Synthesis, docking and biological evaluation of purine-5--isosteresas anti-inflammatory agents

• Published in: RSC advances Vol. 14; no. 25; pp. 17785 - 178
• Main Authors: El-Saghier, Ahmed M, Enaili, Souhaila S, Abdou, Aly, Hamed, Amany M, Kadry, Asmaa M
• Format: Journal Article
• Published: 03-06-2024
• ISSN: 2046-2069
• DOI: 10.1039/d4ra02970d

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 IC
50
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 IC
50
= 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 (Δ
E
) of the mentioned compounds was found to be less than that of indomethacin.
An operationally simple one-pot three-component synthesis method for a series of diverse purine analogues of [1,2,4]-triazolo[1,3,5]triazine-2-carboxamide derivatives generated
in situ via
reaction of 2-hydrazinyl-
N
-(4-sulfamoylphenyl)-2-thioxoacetamide, cyanoguanidine and a variety of aldehydes.