Environmentally friendly catalyst- and solvent-free synthesis of 2-anilino nicotinic acids derivatives as potential lead COX inhibitors

Abstract

In this study, an environmentally friendly, solvent- and catalyst-free synthesis of 2-anilino nicotinic acids derivatives is reported. This operationally simple and green procedure was applied to a selection of primary aromatic amines giving rise to 23 derivatives of 2-anilino nicotinic acids in a very short reaction time (15-120 min) with good to excellent yield. Next, similarity searches were executed on these derivatives to find the possible biological target. These products were screened for inhibition of COX-1 and COX-2 by molecular docking and dynamic studies. In silico studies revealed that among these derivatives, the structure 10 bearing meta-chlorine substitutions could act as COX-1 and COX-2 inhibitors. These results can be used in designing important lead compounds for further development as potential anti-inflammatory drugs.

Keywords: 2-Anilino nicotinic acids; COX; Molecular dynamic simulations; Similarity search; Solvent -free synthesis.

Fig. 1

Amination of 2-chloronicotinic acid under catalyst-free solvent-free conditions

Fig. 2

Catalyst and Solvent-Free Synthesis of 2-Anilino Nicotinic Acids Derivatives as Potential COX Inhibitors

Fig. 3

Chemical structures of COX inhibitors with pyridine structure

Fig. 4

RMSD plot of the COX-1 in complexed compound 10 in the MD simulations time. RMSD values of the Ca atoms of the protein are depicted in blue, and ligand-complex values are exhibited in red

Fig. 5

The RMSF graph of COX-1 in complex with 10

Fig. 6

RMSD plot of the COX-2 in complexed compound 10 in the MD simulation time. RMSD values of the Ca atoms of the protein are depicted in blue, and ligand-complex values are exhibited in red

Fig. 7

RMSF plot of the COX-2 residue in complexed with compound 10