In this study, a series of new organic compounds with piperazine as a fundamental skeleton was synthesized and evaluated for their tyrosinase inhibitory potentials by in vitro and in silico studies. The in vitro studies have shown that compounds 10a and 10b bearing 1,2,4, triazole nucleus could be considered potent tyrosinase inhibitors with IC 50 values of 31.2 ± 0.7 and 30.7 ± 0.2 µM, respectively. 10b (K i = 9.54 µM, mixed type inhibition) with the lowest IC 50 value among derivatives was selected to determine kinetic constants and inhibition types. Furthermore, molecular docking analysis was performed for all compounds and it was observed that 4b, 5a, 4c, and 10b showed promising inhibitory effect on tyrosinase activity. Based on docking results, ADME predictions and in vitro studies, 10b might be considered suitable oral drug candidates for further studies.

No abstract

Many toxic insecticides used worldwide are organophosphates (OPs) derivatives. Phosphotriesterase (PTE) has been rewarding to protect against OP poisoning in vivo or in vitro, associated with advanced catalytic efficiency and stereoselectivity toward the hydrolysis of OPs. Phosphotriesterase homology protein (PHP) exhibits high sequence identity and similarity to PTE. In this study, site-directed mutagenesis on recombinant Geobacillus caldoxylosilyticus TK4 PHP (TK4PHP) was performed for improving the existing esterase activity, even gaining a new PTE activity. After eliminating the deficiencies in the recombinant TK4PHP gene, mutant proteins were purified and characterized biochemically. Considering all the data obtained, it was determined that the major sequence differences between PTE and TK4PHP were removed by three site-directed mutations. However the mutant TK4PHPs did not have PTE activity, it was informed that mutant esterases were more resistance to some metal ions and organic solvents and more thermal stable when it was compared with recombinant type.