Synthesis And Bioactivities Evaluation Of1,3-thiazin-4-one Derivatives

Thiazinone ring structure is very popular in the field of pesticide and pharmaceutical applications, compounds with a thiazinone ring are used to prepare antifungal agents, anticancer drugs and pesticides. Based on1,3-thiazin-4-one, a total of39compounds of three categories were synthesized through rational molecular design. The compounds were confirmed and identificated by1H NMR、13C NMR and HRESI. The/hDHODH inhibition activities of all synthesized compounds were tested in vitro and at celluar level. Results in vitro showed that the inhibition activities of biphenyl series were better than benzene series, the bioactivities of aniline formylphenyl series were significantly higher than biphenyl series. Compound IPP187108in biphenyl series has the highest inhibition activity against hDHODH, IC50value is2.56μM; while, IC50value of compound IPP187210in aniline formylphenyl series is0.43μM. At the celluar level, the activities of aniline formylphenyl series were the best. When the substitutent located in4-position substitution of benzene ring in aniline formylphenyl series, the activity was genernally higher than others. The influence of electron donatings and the electron withdrawing of substitutents were not obvious on the activity. The inhibition activities of Compound IPP187115and IPP187212among them against T lymphocytes cell induced by ConA is0.11μM and0.17μM, respectively, which is much better than the control (IC50=6.94μM). Molecular docking showed that the binding mode of pheyl-4-thiazlone TM-1with/hDHODH was the same as teriflunomide(A771726), acting on Tyr356by hydrogen bonding. The binding mode of bipheyl-4-thiazlone TM-2was similar to A771726, there were hydrogen bonds mediated through water to Leu46in addition to direct H-bond interaction with Arg136. There was direct H-bond between the carbonyl oxygen atom of the compound IPP187102’s ester group and Tyr356and hydrogen bonds mediated through water between the carbonyl oxygen atom of thiazione ring and Arg136. In addition, the nematicidal activities of all target compounds were tested. The test results showed that the inhibition rate of compounds IPP187102、IPP187103、IPP187106、IPP187107, IPP187109. IPP187203、IPP187204、IPP187205were over90%at the concentration of20ppm. The inhibition rate of compound IPP187203reached to71.6%at a concentration of5ppm. Greenhouse tests of compound IPP187102and IPP187203are ongoing.