Synthesis and NMR Characterization of a 4-Aminochalcone–Salicylic Acid Azo Conjugate as a Potential Prodrug

This work describes two synthetic routes to a 4-aminochalcone-derived salicylic acid azo conjugate (1), proposed as a potential colon-targeted prodrug. In the first route, 4-nitroacetophenone was reduced to the corresponding 4-aminoacetophenone, which subsequently underwent a Claisen–Schmidt condensation with benzaldehyde to afford 4-aminochalcone. The latter was diazotized using NaNO₂, and the resulting diazonium intermediate was coupled with salicylic acid at its 5-position to obtain the target compound 1 in an overall yield of 50%.

An alternative synthetic route to compound 1 was also investigated. First, 4-nitroacetophenone was reduced and subsequently diazotized. The resulting diazonium intermediate was then coupled with salicylic acid to afford the 4-aminoacetophenone-derived salicylic acid azo conjugate (2). This intermediate was subjected to a Claisen–Schmidt condensation with benzaldehyde to produce compound 1 in an overall yield of 51%.

The ¹H NMR spectrum of compound 1 showed the expected olefinic resonances of the α,β-unsaturated carbonyl system and the corresponding aromatic signals, supporting the proposed structure. Compound 1 represents a potential synthetic platform for the development of azo prodrugs intended for the treatment of inflammatory bowel disease (IBD). Reduction of its azo bond by colonic azoreductases could potentially release 4-aminochalcone, which has reported antimicrobial activity, and 5-aminosalicylic acid, an anti-inflammatory drug widely used in the management of ulcerative colitis and Crohn’s disease.