Estudo de Chalconas como Antibacterianos Potenciais: Síntese, Avaliação da Ação Antibacteriana e das Propriedades Físico-químicas

Abstract

Chalcones are vegetal origin compounds and they present a simple chemical structure which is widely used as a molecule prototype in order to obtain new bioactive compounds by structural changes in their aromatic rings. Such fact is important as the American Society of Infectious Diseases has released the “10 x 20” initiative, meaning the fast development of 10 new antibiotics up to 2020. This study aims to obtain and establish chalcone’s physical- chemical and biological properties with potential antibacterial activity. The molecules were designed by the classic bioisosterismo classic methodology, proposing the modification of the hydroxyl existent in licochalcone’s position 4 of ring A in the amino group, in ring B groups were introduced in para and meta positions, with variable degrees of electronical effects, according to the usage of Craig ́s Diagram. The replaced aminochalcones were synthesized by the Claissen-Schimdt reaction with equimolar quantities of 4-aminoacetophenone and varied benzaldehydes and purified by column chromatography or recrystallization for further characterization by infrared spectroscopy and nuclear magnetic resonance. The evaluation of the antibacterial and synergic activity was made through Microdilution Methods described by the Clinical and Laboratory Standards Institute and checkerboard test against reference strains of gram-positive and gram-negative (Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922), plus S. aureus meticillin resistant (N315). Spartan’08 for Windows was the computational program used to establish the 3D chemical structure and the HOMO’s and LUMO’s energy amount figures. The theoretical study of Physical-chemical properties was accomplished by Chem3D Ultra, Molinspiration and MarvinSketch 6.2 programs. In order to theoretically study both toxicity and profile of druglikeness and drugscore, Osiris Property Explorer program was used. The compounds 1, 3 and 7 showed the smallest CIM values when against both S. aureus strains, which suggests that the bacterial resistance mechanism doesn’t affect the 4-aminochalcones activity. Compounds 5 and 8 were more actives against strains E. coli. There was no significant interaction among the 4- aminochalconas and the antibiotics tested (oxacilin and chloramphenicol). Throughout the structural-activity relation evaluation, it was verified that compound 8 presented several parameters that may justify its action facing Gram-negative bacteria, such as the growth of its molecular weight and decreased values of cLogP and LogD7,4 . Levofloxacin superior results were also certified when its potential of druglikeness and drugscore were figured. All the compounds have presented a high theoretical risk to the mutagenic effect and low toxicological profile to the irritant effect. Relating to the effects in the reproductive system, only compound 1 has presented a mid-risk and compound 2 and 3 high risk to tumorigenic effect. Even though these molecules have showed low antibacterial activity, they might outline changes in their structure aiming the biological action growth as they all fit the Rule of Five parameters and as a result, they tend toward a good oral bioavailability.