Activity evaluation of multifunctional H2S donors for anti-inflammatory, cardioprotective, and hepatoprotective applications

Introduction As an important gas signaling molecule, hydrogen sulfide (H 2 S) exhibits therapeutic potential in inflammatory and oxidative stress-related diseases. This study developed and evaluated novel H 2 S donor derivatives based on the phenylphosphonothioic dichloride scaffold. Methods Derivatives were synthesized based on the phenylphosphonothioic dichloride scaffold. Compound 3b‐1 was selected for its high H 2 S release capacity and favorable safety profile. Its anti-inflammatory activity was evaluated by measuring inhibition of TNF‐α, TNF‐β, and nitrite. Hepatoprotective effects were assessed in an H 2 O 2 ‐induced injury model using oxidative stress markers (MDA, SOD, GSH) and HSC activation. Cardioprotective effects were examined in an LPS-induced model by analyzing mitochondrial membrane potential, cardiac markers (LDH, CK‐MB), and oxidative balance. Results Compound 3b-1 showed the highest H2S release capacity and inhibited TNF‐α (86%), TNF‐β (82%), and nitrite (67%). In the hepatocyte model, it reduced MDA (79%), enhanced SOD (49%) and GSH (76%), and suppressed HSC activation (55%). In the myocardial model, 3b‐1 attenuated mitochondrial membrane potential dissipation, decreased LDH (34%) and CK-MB (24%), and restored GSH activity (73%) while reducing MDA (48%). Discussion The phosphorus-sulfur scaffold‐based H 2 S donor 3b‐1 demonstrates synergistic anti-inflammatory, antioxidant, and organ-protective effects, highlighting its promise as a drug candidate for treating inflammation- and oxidative stress-related disorders.