Design,Synthesis And Bioactivity Of Inhibitors On Tyrosinase

As the "3R" problems getting serious, the pesticides with low toxicity,pleasant safety to non-target organism are becoming more popular in crop protection. Design based on the target is a potent way to find new agrochemicals.Tyrosinase is widely distributed in nature, and is a metalloenzyme oxidase in melanin synthesis with important physiological functions. Tyrosinase chosen as a target, research works were done and the results described as follows:1. Based on related literatures and the structure of tyrosinase, four series of compounds were designed by chosen cinnamaldehyde and phenylthiourea as lead compounds. In this study, four series of 151 compounds were designed while considering substructure link principle and anti-tyrosinase as well as insecticidal, fungicidal, herbicidal activity were tested. Their general structures are shown below.2. All compounds against mushroom tyrosinase showed certain inhibitory activity. Most of series I showed better than lead cinnamaldehyde. Series ⅡB showed higher activity than series ⅡA, and most of the ⅡB series were better than control kojic acid. Most of series Ⅲ compounds showed higher inhibitory activity than kojic acid against mushroom tyrosinase (Activity: ⅢA=ⅢB>ⅢC-ⅢD), among them, ⅢA-05, ⅢA-15 and ⅢA-18 exhibited best inhibitory activity. ⅢA and ⅢB showed higher inhibitory activity than kojic acid and tropolone against Helicoverpa armigera tyrosinase. Series Ⅳ showed certain activity, but compared with lead ⅢB-02 andⅢB-03, no obvious improving. The kinetic assay of ⅡB-06 and ⅢA-18 was studied, and the result indicated that they were non-competitive inhibitors of tyrosinase.3. The result of docking study showed compounds with high activity almost got high score. The binding mode of series Ⅱmight be that the part of phenylthiourea was near Cu ion and hydrogen bond was formed between H of N-H and GLY281. The binding mode of series Ⅲ might be not only hydrogen bond formed between H of N-H and GLY281, but also amino acid residues ASN 260, HIS 263 and so on..4. All target compounds exhibited certain fungicidal activity. Series Ⅰ showed certain activity against F. graminearum, B. cinerea, and C. lagenarium. Series ⅢB showed higher activity than series ⅡA, especially ⅡB-04 exhibited equal activity with Polyoxin B against B. cinerea. SeriesⅢ showed certain fungicidal activity (Activity: ⅢA=ⅢB>ⅢC=ⅢD),and some compounds exhibited better activity than Polyoxin B, especially ⅢB-02 and ⅢB-03. But series Ⅳ exhibited weaker fungicidal activity than ⅢB-02 and ⅢB-03.5. Further fungicidal study of ⅢB-02 and ⅢB-03 showed good activity against 11 fungi. ⅢB-03 showed better activity than Difenoconazole against R. solani, while ⅢB-02 showed good activity against 11 strains of G. graminis. Field efficacy study showed ⅢB-02 had equal activity with Latitude without damage to crops.6. All the target compounds showed few insecticidal,herbicidal activity,except Ⅰ-13 showed good herbicidal activity.Among of 151 target compounds of this study. 3 compounds (ⅢA-05, ⅢA-15 and ⅢA-18)exhibited higher inhibitory activity against mushroom tyrosinase,and they were proved to be non-competitive inhibitors. 2 compounds (ⅢB-02 and ⅢB-03) exhibited higher inhibitory activity against fungi,especially against G.graminis which need to further study. Comparing the anti-tyrosinase activity and fungicidal activity, we speculated the tyrosinase might be a key enzyme in fungi and it might be a effective way to screen new compounds.