title: Design, synthesis, characterization, quantum-chemical calculations and anti-inflammatory activity of novel series of thiophene derivatives.
abstract: 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.
authors.affiliation: 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.
authors.forename: M H
authors.initials: MH
authors.lastname: Helal
authors.affiliation: Department of Chemistry, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt.
authors.forename: M A
authors.initials: MA
authors.lastname: Salem
authors.affiliation: Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt; Department of Chemistry, Faculty of Science and Arts, Taibah University, Ulla 41411, Saudi Arabia.
authors.forename: M A
authors.initials: MA
authors.lastname: Gouda
authors.affiliation: Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha, Saudi Arabia; Department of Chemistry, National Institute of Oceanography and Fisheres, Alex, Egypt.
authors.forename: N S
authors.initials: NS
authors.lastname: Ahmed
authors.affiliation: Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt. Electronic address: aelsherif72@yahoo.com.
authors.forename: A A
authors.initials: AA
authors.lastname: El-Sherif
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002351:Carrageenan; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D017208:Rats, Wistar; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D013876:Thiophenes; D002351:Carrageenan
keywords: Anti-inflammatory; Modeling; Morpholine; Spectra; Synthesis; Thiophene