Synthesis and Biological Evaluation of p-Aminophenol Derivatives Applying In Vivo, Ex Vivo, and In Silico Approach

Abstract

The study aims to synthesize benzamide derivatives of p-aminophenol (PAP) by reacting with 4-benzoyl chloride. The reaction of PAP yields four derivatives: P-1 [N-(4-hydroxyphenyl)benzamide], P-2 [4 &apos;-bromo-N-(4-hydroxyphenyl)benzamide], P-3 [4 &apos;-nitro-N-(4-hydroxyphenyl)benzamide] and P-4 [3 &apos;,5 &apos;-dintro-N-(4-hydroxyphenyl)benzamide] and evaluation of biological activity. PAP derivatives hot plate analgesic test produced a significant analgesic effect. The higher analgesic activities were observed at 60 min for all derivatives P-1, P-2, P-3, and P-4 at 47.65, 48.13, 47.08, and 45.47%, respectively. Derivatives of PAP were also shown to have statistically significant (p < 0.001) analgesic efficacy in the writhing test. The maximum percent inhibition of the writhing by P-2 (82.11%). In vivo anti-inflammatory examination confirmed that P-1, P-2, and P-4 prevented carrageenan-induced rat paw edema for 60-240 min. The toxicity of PAP derivatives P-1 and P-4 was lower than paracetamol. Experiments demonstrate that derivatives exhibit less cytotoxicity. The compounds P-3 and P-4 inhibited egg and bovine albumin denaturation better at lower dosages in anti-inflammatory experiments. Molecular docking and ADMET showed that derivatives might inhibit COX-1 and COX-2. Also, P-4 demonstrated the highest binding affinity (-8.2 kcal/mol) for COX-1 and P-1 (-8.4 kcal/mol) for COX-2. According to computational and experimental studies, PAP derivatives may inhibit cyclooxygenase to relieve pain, inflammation, and fever.