Planejamento, síntese e avaliação in silico de compostos α, β- insaturados atuarem como possíveis antibacteriano e inibidores de β-lactamases

Abstract

Enzymatic inhibition results in the ineffectiveness of some mechanisms of bacterial resistance, therefore the compounds reported in the present study were designed with the intention of acting as potential inhibitors, and must interact with the active sites of β-lactamases and through an addition reaction Michael's covalently bonding to it, preventing hydrolysis of the β-lactam ring; the ability to act as a possible antibacterial was further evaluated. For this purpose, docking studies were initially carried out with the AutoDockTools version 1.5.6 program for the main β-lactamases: ESBL (Extended Spectrum β-lactamase) and Oxacillinase; in addition to this, the inhibition of Protein Binding Penicillin (PBP) and 16S rRNA was also tested to verify other mechanisms of antibacterial action of twelve compounds. The reactions took place by Knoevenagel condensation in a basic medium and the structures of five compounds were proven, using 1H and 13C NMR spectroscopy. Hemolytic potential can be assessed from human erythrocytes to solutions with a concentration of 5%. The presumptive antibacterial evaluation was carried out by successive dilutions for E. Coli ATCC25922. Mostly the twelve planned molecules showed promising results in relation to the co-crystallized ligands and the inhibition constants for the series of compounds, with APB being the most promising for all targets, mainly for oxacillinase when related both energetic aspects and inhibition constant having these ranged from -7.59 to -7.76 Kcal.mol-1 and 2.75 to 2.06 nM for APB-03 and APB-02 respectively. The in silico pharmacokinetic predictions concluded that all compounds were consistent with the criteria of druglikeness established by Lipinski, Ghose and Egan, pharmacokinetics, toxicity and eco-toxicity. Further studies will be necessary in order to carry out new characterizations and to evaluate antibacterial and modulating activities in vitro. All the planned compounds were synthesized, with yields varying between 33.04 and 99.04%. Its purity can be assumed by the melting range technique, varying from 1 to 3 ºC; in NMR spectroscopies they showed diagnostic signs indicating the success of the reaction, such as chemical shifts to hydrogen (8.19 ppm, s, 1H) and characteristic vinyl carbons (151 and 107 ppm). Hemolytic potentials could be assessed, which, with the exception of APB-02, showed values below 10%.