AUTHOR=Wang Donghe , Meng Yujie , Liu Yihong 

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

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2025.1643663

DOI=10.3389/fchem.2025.1643663

ISSN=2296-2646

ABSTRACT=IntroductionAs an important gas signaling molecule, hydrogen sulfide (H2S) exhibits therapeutic potential in inflammatory and oxidative stress-related diseases. This study developed and evaluated novel H2S donor derivatives based on the phenylphosphonothioic dichloride scaffold.MethodsDerivatives were synthesized based on the phenylphosphonothioic dichloride scaffold. Compound 3b‐1 was selected for its high H2S 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 H2O2‐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.ResultsCompound 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%).DiscussionThe phosphorus-sulfur scaffold‐based H2S 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.