ABSTRACT
An operationally simple one-pot three-component and convenient synthesis method for a series of diverse purine analogues of 5-amino-7-(substituted)-N-(4-sulfamoylphenyl)-4,7-dihydro-[1,2,4]-triazolo[1,5-a][1,3,5]triazine-2-carboxamide derivatives generated in situ via the reaction of 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide, cyanoguanidine and a variety of aldehydes was achieved under green conditions. This experiment was conducted to evaluate the anti-inflammatory effect of the newly synthesized compounds using indomethacin as a reference medication; all compounds were tested for in vitro anti-inflammatory activity using the inhibition of albumin denaturation, RBC hemolysis technique and COX inhibition assay. The results showed that all evaluated compounds exhibited significant in vitro anti-inflammatory efficacy leading to excellently effective RBC membrane stabilization, inhibition of protein denaturation, and inhibition of COX enzymes when compared to those of indomethacin. At concentrations of 50, 100, 200, and 300 µg ml-1, these compounds decreased COX-1 and COX-2 activities more than indomethacin and have IC50 values in the range of 40.04-87.29 µg ml-1 for COX-1 and 27.76-42.3 µg ml-1 for COX-2 while indomethacin showed IC50 = 91.57 for COX-1 and 42.66 µg ml-1 for COX-2. The anti-inflammatory findings show the need for more investigation to define the properties underlying the evaluated compounds' anti-inflammatory abilities. The enzyme cyclooxygenase-2 (COX 2) (PDB ID: 5IKT) was docked with ten synthetic substances. With docking scores (S) of -8.82, -7.82, and -7.76 kcal mol-1, 7-furan triazolo-triazine (4), 7-(2-hydroxy phenyl) triazolo-triazine (11), and 7-(4-dimethylamino phenyl) triazolo-triazine (12) had the greatest binding affinities, respectively. Therefore, these substances have COX-2 (PDB ID: 5IKT) inhibitory capabilities and hence may be investigated for COX 2 targeting development. Furthermore, both the top-ranked compounds (4 and 11) and the standard indomethacin were subjected to DFT analysis. The HOMO - LUMO energy difference (ΔE) of the mentioned compounds was found to be less than that of indomethacin.
ABSTRACT
Rheumatoid arthritis (RA) is characterized by chronic inflammation and synovial hyperplasia that eventually leads to the destruction of the joints. CXCL10 has been originally identified as a pro-inflammatory chemokine that mediate leukocyte trafficking and modulate innate and adaptive immune responses. It plays a critical role in the inflammatory response and is involved in several biological processes. The aim of the study was to assess the diagnostic efficacy of serum CXCL10 levels in early RA patients. Patients and methods: The study included 60 RA patients; 30 of them were early diagnosed, and 30 longstanding RA and 30 healthy controls. Clinical examination was done for all patients. Measurement of serum CXCL10 level was done by ELISA, while assessment of disease activity in patients was done using disease activity score (DAS-28). Serum levels of CXCL10 were significantly higher in RA patients than controls (P < 0.001), and was more elevated in early diagnosed than longstanding RA patients, with a a significant positive correlation with DAS-28 ESR (r=0.361, P=0.005), number of tender joint (r=0.319, P=0.013), and number of swollen joint (r=0.280, P=0.030). A cutoff at 470.0 pg/ml was able to recognize longstanding RA with a sensitivity of 88.3% and a specificity of 90% , while a cutoff of 793 pg/ml was able to diagnose early RA with 65% sensitivity and 77% specificity (P=0.009). in conclusion, serum CXCL10 may be a useful biomarker for diagnosis of early RA and determination of disease activity.
