Abstract
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.