Synthesis And Bioactivity Of Purine Pentadienone Derivatives

Purine derivatives possess a wide range of pharmacological activities, including antiviral, antitumor, anti-inflammatory, anti-HBV, antimalarial and antiangiogenic activities, and purine represents a key moiety in novel good agrochemical and medicinal products developed recently, which make purine derivatives have great potential for being designed and used to develop several powerful drugs. 1,4-pentadien-3-one, a curcumin derivative, also exhibited potential biological activities, including antifungal, insecticidal, anticancer and antiviral activities. In our previous study, we have synthesized a series of 1,4-pentadien-3-one derivatives which displayed excellent antiviral bioactivity.This study hold the parent 1,4-pentadien-3-one skeleton and purine moiety together, aiming to synthesize a series of novel antiviral purine derivatives containing 1,4-pentadien-3-one moiety. 25 target compounds A1–A25 were synthesized. The structures of all the target compounds were elucidated by elemental analysis, IR, 1H NMR and 13 C NMR spectra. The results of my findings and all work are outlined below:1. Compound A7 as an model, the reaction conditions of compounds was optimized, involved with investigation of reaction solvents, material mole ratio, catalysts, reaction temperature and reaction time. The optimized reaction condition was using DMF as solvent, KOH as an acid binding agent, under 40 °C stirring for refluxing 2 h.2. The antiviral activities against CMV of the title compounds A1–A25 were tested in vivo using the half leaf method. Most of the title compounds showed excellent antiviral activities against CMV in vivo. Compounds A1(60.9%), A3(59.8%), and A12(58.4%) at 500 μg/m L exhibited similar curative activities to Ningnanmycin(61.4%). Meanwhile, compounds A1(71.1%), A3(64.2%), A5(61.2%), A7(62.2%), A11(68.4%), and A17(60.6%) exhibited higher protection activities than Ningnanmycin(59.0%). However, the inactivation activities of the titlecompounds(31.2% to 80.0%) against CMV were lower than that of Ningnanmycin(89.2%). On the basis of previous bioassays, the 50% effective concentration(EC50) values of protective activities against CMV of the title compounds were tested. The test results indicated that compounds A1, A3, A5, A7, A18, and A19 exhibited remarkable protection activities against CMV, with EC50 values of 189.0, 194.6, 125.6, 134.1, 137.8, and 195.4 μg/m L, respectively, which were even better than that of Ningnanmycin(271.1 μg/m L).3. The structure-activity relationship(SAR) of the compounds was studied using the three-dimensional quantitative structure-activity relationship(3D-QSAR) method of comparative molecular field analysis(Co MFA) based on the protection activities against CMV EC50 values. 17 molecules of total compounds were randomly chosen as the training set for Co MFA model and the other 8 compounds were used as the testing model.The results demonstrated that the Co MFA model exhibited good predictive ability with the non-cross-validated r2 and cross-validated q2 values of 0.927 and 0.501, respectively.