Novel nitroreductive prodrugs of 5-aminosalicylic acid:Docking and Synthesis

Abstract

Novel nitroreductive prodrugs of 5-aminosalicylic acid(5-ASA) were designed and synthesized 2-hydroxy-5-[[(Z)-2-methyl-3-(nitrophenyl)prop-2’-enoyl] amino]benzoic acid derivatives (AN2-AN4) from different nitrocinnamaldhyde, with 5-ASA and 2- hydroxy-5-[[(Z)-2-methyl-3-(nitrophenyl) prop-2’-enoyl] amino]benzoic acid derivatives (COAN2-COAN4) form different nitrocinnamic acid with 5-ASA. Molecular docking was performed using AUTO DOCK 4.2 and in-vitro kinetic studies were performed using collective biological samples from rats and quantitative estimation of release profile of 5-aminosalicylic acid done by UV, HPTLC method. Invitro kinetics study was performed in acetate buffer (pH 4.5) isotonic phosphate buffer (pH 6.8) and rat fecal matters. Molecular modelling study suggested that 3-nitro substituted analogs are poor candidate against nitroreductase Escherichia coli B (NTR) enzyme. But 4-nitro substituted analogs are good candidates for nitroreductase enzyme. The In vitro Kinetics study of the synthesized was carried out for determination of release profile of 5-ASA. Quantification of 5-aminosalicylic acid was done by HPTLC method. Kinetics study of the prodrugs in acetate buffer (pH 4.5) isotonic phosphate buffer (pH 6.8) shows the negligible release of 5-ASA. The stability of prodrugs was found satisfactory in various intestinal pH. Release studies of 5-ASA from synthesized prodrugs was confirmed by identical peaks in HPTLC and specific absorption in UV. Result indicates that amide linkage in between nitrocinnamic acid and 5-ASA is a better for the prodrugs design to release 5-ASA in presence of colon specific nitroreductase enzyme. Amide linkage and 4- nitro substituted analogs are better for the prodrug designing.