Synthesis and Evaluation of Persulfide Generating Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely utilized pharmacological agents for treating conditions like inflammation and pain. Hydrogen sulfide (H2S) and derivatives associated with it, such as persulfide (RS-SH), are essential in the modulation of antioxidant responses and provide cellular protection against oxidative stress. Hybrids of these distinct yet related pharmacological agents have shown promise in clinical trials, and are superior to the parent NSAID. We recently developed mercapto-Nabumetone derivatives that generated H2S along with NSAID. By taking motivation from this result, we have introduced a mercapto group to the alpha position of 6-MNA, the active metabolite of the parent drug Nabumetone. We have designed various ester prodrugs of the 6-MNA and docked them against the 3-MST enzyme, an enzyme involved in H2S biosynthesis and antioxidant response. We show that mercapto-6-MNA-methylester is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST). Other mercapto-NSAID-ester prodrugs are inactive substrates. This provides novel insights into 3-MST catalysis, and how the modulation of reaction can be achieved by the keto-enol equilibrium. Next, we developed a persulfide attached to the 6-MNA, as persulfides are thought to be better antioxidants than H2S. Here, we show that the release of persulfide from the hybrid. Overall, first, we show the generation of H2S through an enzymatic pathway along with NSAID, and in the next part, we have developed an NSAID-persulfide donor that offers higher potential for enhancing both antioxidative and anti-inflammatory responses.