Síntese, caracterização e avaliação biológica de derivados quinazolínicos inibidores da proteína FtsZ

Abstract

As a result of the increasing demand for new compounds with antibiotic potencial, mainly due to resistance mechanisms developed by bacteria, it is important to search for new drugs that act on biological targets different from those already known. This project is part of the program coordinated by professor Jared Shaw from University of California, Davis, which aims to discover new natural or synthetic compounds capable of inhibiting the protein FtsZ, that are related to the bacterial cell division process. Initially, the synthesis of several compounds was planned using the quinazoline nucleus of the zantrin Z3 (10) as model molecule, which can be substituted in positions 2, 4 and 6 , named by regions 3, 2, and 1, respectively. In this work, analogous of 10 were synthesized with different substituents in region 3, which were evaluated as potential inhibitors of the protein FtsZ. Further, intermediates 28–38 were prepared through a reaction which its mechanism is known as Horner-Wadsworth-Emmons. Then, these compounds were purified by flash chromatography using the Teledyne ISCO CombiFlashRf+ equipment. Additionally, the protection group was removed from the intermediates (28–38) through a reaction using a solution of HCl 2M in methanol to obtain the analogous 39–48. Characterization of the synthesized compounds was made by spectroscopy (1H and 13C nuclear magnetic resonance) and spectrometric methods (mass spectrometry) and the evaluation of the inhibitory activity of the FtsZ was made for the analogous 44 and 45, which exhibited IC50 values of 626 and 836 µM, respectively. These results when compared to the zantrin Z3 (9,4 µM), suggest that the isopropyl and terc-butyl substitutes from analogous 44 and 45 did not contribute for the enzyme inhibition.