroxy-bis-oxindoles as products, which were subsequently dehydrated into isoindigos. The third strand was the synthesis of azaisoindigos, from the same synthetic methodologies to carry out the coupling between isatin derivatives and the 7- azaoxindole molecule. A large part of the substances synthesized in this thesis were submitted to biological tests against SARS-CoV-2 through the assay with Vero E6 cells in a High Content Screening platform. These compounds were tested at a single concentration of 10 μM, with chloroquine used as a control. Preliminary results demonstrated that 5,7-dibromoisatin (EC50 = 1.98 μM and CC50 = 1.84 μM), 5'-bromo- 7-azaisoindigo (EC50 = 10.4 μM and CC50 = >10 μM), 7-azaoxindol-5'-chloro-3'- hydroxyoxindole (EC50 = 2.42 μM and CC50 = >10 μM) were the ones that presented the best results of biological activity against this virus, even superior to that of chloroquine (EC50 = 2.49 μM and CC50 = 9.49 μM).