Synthesis and Ameliorative Effect of Isatin-Mesalamine Conjugates on Acetic Acid-induced Colitis in Rats

摘要

A series of new isatin-mesalamine conjugates (9a-g) were synthesized via conjugation of isatin (3a) and its derivatives (3b-3d, 4, 5, and 6) with mesalamine (7) by using chloroacetyl chloride as a bifunctional linker. Compounds 3a-3d were prepared by employing Sandmeyer reaction. Compounds 4, 5, and 6 were obtained from isatin (3a) via previously reported methods. The synthesized compounds were characterized by IR, mass, H-1 NMR, and C-13 NMR spectral techniques. Synthesized compounds (3a-d, 4, 5, 6, and 9a-g) were evaluated for in vitro antioxidant activity by DPPH assay method using ascorbic acid as standard. Hybrids 9b (IC50 = 368.6 +/- 3.5 mu M) and 9f (IC50 = 335.1 +/- 2.9 mu M) showed better antioxidant activity than its parent compounds such as 3a (IC50 = 556.8 +/- 2.9 mu M), 5 (IC50 = 511.9 +/- 3.6 mu M), and 7 (IC50 = 768.9 +/- 2.7 mu M). Acetic acid-induced ulcerative colitis in rat model was chosen to examine the antioxidant potential of the synthesized hybrids (9b and 9f) in the amelioration of ulcerative colitis. Colonic myeloperoxidase and malondialdehyde enzymes were used as biomarkers of anti-ulcerative colitis activity. In the present study, hybrids 9b and 9f reduced the levels of colonic myeloperoxidase and malondialdehyde enzymes significantly (p < 0.05) when compared with control (colitic), at a dose (0.03 mM/12.5 mg/kg b.w. p.o.) (50%) less than that of its parent moieties mesalamine (0.16 mM/25 mg/kg) and isatin (0.16 mM/25 mg/kg). Thus, the molecular hybridization was proved to be significant in enhancing the activity of hybrids 9b and 9f by reducing the dose.