Planejamento estrutural, síntese e avaliação farmacológica de inéditos tiazóis para tratamento do Câncer e das Doenças Negligenciadas

Abstract

Cancer is the clonal expansion of malignant cells, whose disordered growth promotes tissue and organ invasion. The available chemotherapic drugs present issues regarding specificity and potential. Neglected diseases comprise a group of communicable diseases that mostly occur in tropical countries. In this group, Chagas Disease and Leishmaniasis stand out as the main parasitic diseases, and Zika virus fever (ZIKV), considered a threat to global health. Treatment for Chagas disease and Leishmaniosis is still very limited and there is no specific treatment for ZIKV. Therefore, there is a need for new therapies against these diseases. The literature reports that the thiazole group has a range of biological activities, with an emphasis on antitumor, antiparasitic and antiviral activity. Thus, this work presents the planning, synthesis, and pharmacological evaluation of 46 thiazoles derived from isatin and from aryloxythiosemicarbazone. The compounds derived from isatin were synthesized and tested against lineages of breast cancer, trypomastigote and amastigote forms of T. cruzi, and promastigote and amastigote forms of L. amazonensis and L. infantum. On the other hand, the aryloxythiosemicarbazone derivatives were synthesized and evaluated against ZIKV. Among the tested compounds, LAB-2C and LAB-2A stood out for antitumor activity with IC50 values of 1.23 and 1.39 uM, respectively, compared to the MDA-MB-231 strain and both IC50 values 0.45 uM for an MCF-7 strain. Regarding antiparasitic activity, LAB-1N stood out against the trypomastigote form of T. cruzi (IC50 1.72 uM), with non-parasitic ultrastructural changes and induction of a marking compatible with necrosis being observed, as well as good activity against promastigotes of L. amazonensis and L. infantum, with IC50 values of 6.17 and 6.04 uM, respectively. Regarding the activity against ZIKV, DLT-1I and DLT-1H stood out with higher percentages of virus inhibition, with 99.92% and 99.77%, respectively. Overall, this work presents promising compounds for multiple targets such as antitumor, antiparasitic, and antiviral activity against ZIKV.