Abstract：
Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC50 values of 0.02-0.83 μM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO4 and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders.
摘要：
具有巯基取代基的化合物和唑类化合物表现出有效的抗酪氨酸酶效力。2-噻吩并噻唑(2-TBT),巯基和唑的杂化结构，以两种互变异构形式存在，根据几项研究，硫酮形式占优势。2-TBT衍生物被合成为潜在的酪氨酸酶抑制剂，因为硫酮互变异构形式具有与苯基硫脲（PTU）相同的N-CS部分，其适于与酪氨酸酶活性位点中存在的铜离子螯合。10种2-TBT衍生物中有8种抑制蘑菇酪氨酸酶的单酚酶和二酚酶活性，IC50值为0.02-0.83μM。进行动力学研究和分子动力学模拟以确定它们的作用模式并确认2-TBT衍生物以高稳定性结合酪氨酸酶活性位点。衍生物3、4、8和10强烈抑制B16F10细胞中的黑素生成，其模式类似于细胞酪氨酸酶抑制的结果，从而表明它们抑制黑素生成的能力是由于它们的酪氨酸酶抑制活性。在一个用斑马鱼胚胎进行的脱色实验中,所有2-TBT衍生物均显示出比曲酸更好的效力，即使浓度低400到2000倍，1和10即使在低20倍的浓度下也比PTU更强烈地减少斑马鱼幼虫的色素沉着。研究在存在和不存在CuSO4的情况下2-TBT衍生物的酪氨酸酶抑制活性变化及其铜螯合能力的实验表明，这些衍生物通过螯合酪氨酸酶的铜离子而发挥其抗黑色素生成作用。这些结果表明2-TBT衍生物是治疗色素沉着过度相关疾病的有希望的候选物。
