Synthesis, biological evaluation, and in silico studies of chalcone-based ketamine derivatives with preferential COX-2 inhibitory activity

Abstract

This study focused on synthesizing novel chalcone-ketamine derivatives and evaluation of their anti-inflammatory properties. Eighteen compounds were synthesized via a one-pot condensation of ketamine with various aldehydes under basic conditions. Compounds were characterized by FTIR, NMR, mass spectrometry, and elemental analysis. Molecular docking studies revealed that several of these molecules possessed low binding affinities for COX-2 than COX-1. An in vitro enzyme inhibition analysis of molecules also suggested similar trend with compounds 1n and 1q exhibiting the greatest preferential inhibition of COX-2 than COX-1. Key structural modifications such as specific functional groups in compounds 1n and 1q were identified through SAR analysis. QSAR modeling revealed a predictive correlation between structural features and inhibitory potential of synthetized molecules. Molecular dynamics (MD) simulations of the best-docked complex were carried out to assess the stability and dynamics of compound-receptor complexes followed by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations. Density functional theory studies were also performed on molecules 1n, 1q and ketamine to determine the energy of frontier molecular orbitals, HOMO-LUMO band gap and Mulliken charges on the optimized structures. Significant steric and electrostatic descriptors were found to influence COX-2 selectivity. In vivo analgesic and anti-inflammatory effects of 1n and 1q were further evaluated in hotplate, acetic acid-induced writhing, and carrageenan-induced paw edema models, with both compounds showing significant anti-inflammatory activities. Biochemical analysis indicated significant reductions in inflammatory mediators (IL-1β, TNF-α, COX-2) in the paws of mice treated with 1n and 1q than disease controls. In conclusion, novel chalcone-ketamine derivatives were synthesized with preferential inhibitory activity for COX-2 than COX-1.