Potential effect of novel thiadiazole derivatives against radiation induced inflammation with low cardiovascular risk in rats
Medicinal Chemistry Research(2022)
Abstract
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 IC 50 0.09 µM 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. Graphical abstract
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Key words
Thiadiazole, Amino acids, COX-2, MPO, Irradiated rats
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