Design, Synthesis, and Evaluation of the COX-2 Inhibitory Activities of New 1,3-Dihydro-2H-indolin-2-one Derivatives

Abstract

Thirty-three 1, 3-dihydro-2H-indolin-2-one derivatives bearing α, β-unsaturated ketones were designed and synthesized via the Knoevenagel condensation reaction. The cytotoxicity, in vitro anti-inflammatory ability, and in vitro COX-2 inhibitory activity of all the compounds were evaluated. Compounds 4a, 4e, 4i-4j, and 9d exhibited weak cytotoxicity and different degrees of inhibition against NO production in LPS-stimulated RAW 264.7 cells. The IC50 values of compounds 4a, 4i, and 4j were 17.81 ± 1.86 μM, 20.41 ± 1.61 μM, and 16.31 ± 0.35 μM, respectively. Compounds 4e and 9d showed better anti-inflammatory activity with IC50 values of 13.51 ± 0.48 μM and 10.03 ± 0.27 μM, respectively, which were lower than those of the positive control ammonium pyrrolidinedithiocarbamate (PDTC). Compounds 4e, 9h, and 9i showed good COX-2 inhibitory activities with IC50 values of 2.35 ± 0.04 µM, 2.422 ± 0.10 µM and 3.34 ± 0.05 µM, respectively. Moreover, the possible mechanism by which COX-2 recognized 4e, 9h, and 9i was predicted by molecular docking. The results of this research suggested that compounds 4e, 9h, and 9i might be new anti-inflammatory lead compounds for further optimization and evaluation.

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

“…Inhibitor discovery, as evidenced by its role in the development of analog such as sunitinib and nintedanib, used in cancer and idiopathic pulmonary fibrosis treatments, respectively [10]. Morever, indolin-2-one-based anti-inflammatory inhibitors have been reported in recent literature [11][12][13][14]. Significantly, KMU-11342 exhibited potent inhibition of protein kinases associated with inflammation (Table 2).…”