Chiriapkin Alexey, Kodonidi Ivan, Pozdnyakov Dmitry
Department of Organic Chemistry, Рyatigorsk Medical Pharmaceutical Institute of Volgograd Medical State University, 357532, Pyatigorsk, Russia.
Department of Pharmacology with the course of clinical pharmacology, Рyatigorsk Medical Pharmaceutical Institute of Volgograd Medical State University, 357532, Pyatigorsk, Russia.
Iran J Pharm Res. 2022 May 13;21(1):e126557. doi: 10.5812/ijpr-126557. eCollection 2022 Dec.
The high prevalence of skin hyperpigmentation makes it necessary to search for remedies that could hinder this process. Among such substances, tyrosinase inhibitors can be distinguished, which may be pyrimidine derivatives.
This study aimed to investigate new compounds with anti-tyrosinase activity in 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one by an in vitro analysis and investigating their molecular docking.
A molecular docking was performed using AutoDock 4.0 with the 3-dimensional structure of tyrosinase of the fungus Agaricus bisporus from the Protein Data Bank (PDB; rcsb.org) with identification number 2Y9X. A synthesis of 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one was carried out during the heterocyclization reaction of azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide in glacial acetic acid with the addition of dimethyl sulfoxide. Tyrosinase activity was determined in vitro by the spectrophotometric method.
Molecular docking data suggest the feasibility of synthesizing 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one as possible tyrosinase inhibitors. Of particular interest are compounds with hydroxy groups in the radical. Next, pharmacological screening showed that the leading compound is 4g. It is likely that metal-ligand interactions are the main interactions in the active site of tyrosinase because kojic acid, hydroquinone, and lactic acid (reference compounds), as well as compounds with only hydroxy groups in phenyl substituents (4b, 4c, and 4g), have the greatest anti-tyrosinase activity.
As a result of molecular docking studies, the feasibility of synthesizing 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one as potential tyrosinase inhibitors was justified. 2-Substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one was obtained using new synthesis conditions. The leading compound is 4g containing a fragment of 2,4-dihydroxybenzene.
皮肤色素沉着过度的高发生率使得有必要寻找能够阻碍这一过程的治疗方法。在这类物质中，可以区分出酪氨酸酶抑制剂，其可能为嘧啶衍生物。
本研究旨在通过体外分析和分子对接研究，探究2-取代四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮中具有抗酪氨酸酶活性的新化合物。
使用AutoDock 4.0对来自蛋白质数据库（PDB；rcsb.org）、识别号为2Y9X的双孢蘑菇酪氨酸酶的三维结构进行分子对接。在2-氨基-4,5,6,7-四氢-1-苯并噻吩-3-甲酰胺的甲亚胺衍生物于冰醋酸中进行杂环化反应并添加二甲基亚砜的过程中，合成2-取代四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮。通过分光光度法体外测定酪氨酸酶活性。
分子对接数据表明合成2-取代四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮作为可能的酪氨酸酶抑制剂具有可行性。特别令人感兴趣的是基团中含有羟基的化合物。接下来，药理筛选表明先导化合物为4g。酪氨酸酶活性位点的主要相互作用可能是金属-配体相互作用，因为曲酸、对苯二酚和乳酸（参考化合物）以及苯基取代基中仅含羟基的化合物（4b、4c和4g）具有最大的抗酪氨酸酶活性。
作为分子对接研究的结果，合成2-取代四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮作为潜在酪氨酸酶抑制剂的可行性得到了验证。使用新的合成条件获得了2-取代四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮。先导化合物是含有2,4-二羟基苯片段的4g。
