Synthesis And Biological Activity Of Aminothiazole Derivatives

Thiazole compounds are widely used in medicine,pesticides,fine chemicals and other fields because of the unique nitrogen,sulfur heterocyclic structure and wide bioactivity.We have sythesised thiazole compounds P6 and P12 with certain inhibition activity against Meloidogyne incongnita in our group.Based on this struacture,structural modification was carried out to find leading compounds with higher inhibition activity against Meloidogyne incongnita and other bioactivities.On basis of the structural analysis of compounds P6 and P12,29 amino thiazole compounds were designed and synthesized,and their inhibition activity against Meloidogyne incongnita was investigated.Although the nematicidal activity of the derivatives was not improved,we discovered the synergist effect between the target compounds and polymixin B,further investigation was carried out about the antibacterial activity and synergist effect of compounds with polymixin B.The results showed that the amino thiazole compounds have obvious synergist effect with polymixin B against the test strains(Acinetobacter baumannii ATCC19606 and Klebsiella pneumoniae SIPI-KPN-1712).When 4-trifluoromethy was introduced in the benzene ring of the amino thiazole structure,the antibacterial synergistic effect increased.On the basis of 4-trifluoromethylbenzimidothiazoles,at the 4-position of the thiazole ring,different substituted phenyl and aromatic heterocycles were introduced and 19 target compounds were synthesized.The synergistic antibacterial activity test showed that when the concentration of compounds was 4 μg ml-1 in combination theropy,most compounds can reduce the MIC of polymixin B.The MIC of polymixin B against Acinetobacter baumannii ATCC19606 could be decreased from 1 pg ml-1 to 0.125 μg ml-1 and 0.0625 μg ml-1 by compounds B6 and B16,respectively,and the MIC of polymixin B against Klebsiella pneumoniae SIPI-KPN-1712 could be decreased from 32 μg ml-1 to 1μg ml-1 and 4 μg ml-1 by compounds B6 and B16,respectively.Time-kill curves showed that the combination therapy can reduce the amount of polymyxin B and shorten the time to reach sustained sterilization effect.Moreover,the antimicrobial activity of target compounds against Gram-positive bacteria was significant.In order to improve their solubility,5 salts and a phosphonate prodrug of 4-trifluoromethylbenzimidothiazoles with better synergistic activity were synthesized.The solubility and synergistic activity of salts and prodrug were evaluated.The results showed that the target salt compounds maintained the synergistic activity with polymyxin B against Acinetobacter baumannii,but no significant increase in water solubility was observed.The prodrug’s water solubility was improved,its saturated solubility in pure water was 134.40 ppm,but the prodrug didn’t exhibit any synergistic activity in vitro,pharmacodynamic tests in vivo are in progress.