The treatment of ulcerative colitis (UC) has been a major medical challenge due to the lack of safe and effective drugs. Molecular hybridization is a promising strategy for the development of drugs with pleiotropic activity, which has been demonstrated in a wide range of diseases. Tofacitinib has exhibited significant effects on the remission of UC, but a series of adverse effects have occurred during its clinical application. Herein, we propose to utilize a molecular hybridization strategy to link tofacitinib with a cytoprotective H2S donor (ADTOH) to obtain a series of hybridized molecules ZX-4C~ZX-6C. Among them, ZX-4C exhibited the best performance in the H2S release rate and the cytoprotective effects against dextran sulfate sodium (DSS)-induced injury. The in vivo studies showed that ZX-4C could effectively alleviate DSS-induced colitis by enhancing oxidative stress defense and reducing the inflammatory response, demonstrating that it is more potent than the parent drugs. The data from the present study support that this molecular hybridization strategy provides a promising avenue for the treatment of UC.
