Molecular Modeling, Synthesis and Pharmacological Evaluation of Aminosubstituted Derivatives of Coumarin

Abstract

Due to the importance of coumain derivatives and amino substituted derivatives several investigators have been investigating various compounds bearing single substituent or more complicated substituent in heterocyclic ring system mainly in 3- ,4- and/or 7-position. Encouraged by the above observations we synthesized coumarin derivatives using various aromatic and heterocyclic amines, and tested the target compound for its analgesic and anti-inflammatory activity. Compounds mp7, mp8 and mp25 showed significant anti-inflammatory and analgesic activity. The synthesized compounds, then docked on COX-2(PDB entry: 4COX) to predict the binding affinity and orientation at the active site of the receptor. It was found that the active compound mp7, mp8 and mp25 intact mainly with gln 192 amino acid, which may be involved in COX-2 inhibition. A three-point pharmacophore of COX-2 selective inhibitors was derived from a training set of 10 compounds, using the DISCOTECH program of SYBYL X1.2 It consists of a acceptor atom, hydrophobic moiety and aromatic moiety , in accordance with SAR data of the compounds and with topology of the COX-2 active site. The compound were also docked on Protien kinase MEK (PDB entry: 1S9J) to identify coumarin-based compounds as a novel class of allosteric MEK1 inhibitors. The synthetic protocol for the target molecules involved 3 steps. Initially the 7- hydroxy-4-methyl-2H-chromen-2-one is likely formed via Pechmann reaction between resorcinol and ethyl acetoacetate. In the second step, 4-methyl-7-(oxiran-2- ylmethoxy)-2H-chromen-2-one was synthesized by reacting 7-hydroxy-4-methyl-2Hchromen- 2-one with excess of epichlorohydrin in presence of K2CO3 under reflux conditions. 7-(3-chloro-2-hydroxypropoxy)-4-methyl-2H-chromen-2-one was obtained as a side product in low yield in the preparation of compound. The structure elucidation of synthesized compounds was carried out by IR, Mass and Proton NMR. All the synthesized compounds were evaluated for anti-inflammatory, analgesic and ulcerogenic potential. Most of the compounds showed significant In-vivo antiinflammatory and analgesic activities. Comparing pharmacological activity and docking results, we conclude that heterocyclic derivatives linked with nitrogen at 7- position of coumarin seem to be potentially active drug.