1 research outputs found
Synthesis and Pharmacological Evaluation of Novel Adenine–Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents
This
work deals with the design, synthesis, and evaluation of the
cardioprotective properties of a number of novel hybrid compounds
combining the adenine nucleus with a suitable H<sub>2</sub>S slow-releasing
moiety, coupled via a stable ether bond. The H<sub>2</sub>S release
rate of the hybrids and their ability to increase cGMP were estimated
in vitro. The most promising derivatives <b>4</b> and <b>11</b>, both containing 4-hydroxythiobenzamide
moiety as H<sub>2</sub>S donor, were selected for further in vivo
evaluation. Their ability to release H<sub>2</sub>S in vivo was recorded
using a new fully validated UPLC-DAD method. Both compounds reduced
significantly the infarct size when administered at the end of sustained
ischemia. Mechanistic studies showed that they conferred enhanced
cardioprotection compared to adenine or 4-hydroxythiobenzamide. They
activate the PKG/PLN pathway in the ischemic myocardium, suggesting
that the combination of both pharmacophores results in synergistic
cardioprotective activity through the combination of both molecular
pathways that trigger cardioprotection