Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity

摘要

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b] thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 mu M) value which is significantly lower than the activity of trimethoprim (IC50 39.23 mu M). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 mu M). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 similar to 880 mu M). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 mu M. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 mu M), respectively, which is ten times higher than well-known antioxidant BHT. (C) 2019 Elsevier Masson SAS. All rights reserved.