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

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 A degrees 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.