Síntese de novos híbridos moleculares contendo núcleos heterocíclicos e ferroceno com potencial atividade anticâncer

Abstract

Cancer is a frightening disease that has an arsenal of more than 100 different types of diseases that plague thousands of people worldwide. The tenacity of this pathology requires the search for effective treatments, and one of the main methods is called chemotherapy. Although widely used, multiple drugs resistance (MDR) decreases the efficiency of treatment. Based on these challenges, the concept of molecular hybridization is used, an effective synthetic strategy explored among synthetic organic chemists and employed in this work. The design of compounds containing the pharmacophoric groups was rationalized: heterocycles (pyrimidine, pyrazole and triazole), naphthoquinone and the ferrocene scaffolds. Six chalcones (276a-f) were obtained, essential precursors, containing the ferrocenic or triazolic portion through the Claisen-Schmidt reaction, in intervals of 3-240h and yields of 45-97%, being 276f inedited. Then, eleven molecular hybrids (277a-f, 278a-c and 279) were synthesized, seven of them unpublished (277cf, 278b-c and 279), through different methodologies, such as Biginelli reaction modify by Atwal and cyclocondensation (both optimized by microwave) and also Mannich reaction, with reaction times of 5min-24h and yields of 52-78%. In addition, eight crystals were obtained, seven of which were deposited in the crystallography database for the first time, for unequivocal confirmation of the proposed structures. The anticancer activity of the 276d-f triazole chalcones against PC-3 prostate cancer cells was also evaluated, obtaining an IC50 of 28.55 µM for 276d. While the molecular hybrids 277a-f, 278a-c and 279 were tested against four cancer cell lines - HCT116, PC-3, HL-60 and SNB-19 - where compound 278c stood out against HCT116 and SNB-19 with IC50 of 3.12 and 60, 44 µM, respectively. While 277a showed promise against HL-60 with an IC50 of 3.98 µM and still 279 showed greater activity against the PC-3 cell line with an IC50 of 36.59 µM. Computational studies of structure-activity relationship (SAR) of the tested triazole chalcones were developed, where the results showed that the polarity of the molecular surface area must have some relevance for the efficiency of the compounds. In addition, molecular docking simulation and machine learning methods were performed for the molecular hybrids 277a-f and 278a-c. For compounds 277a and 278c that showed the best values of biological activity for HCT116, SNB-19 and HL60, promising binding energies of -8.3, -7.4 and -7.6 Kcal.mol-1 were obtained, respectively, if compared to the crystallographic ligands of the respective target.