Antiparisitic, antimicrobial and antiviral agents Flashcards
What is a brief overview of the mechanism of malaria?
Parasite breaks down red blood cells by cutting up haemoglobin to produce amino acids for itself, then stores resulting heme units as hemozoin
What key process can we attack in the context of malaria?
Formation of hemozoin - heme units are toxic to the parasite and it avoids toxicity by formation of hemozoin. Inhibit formation, parasite dies by heme.
What interactions does chloroquine disrupt in the parasite responsible for malaria?
Positive charge of chloroquine disrupts formation of carboxylic acid salt bridges, and aromatic system on chloroquine disrupts pi-pi stacking through intercalation.
How does ferroquine work?
Ferroquine = ferrocene + chloroquine.
Chloroquine disrupts carboxylate salt bridges with positive charge and pi-pi stacking interactions through intercalation with aromatic parts. This prevents formation of hemozoin, allowing build-up of toxic heme.
Ferrocene addition generates ROSs which react with fatty acid membrane of parasite’s vacuole
What is the logic behind the design of ferroquine?
Taking ferrocene with all its cool chemistry and appending a known drug molecule
What mechanisms of action does silver undergo?
Silver will mismetallate with zinc fingers, bind to sulfur (prevent formation of disulfide bridges) and destabilise Fe-S clusters (which undergo catalytic redox processes)
How do metal complexes work against tuberculosis?
Formation of isonicotinoyl radical via KatG mediated reaction to form disruption of cell wall biosynthesis. Metal complexes allow for formation of this radical without use of the KatG enzyme (often reduced in resistance).
How do metal complexes work against H.pylori?
Mismetallation of Bi vs Ni in bacterial enzyme leads to suppression of NH3 production which prevents burrowing and protection of bacteria from low pH, clusters precipitate at ulcer providing protective layer and salicylate ligand may be acting as an anti-inflammatory
What is mismetallation and how does it cause problems?
Mismetallation is the replacement of the active metal by an inactive metal. It may disrupt structure or function or both.
How does catalysis work as a mode of action?
Catalysis of ROS - promotes uncontrolled formation of ROS via catalytic mechanism
Why are exchange kinetics important and what factors can impact them?
Exchange kinetics are important because hydrolysis of complexes can impact activity. Other ligands (either via sterics or electronics) can play a role in affecting the exchange kinetics or enable dual-action drugs based on additional shrubbery.
