Synthesis and protective effect of isosorbide mononitrate acetyl ferulate amide on ischemic myocardium in rats

AIM:To design and synthesize isosorbide mononitrate acetyl ferulate amide (AcFA-201) and to study the protective effect of AcFA-201 on myocardial ischemia/reperfusion (MI/R) injury in rats. We compared its effect with that of sodium ferulate (SF), isosorbide mononitrate (ISMN) and isosorbide mononitrate acetyl ferulic acid ester (AFI) and compared the stability of AFI and AcFA-201 in simulated gastric fluid. METHODS: We first translated the hydroxyl of ISMN into amino, caused it to react with acetylated ferulic oxychloride and then obtained AcFA-201 with chemical yield of 81.8%. Male Sprague Dawley rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion and then randomly received one of the following treatments separately: SF, ISMN, AFI or AcFA-201. The recovery of cardiac function was recorded and serum creatine kinase (CK) activity, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, hydrogen peroxide (H2O2) level, malondialdehyde (MDA) and nitric oxide (NO) content were determined at the end of reperfusion. RESULTS: Synthetic route was feasible and the chemical yield of AcFA-201 was 81.8%. Studies of the stability in simulated gastric fluid showed that little AFI remained after 10 min and disappeared in 30 min. Meanwhile, AcFA-201 retained the initial drug concentration even 180 min after dosing. Compared with SF and ISMN treatment groups, AcFA-201 treatment group significantly improved cardiac functions as evidenced by increasing left ventricular development pressure (LVDP) and ±dp/dtmax (n=8, P<0.05), reducing serum CK and LDH activities as well as H2O2 and MDA levels and obviously increasing NO content. However, no significant differences were observed between AcFA-201 group and AFI group. CONCLUSION: AcFA-201 showed a stronger cardioprotective effect against MI/R injury than SF and ISMN and there was no significant difference between AcFA-201 and AFI. AcFA-201 is more stable than AFI in simulated gastric fluid and AcFA-201 is thus more suitable for the development of oral drugs.