Synthesis, characterization, anti-inflammatory activity and molecular docking studies of aromatic aldehydes substituted oxazine derivatives derived from 3-methoxy chalcone

Abstract

In this study, a novel synthesis series (R4, D1-D10) of 4-[2-Amino-4-(3‑methoxy-phenyl)-6H-[1,3]oxazin-6-yl]-phenol derivatives was synthesised by the condensation of substituted aromatic aldehydes. Structures of the synthesised compounds were characterised using 1H and 13C nuclear magnetic resonance (NMR), fourier transform infrared spectroscopy (FT-IR), and mass spectrometry (MS) spectroscopic data. Further, the compounds were screened for in vivo anti-inflammatory activity by the carrageenan-induced paw edema method. Tested compounds have shown mild-to-moderate anti-inflammatory activity. The COX-2 selective compounds anti-inflammatory of five-oxazine derivatives (D7, D9, D5, D10, and D2) was modest. In comparison to the reference drug parecoxib (% edema inhibition = 29.2, 1 h; 23.30, 3 h; 21, 6 h), the most active compounds demonstrated exceptional In vivo anti-inflammatory action (% edema inhibition = 40–52, 1 h; 40.70–60.40, 3 h; 30–47.80, 6 h). Also, compounds 4-{6-(3-Methoxy-phenyl)-2-[(4-nitro-benzylidene)-amino]-6H-[1,3]oxazin-4-yl}-phenol (D7) and 4-[2-[(3-Fluoro-benzylidene)-amino]-6-(3-methoxy-phenyl)-6H-[1,3]oxazin-4-yl]-phenol (D9) have shown excellent anti-inflammatory action (% edema inhibition = 52–59.3 & 46.7–60.40). The molecular docking studies were also carried out at the active sites of COX-1 and COX-2 enzymes (PDB ID: 4O1Z, 4M11) using the docking algorithm offered by AutoDock Vina. The compounds D7, D9, and D5 exhibited good docking scores of −10.30, −10.20, and −10.10 onto the active site of COX-2 and least dock scores of −10.10, −9.80, and −10.00 on COX-1 enzymes and were comparable with standard COX-2 inhibitor parecoxib. A significant correlation was observed between the in silico and the in vivo studies. The anti-inflammatory and docking results highlight the fact that the synthesised compounds D7, D9, and D5 could be considered as possible hits as therapeutic agents.