Department of Physiology & Biochemistry, Cholistan University of Veterinary and Animal Sciences , Bahawalpur, Punjab , Pakistan.
Department of Chemistry, Allama Iqbal Open University , Islamabad , Pakistan.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1-11. doi: 10.1080/14756366.2019.1654468.
The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives and as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives and was determined and it was found that derivative possesses excellent activity with IC = 0.0089 µM compared to standard kojic acid (IC = 16.69 µM). The presence of hydroxyl groups at the and the position of cinnamic acid phenyl ring in compound plays a vital role in tyrosinase inhibitory activity. The compound also exhibited good activity (IC = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound is a competitive inhibitor while is a mixed-type inhibitor. The mode of binding for compounds and with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative formed stable complex with target protein. The cytotoxicity results showed that compound is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound may serve as a lead structure to design more potent antimelanogenic agents.
黑色素生成酶如酪氨酸酶的过度表达导致了许多色素沉着紊乱。本工作描述了羟基取代的 2-[(4-乙酰苯基)氨基]-2-氧代乙基衍生物 和 的合成，作为抗黑色素生成剂。合成衍生物 和 的酪氨酸酶抑制活性被测定，发现衍生物 具有优异的活性，IC = 0.0089 μM，与标准曲酸（IC = 16.69 μM）相比。肉桂酸苯环上和 位置的羟基的存在对酪氨酸酶抑制活性起着至关重要的作用。化合物 也表现出良好的活性（IC = 8.26 μM），与标准曲酸相比。酶抑制动力学结果表明，化合物 是一种竞争性抑制剂，而 是一种混合型抑制剂。还评估了化合物 与酪氨酸酶的结合方式，发现两种衍生物均不可逆地与靶酶结合。还进行了分子对接和分子动力学模拟研究，以确定合成化合物在酪氨酸酶（PDB ID 2Y9X）上的结合位置。结果表明，所有合成的化合物都与活性结合位点结合良好，最有效的衍生物 与靶蛋白形成稳定的复合物。细胞毒性结果表明，化合物 在 12 μg/mL 剂量下对小鼠黑色素瘤（B16F10）细胞是安全的。选择相同剂量的 来确定抗黑色素生成活性；结果表明，它在小鼠黑色素瘤（B16F10）细胞中产生了抗黑色素生成作用。基于我们的研究，提出化合物 可能作为设计更有效的抗黑色素生成剂的先导结构。
