Revisão de estudos da combinação de fotossensibilizadores com inibidores de bomba de efluxo NorA na Terapia Fotodinâmica Antimicrobiana e planejamento de um híbrido de Azure A com Capsaicina

Abstract

Antimicrobial Photodynamic therapy (aPDT) is a method of inactivating microorganisms through photosensitization using a reactive compound in the presence of light (PS), that causes the release of reactive oxygen species (ROS), especially singlet oxygen (1O2), which are known for damaging cells. There are several classes of photosensitizers that can be applied in eukaryotic and prokaryotic cells, and its application in each case depends upon their chemical properties. Phenothiazine compounds were initially designed for Photodynamic therapy to tumor cells; however, due to their cationic nature and antibiotic activity even in the dark, they are studied in TFDA due to their high affinity to the bacterial cell walls, especially in Gram-positive. In addition, it is known that the photoactivity of these compounds is reduced in species of Gram-positive and Gram-negative bacteria as a consequence of the presence of efflux pumps in the membrane, that actively transport toxic substances throughout the cell, which confers Multiresistance to drugs in several microorganisms. The NorA efflux pump in Staphylococcus aureus is an example of a resistance mechanism, that has cationic compounds as substrates, such as phenothiazine PSs; therefore, the antibiotic activity becomes reduced. For the application of aPDT in these cells is necessary the use, throught synergy or throught modification of PSs, of efflux pump inhibitors, that are site competitors against photosensitizers and allow their incorporation into the membrane. In this project, known properties of phenothiazine compounds were revised, in addition to proposing a new structure based on the connection of Azure A (PS) to a NorA efflux pump inhibitor, Capsaicin. The synthesis routes for the target compound were tested in a model compound, where the etherification of the phenolic fragment of 2-methoxyphenol for subsequent amidation of the PS showed greater chemoselectivity when compared to amidation followed by nucleophilic substitution.