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      Synthesis and Pharmacological Evaluation of Novel Adenine-Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents.

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          Abstract

          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 H2S slow-releasing moiety, coupled via a stable ether bond. The H2S release rate of the hybrids and their ability to increase cGMP were estimated in vitro. The most promising derivatives 4 and 11, both containing 4-hydroxythiobenzamide moiety as H2S donor, were selected for further in vivo evaluation. Their ability to release H2S 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.

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          Author and article information

          Journal
          J. Med. Chem.
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          1520-4804
          0022-2623
          Mar 10 2016
          : 59
          : 5
          Affiliations
          [1 ] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
          [2 ] Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg , 91054 Erlangen, Germany.
          [3 ] Second University Department of Cardiology, Medical School, Attikon General Hospital, National and Kapodistrian University of Athens, 12462, Athens, Greece.
          [4 ] Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
          Article
          10.1021/acs.jmedchem.5b01223
          26809888

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