Helal M H, Salem M A, Gouda M A, Ahmed N S, El-Sherif A A
Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha, Saudi Arabia; Department of Chemistry, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt.
Department of Chemistry, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt.
Spectrochim Acta A Mol Biomol Spectrosc. 2015 Aug 5;147:73-83. doi: 10.1016/j.saa.2015.03.070. Epub 2015 Mar 11.
Interaction of 1-(4-morpholinophenyl)ethanone 1 with either malononitrile or ethyl cyanoacetate 2 afforded Knoevenagel-Cope product 3. In subsequent treatment of 3 with sulfur, the 2-aminothiophene derivatives (4a, 4b) are formed under basic conditions. The solvent-free reaction of thiophene derivative 4a with ethyl cyanoacetate afforded thieno[2,3-d][1,3]oxazine derivative 6. The base catalyzed condensation of 2-aminothiophene derivative (4a) with ethyl cyanoacetate afforded N-(thieno-2-yl) cyanoacetamide derivative 7. The latter was used to synthesize different heterocyclic derivatives comprising, pyridine and coumarin rings. Also, several substituted thieno[2,3-d]pyrimidines have been prepared from reaction of 2-aminothiophene-3-carbonitrile 4b with some electrophilic reagents. The structure of the newly compounds were confirmed on the basis of elemental analysis and spectral data. The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Evaluation of anti-inflammatory activity of the tested compounds was performed in albino rats by producing carrageenan induced paw oedema and measuring the zone of inflammation at different time intervals i.e. 1, 2, 3 and 4h after carrageenan injection. Results indicated that most of the tested compounds showed moderate to good activity comparable to indomethacin. Also, compound 16 with additional morpholine ring beside the thiophene ring inhibits carrageenan induced paw oedema more than the standard indomethacin drug at all the time scales studied. Thus, compound 16 is considered as a promising compound for further modification to obtain clinically useful anti-inflammatory agent.
1-（4-吗啉基苯基）乙酮1与丙二腈或氰基乙酸乙酯2相互作用，得到Knoevenagel-Cope产物3。随后在碱性条件下，用硫处理3，生成2-氨基噻吩衍生物（4a、4b）。噻吩衍生物4a与氰基乙酸乙酯的无溶剂反应得到噻吩并[2,3-d][1,3]恶嗪衍生物6。2-氨基噻吩衍生物（4a）与氰基乙酸乙酯的碱催化缩合反应得到N-（噻吩-2-基）氰基乙酰胺衍生物7。后者用于合成包含吡啶环和香豆素环的不同杂环衍生物。此外，通过2-氨基噻吩-3-腈4b与一些亲电试剂反应制备了几种取代的噻吩并[2,3-d]嘧啶。根据元素分析和光谱数据确定了新化合物的结构。绘制了合成化合物的分子模型并计算了它们的分子参数。此外，通过计算化合物的电负性、净偶极矩、总能量、电子能量、结合能、最高占据分子轨道（HOMO）和最低未占分子轨道（LUMO）能量等分子参数，获得了有价值的信息。通过制备角叉菜胶诱导的爪肿胀，并在角叉菜胶注射后的不同时间间隔（即1、2、3和4小时）测量炎症区域，对白化大鼠进行了受试化合物抗炎活性的评估。结果表明，大多数受试化合物表现出中度至良好的活性，与吲哚美辛相当。此外，在研究的所有时间尺度上，除噻吩环外还带有吗啉环的化合物16比标准吲哚美辛药物更能抑制角叉菜胶诱导的爪肿胀。因此，化合物16被认为是一种有前景的化合物，可进一步修饰以获得临床上有用的抗炎剂。
