Photocontrol of Antibacterial Activity stars

  1. Elena Contreras García
Supervised by:
  1. Diego Sampedro Ruiz Director

Defence university: Universidad de La Rioja

Year of defence: 2020

  1. Santi Nonell Marrugat Chair
  2. Raúl Pérez Ruiz Secretary
  3. Tomás Slanina Committee member
Doctoral thesis with
  1. Mención internacional
  1. Chemistry
Doctoral Programme:
  1. Programa de Doctorado en Química por la Universidad de La Rioja

Type: Thesis


This doctoral thesis describes the design, synthesis, and evaluation of compounds whose antibacterial activity can be controlled using light. In the first chapter, a brief historical perspective in photochemistry and the use of light in medical therapy is introduced. From the evolution of these two areas have emerged different alternatives that rely on light stimuli to treat diverse diseases. The second chapter focuses on some of these alternatives: the photopharmacological approach and the use of photoreleasable protective groups to cage drugs. Photopharmacology is based on bioactive molecules that incorporate in their structure a molecular switch. The photoactive moiety can undergo an isomerization process that induces changes in the molecule properties like dipole moment, geometry, or electronics. These changes can result in isomers with different biological activity. Thus, a reversible system can be created where one isomer presents activity against the desired target while the other does not. On the contrary, the use of a photoreleasable protective group to cage a drug creates an irreversible system. The protective group is linked in a position that renders the drug inactive, upon light irradiation, the drug is released recovering its activity. These two options can help to solve some of the problems that classic pharmacological agents present. More specifically, the work here described is aimed at antibiotic drugs. The objectives of this thesis are listed in the third chapter. The fourth chapter focuses on the photopharmacological approach. Several molecules were designed with their structure based on quinolone antibiotics and a molecular switch linked in different positions. The molecular switches employed were based on the hydantoin structure and the pyrrole of the phytochrome chromophore. After their synthesis, their photochemical properties were evaluated. All of them were able to carry out the isomerization process with UV or visible light, and different photostationary states were found. Furthermore, the characteristics of one of the derivatives were studied more in-depth to test its efficiency and stability as a molecular switch. Finally, a study to evaluate possible changes in the activity of the initial isomers and the photostationary states obtained was carried out. The biological study showed that two compounds changed their activity after irradiation. The fifth chapter describes the caging process of ciprofloxacin, a quinolone antibiotic, using oxime esters. Different oxime parts were synthesized to try to achieve a bathochromic shift in their absorption. The coupling reaction between the oxime and the antibiotic was designed to form an oxime ester at position 3 of ciprofloxacin. This position is of great importance for the antibacterial activity of the drug. The study of the photochemical properties showed strong absorption in the UV region for all derivatives. The release reaction was successfully induced in all cases with good yields. Moreover, absorption in the visible region was achieved when tetrafluoroboric acid was added to the samples in halogenated solvents. A new band in the blue region of the spectrum appeared, making possible their irradiation with visible light. Finally, to improve the solubility in water of these compounds, one of the oxime esters was trapped in a polymeric micelle, which highly enhanced this property. Lastly, the sixth chapter also focuses on the caging technique and tries to solve some of the drawbacks that oxime esters present. In this chapter, a new photoreleasable group was employed, known as BODIPY. Several BODIPY structures were synthesized to achieve absorption inside the therapeutic window and make the molecules totally or partially soluble in water. This group was coupled at position 3 of two quinolones antibiotics: nalidixic acid and ciprofloxacin. All photoreleasable quinolones displayed absorption in the visible region varying from the green to the NIR region. Irradiation of the samples with visible light allowed the complete release of the antibiotic part in all cases. Furthermore, their stability and efficiency were evaluated. Finally, a biological study was performed to evaluate possible differences in the activity of the caged and uncaged compound. Results showed a strong deactivation of the antibacterial properties when the BODIPY group was linked to the antibiotic. Upon light irradiation, the activity of the drugs was recovered.