Green synthesis of new chiral amino acid urea derivatives and evaluation of their anti-inflammatory activity

Abstract

A practically simple, mild and efficient method is developed for the synthesis of a series of new chiral urea derivatives by nucleophilic addition of amines from natural (L)-amino acids to various aryl isocyanates in alkaline aqueous medium, without organic co-solvent and under room temperature conditions. The synthesized compounds were obtained in good to excellent yields with high chemical purity by applying simple filtration and their structures were confirmed by spectral analysis (¹H, ¹³C NMR and HRMS). Molecular docking analysis revealed strong hydrogen bonding interactions between the synthesized compounds and COX-1 (PDB ID: 6Y3C) and COX-2 (PDB ID: 5KIR), with binding energies ranging from −6.2 to −9.6 kcal mol⁻¹, compared to the reference drug diclofenac (−7.4 kcal mol⁻¹ for COX-1 and −8.4 kcal mol⁻¹ for COX-2). This study showed interesting anti-inflammatory activities. The selected compounds were subjected to in vivo study for their anti-inflammatory activity. The in vivo results were correlated with molecular docking studies, supporting the prediction that the in silico binding affinities are in good agreement with the observed anti-inflammatory activity. Among the tested compounds, 1e evaluated at 25 mg kg⁻¹ exhibited much better anti-inflammatory activity (edema inhibition = 97.05%) as compared to the standard drug diclofenac (edema inhibition = 63.82%). In silico ADMET, toxicity, and physicochemical properties revealed that the candidate compounds have acceptable values of drug-likeness.