A Highly Atom-Efficient Prodrug Approach to Generate Synergy between H2S and Nonsteroidal Anti-inflammatory Drugs and Improve Safety

Efforts to synergize hydrogen sulfide (H₂S) with NSAIDs have faced challenges due to complex structural entities and independent release kinetics. This study presents a highly atom-efficient approach of using a thiocarboxylic acid (thioacid) as a novel H₂S releasing precursor and successfully employs it to modify NSAIDs, which offers several critical advantages. First, thioacid-modified NSAID is active in inhibiting cyclooxygenase, sometimes with improved potency. Second, this prodrug approach avoids introducing extra structural moieties, allowing for the release of only the intended active principals. Third, the release of H₂S and NSAID is concomitant, thus optimally synchronizing the concentration profiles of the two active principals. The design is based on our discovery that esterases can directly and efficiently hydrolyze thiocarboxylic acids, enabling controlled release H₂S. This study demonstrates the proof of principle through synthesizing analogs, assesses release kinetics, enzyme inhibition, and pharmacological efficacy, and evaluates toxicity and gut microbiota regulation in animal models.