Planejamento e síntese de inibidores de B-Lactamases baseados em ácidos acrílicos: uma abordagem para combater a resistência bacteriana

Abstract

Bacterial resistance is the ability of bacteria to adapt to antibiotics through biochemical mechanisms, representing one of the greatest public health challenges of the 21st century. It is estimated that by 2050, bacterial infections will affect approximately 10 million people worldwide. Resistance to β-lactam antibiotics, which act by inhibiting bacterial cell wall biosynthesis, is particularly concerning as they are considered the last therapeutic resort for treating many infections. The main resistance mechanism involved is the production of serine β-lactamases (SβLs) and metallo-β-lactamases (MβLs), enzymes that degrade the β-lactam ring of these antibiotics. In this context, Brem et al. (2014) identified the compound ML302F as an MβL inhibitor, with an IC50 value of 0.30 μM and a Ki of 183 ± 24 nM. Based on this, the objective of this work was to design and develop 10 analogs containing modifications in the aromatic portion and the substitution of the thiol group with a cyano group on the α-carbon of the double bond. The employed synthetic methodology proved satisfactory for obtaining intermediate and final compounds, with yields ranging from 46.01% to 93.01% and purity above 95%. Furthermore, by determining in silico ADME properties, it was predicted that the 2-cyanoacrylic acid derivatives do not violate Lipinski's and Veber's rules. Finally, the synthesized 2-cyanoacrylic acid derivatives will subsequently be evaluated for their ability to inhibit β-lactamase enzymes in synergy with β-lactam antibiotics, contributing to the development of potent, low-cost, and relatively non-toxic inhibitors for a new approach to bacterial infection treatment.