Abstract：
BACKGROUND: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives.
OBJECTIVE: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent.
METHODS: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity.
RESULTS: The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively.
CONCLUSIONS: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.
OBJECTIVE: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent.
METHODS: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity.
RESULTS: The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively.
CONCLUSIONS: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.
摘要：
背景：根据报告，2022年，印度抑郁症患病率为4.50%，案件为56,675,969起。抗抑郁药的开发减少了抑郁症和自杀病例的数量。许多研究人员发现嘧啶具有抗抑郁活性。在这样的背景下,我们想到了嘧啶衍生物的合成。
目的：本研究的目的是进行分子对接，合成，表征，和评价2-((4,6-二苯基嘧啶-2-基)氧基)-N-苯基乙酰胺衍生物(17-26)作为体内抗抑郁药。
方法：使用Molegro虚拟Docker（MVD）检查设计的化合物的活性，并进一步合成。苯甲醛与苯乙酮反应得到化合物(3),与脲反应后得到化合物(4)。在另一个反应中，使取代的苯胺(5)与氯乙酰氯(6)反应,得到化合物(7-16),其在与化合物(4)进一步反应后得到最终的衍生物(17-26)。通过光谱分析对合成的化合物进行了表征，并检查了其抗抑郁活性。
结果:衍生物的MolDock评分范围为-147.097至-182.095,而活性配体IXX_801为-115.566。所有合成的嘧啶衍生物对与维拉唑酮复合的野生型人5-羟色胺转运蛋白的Cryo-EM结构显示出更好的亲和力，丙咪嗪,和15B8Fab蛋白(PDBID:7LWD)与标准药物氯米帕明(-101.064)相比。与20mg/kg剂量水平的标准氯米帕明HCl相比,在100mg/kg剂量水平下筛选所有合成的衍生物的抗抑郁活性。在所有合成的衍生物中，化合物24显示出最有效的抗抑郁活性，和化合物20显示中等抗抑郁活性，与对照组相比，在100mg/kg剂量水平下，将不动时间的持续时间减少到35.42％和31.97％，分别。
结论:化合物24显示出最高的MolDock评分以及被发现是最有效的抗抑郁药。
目的：本研究的目的是进行分子对接，合成，表征，和评价2-((4,6-二苯基嘧啶-2-基)氧基)-N-苯基乙酰胺衍生物(17-26)作为体内抗抑郁药。
方法：使用Molegro虚拟Docker（MVD）检查设计的化合物的活性，并进一步合成。苯甲醛与苯乙酮反应得到化合物(3),与脲反应后得到化合物(4)。在另一个反应中，使取代的苯胺(5)与氯乙酰氯(6)反应,得到化合物(7-16),其在与化合物(4)进一步反应后得到最终的衍生物(17-26)。通过光谱分析对合成的化合物进行了表征，并检查了其抗抑郁活性。
结果:衍生物的MolDock评分范围为-147.097至-182.095,而活性配体IXX_801为-115.566。所有合成的嘧啶衍生物对与维拉唑酮复合的野生型人5-羟色胺转运蛋白的Cryo-EM结构显示出更好的亲和力，丙咪嗪,和15B8Fab蛋白(PDBID:7LWD)与标准药物氯米帕明(-101.064)相比。与20mg/kg剂量水平的标准氯米帕明HCl相比,在100mg/kg剂量水平下筛选所有合成的衍生物的抗抑郁活性。在所有合成的衍生物中，化合物24显示出最有效的抗抑郁活性，和化合物20显示中等抗抑郁活性，与对照组相比，在100mg/kg剂量水平下，将不动时间的持续时间减少到35.42％和31.97％，分别。
结论:化合物24显示出最高的MolDock评分以及被发现是最有效的抗抑郁药。
