Medicinal Chemistry

Design, Synthesis, In Vivo Anti-inflammatory, Analgesic Activities and Molecular Docking of Some Novel Pyrazolone Derivatives

Abstract

Ahmad Farouk Eweas, Ahmed OH El-Nezhawy, Rehab Fawzy Abdel-Rahman and Ayman R Baiuomy

A novel series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one derivatives were synthesized. The synthesis started with the important building block 3, which was prepared via coupling of from 2-(bi's (methylthio) methylene) malononitrile 1 with 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2. The 5-aminopyrazole derivatives 4-8 were prepared from the cyclocondensationof 3 with the appropriate sulfonohydrazides and pyridine- 4-carbohydrazide respectively. Cyclocondensation of 1 or 9 with pyridine-4-carbohydrazide and 4-methylbenzene sulfonohydrazide corresponding pyrazole derivatives 10, 11, 12 and 13. Condensation 2 and 1-isothiocyanato-4- methylbenzene 14 yielded 15 which was refluxed with malonic acid to yielded1-(1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4-yl)-2-thioxo-3-(2methylphenyl) dihydropyrimidine-4,6(1H,5H)-dione (16). All tested compounds showed analgesic and anti-inflammatory activities in comparison to the reference standard drugs tramadol, acetyl salicylic acid and indomethacin. Maximum protection against the thermal stimulus was observed at 90 min following the administration of the compound (5) (105.8%), which was statistically significant comparable to the reference drug tramadol (148.7%). Compounds (5, 6, 11 and 13) revealed their maximal analgesic effect after 60 min (68.5%, 77.5%, 84.6% and 89.7%, respectively), then their effect started to decrease. In addition, derivatives 10, 12 and 16 showed anti-inflammatoryactivity after 4 hours, which was greater than that of the reference drug indomethacin and reached the maximum effect at the 2nd h. Additionally, a molecular docking study was performed against the COX enzyme using the Molsfot ICM 3.8 software.