4-Fluorophenylhydrazones as potential COX-2 inhibitors: a novel, efficient, one pot solid phase synthesis, docking study and pharmacological evaluation

• Published in: Medicinal chemistry research 2013-12, Vol.22 (12), p.5890-5900
• Main Authors: Kumar, Vinod, Gupta, Girish Kumar, Kaur, Kamalneet, Singh, Randhir
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-013-0566-8

In search of a new class of organic compounds as potential COX-2 inhibitors, various 4-Fluorophenylhydrazones ( 3a – 3i ) have been synthesized and molecular docking study was conducted. All the synthesized compounds were also evaluated for their in vivo anti-inflammatory potential using carrageenan-induced rat paw odema method. In the present manuscript, a novel, simple, and greener protocol has been developed for the first time to prepare the hydrazo compounds by a one pot solid phase reaction between various active methylene compounds and p -fluoroaniline in the presence of p -toluene sulfonic acid as a new solid phase organocatalyst. The catalyst dramatically facilitates the reaction under solvent-free condition at moderate temperature (10–15 °C). The present protocol not only provides an expeditious route to prepare hydrazo compounds in excellent yields (with in 3–5 min) but also avoids the use of two step conventional methods, and formation of side products. The results obtained from in vivo anti-inflammatory activity through carrageenan-induced rat paw odema assay showed that compounds 3a – 3b , and 3d displayed excellent level of activity which was further supported by molecular docking study. A cyclooxygenase-II inhibitory molecular docking study has been carried out using (pdb: 1CX2) via Molegro Virtual Docker version 4.2.1. All the compounds were found to exhibit good level of inhibition and binding in the enzyme active site. Compounds 3a – 3b , 3d , and 3e have been found to display high moldock scores −118.333, −118.778, −118.422, and −111.13, respectively, and are strongly bound with Arg120, Tyr355, His90, and Arg513 amino acids, which are responsible for COX-2 inhibition within the active site. In the present investigation, it can be concluded that the best scored inhibitors with good in vivo anti-inflammtory activity will have better chances to be used as anti-inflammatory leads.