Potential effect of novel thiadiazole derivatives against radiation induced inflammation with low cardiovascular risk in rats

The aim of the present study is to explore new selective anti-inflammatory compounds with low cardiovascular risk. Twelve thiadiazole derivatives incorporating different amino acid moieties were newly synthesized (4-15) as potential anti-inflammatory agents with low cardiovascular risks through dual COX-2/MPO inhibition. Compounds were initially screened for their anti-inflammatory effect by assay of COX-2, the most potent (4-6, 8) were further tested for COX-1 inhibition, myeloperoxidase MPO activity as well as total nitric oxide content NO in heart of irradiated rats. Cardiac toxicity potential was evaluated by assay of creatine kinase-MB (CK-MB), troponin-I (Tn-I) and lactate dehydrogenase (LDH). Celcoxcib was used as reference drug. S-(5-((4-Methoxybenzylidene)amino)-2,3-dihydro-1,3,4-thiadiazol-2-yl)2-amino propanethioate (5) was the most potent anti-inflammatory with the least cardiotoxicity effect. It exhibited IC50 0.09 mu M on COX-2 inhibition with very low activity on COX-1. Troponin I was elevated by 11% using compound 5 in non-irradiated rats. Moreover, compound (5) showed 73% reduction in MPO level. Results were supported by molecular docking into the active sites of COX-2 and MPO enzymes to have more insights about the possible dual inhibition of compound 5 of both enzymes.

Automated summary

The present study synthesized twelve thiadiazole derivatives incorporating different amino acid moieties, which have the potential of being anti-inflammatory compounds with low cardiovascular risks. Compound 5 was identified as the most potent anti-inflammatory agent with the least cardiotoxicity effect.