Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan.
Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, 616, Birkat Al Mauz, Nizwa, Sultanate of Oman.
Sci Rep. 2024 Oct 28;14(1):25754. doi: 10.1038/s41598-024-75100-1.
Tyrosinase is an enzyme crucial for the progression of melanogenesis. Immoderate production of melanin may be the cause of hyperpigmentation and darkening leading to skin diseases. Tyrosinase is the most researched target for suppressing melanogenesis since it catalyzes the rate-limiting stage of melanin production. Thiosemicarbazones have been reported to possess strong inhibition capability against tyrosinase. We have designed and synthesized eighteen N-tosyl substituted indole-based thiosemicarbazones as competitive tyrosinase inhibitors in the current work. All the compounds exhibited outstanding to good potency with half maximal inhibitory concentration in the range of 6.40 ± 0.21 µM to 61.84 ± 1.47 µM. The compound 5r displayed the top-tier inhibition amongst the entire series with IC = 6.40 ± 0.21 µM. Compounds, 5q and 5r exhibited competitive inhibitions in concentration dependent manner with Ki = 3.42 ± 0.03 and 10.25 ± 0.08 µM respectively. The binding mode of 5r was evaluated through in silico molecular dynamics simulations and molecular docking, while ADME assessment studies predicted the drug-like characteristics of the derivatives. The newly synthesized derivatives may serve as a structural guide for designing and developing novel tyrosinase inhibitors.
酪氨酸酶是黑色素生成进展过程中的关键酶。黑色素的过度产生可能是导致色素沉着和皮肤变黑的原因，进而引发皮肤疾病。由于酪氨酸酶催化黑色素生成的限速阶段，因此它是研究用于抑制黑色素生成的最主要靶标。据报道，硫代氨基甲脒类化合物对酪氨酸酶具有很强的抑制能力。在当前的工作中，我们设计并合成了十八个 N-对甲苯磺酰基取代的吲哚基硫代氨基甲脒作为竞争性酪氨酸酶抑制剂。所有化合物都表现出出色到良好的效力，半数最大抑制浓度（IC50）范围为 6.40±0.21µM 至 61.84±1.47µM。化合物 5r 在整个系列中表现出最佳的抑制作用，IC50 值为 6.40±0.21µM。化合物 5q 和 5r 以浓度依赖的方式表现出竞争性抑制，Ki 值分别为 3.42±0.03µM 和 10.25±0.08µM。通过计算机分子动力学模拟和分子对接评估了 5r 的结合模式，同时 ADME 评估研究预测了衍生物的类药性特征。新合成的衍生物可能为设计和开发新型酪氨酸酶抑制剂提供结构指导。
