Synthesis, Oral Bioavailability Evaluation And Antiplatelet Aggregation Activity Of Three Derivatives Of 3,4-Dihydroxyacetophenone

3,4-Dihydroxyacetophenone (DHAP) exerts therapeutic effects on cardiovascular disease and pulmonary heart disease. However, it is not utilized as a clinical drug due to its rapid metabolism, short-acting effect and low oral bioavailability. In the present study, three derivatives of DHAP, including 4-acetyl-1,2-phenylene dipropionate (APDP), 1-(3-hydroxy-4-phenoxy-phenyl)-ethanone (HPPE) and a polymer derivative, PEG-DHAP, were synthesized via the esterification or etherification of hydroxyls at C3 and C4, which are the prime metabolism sites of DHAP. The physicochemical properties, pharmacokinetic and antiplatelet aggregation activities of these derivatives were measured to determine whether they can improve the defects of DHAP. The results revealed that APDP and HPPE exhibited markedly lower water solubility and higher oil-water partition coefficients compared to DHAP. APDP rapidly transformed into DHAP in vivo and in vitro, indicating that there were no significant differences in the values of mean residence time in vivo [MRT (0-t)], half-life [t(1/2)], oral bioavailability and antiplatelet aggregation activity in vivo and in vitro between the two agents. HPPE partially released DHAP for a period of time following oral administration. PEG-DHAP contained 12.47% DHAP dispersed into nanoparticles with a mean particle size of 260.90 nm. This was administered in aqueous solution and was demonstrated to release DHAP slowly following oral administration. These two derivatives significantly prolonged the in vivo acting time and increased the oral bioavailability of DHAP: Following intragastric administration, their MRT (0-t) and t(1/2) values were 3.55-11.47- and 6.63-11.25-fold higher compared with those of DHAP, respectively. Additionally, their relative bioavailability was 394.79 and 331.88%, respectively, and they exhibited longer acting times of significant antiplatelet aggregation activity. The results of the present study may thus provide a reference for the development of DHAP as an oral drug. Furthermore, the results if this study may prove to be useful to researchers addressing the issue of the poor bioavailability of phenolic drugs.