New potent inhibitors of tyrosinase: novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site.
A series of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides were tailored and synthesized as new potent inhibitors of tyrosinase. The rationale for inhibitor design was based on the active site structural evidence from the crystal structures of bacterial tyrosinase and potato catechol oxidase enzymes. Kinetic and active site binding studies suggested mono-dentate binding of thiadiazole, oxadiazole, and triazole rings to the active site dicopper center of tyrosinase including hydrophobicity contributing to the potent inhibition. Kinetic plots showed mixed-type of inhibition by all 25 compounds. Substitutions at C3 of the triazole ring and C5 of the thiadiazole/oxadiazole rings were found to be playing a major role in the high binding affinity to tyrosinase. The current work may help develop new potent tyrosinase inhibitors against hyperpigmentation including potential insecticides.
Ghani
Usman
U
Department of Medical Biochemistry, King Saud University, Riyadh 11461, Saudi Arabia. ughani@ksu.edu.sa
Ullah
Nisar
N
D000818:Animals; D001393:Azoles / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins; D020134:Catalytic Domain; D004156:Catechol Oxidase / Q000037:antagonists & inhibitors; D003300:Copper; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006801:Humans; D017495:Hyperpigmentation / Q000188:drug therapy / Q000517:prevention & control; D007700:Kinetics; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D011198:Solanum tuberosum; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001393:Azoles; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013871:Thiones; D003300:Copper; D004156:Catechol Oxidase; D014442:Monophenol Monooxygenase