Design, synthesis and molecular modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction

“…The chemical synthetic approach of the target chalcone/aryl carboximidamides 4a–f and 6a–f is outlined in Scheme 1 . The intermediate aryl cyanides 1a–f , amidoximes 2a–f and the key chalcones acid 3 and 5 were prepared according to the previously reported procedure 10 , 12 , 22 , 57 . Reacting the synthesised amidoximes 2a–f with the carboxylic acid group of chalcone 3 and 5 using carbonyldiimidazole ( CDI ) in acetonitrile gave the chalcone/aryl carboximidamides 4a–f and 6a–f , respectively, in good yield.…”

“…NO is a core signalling mediator involved in the inflammation through iNOS up-regulation with the subsequent triggering of PGE2 induction and overstated inflammation 10 , 61 . Therefore, compounds ( 4c , 4d , 6a , 6c , 6d and 6e ) demonstrated an excellent inhibition rate of NO release from RAW 264.7 cells, were evaluated for potential inhibition on iNOS activity, NO, and PGE2 production.…”

“…For molecular docking analysis, Discovery Studio 2.5 software (Accelrys Inc., San Diego, CA) was used. The crystal structures of iNOS protein (PDB code: 1r35) was retrieved from protein data bank 1,10,[53][54][55][56] . See Supplementary file.…”

“…The NO overproduction might responsible for the immunological pathology of macrophage-dependent inflammatory and degenerative diseases, together with cancer 9 . In mammals, NO is produced via l -arginine oxidation by NO synthase (NOS); additionally, there are three NOS enzyme isoforms have been detected: endothelial NOS, neuronal NOS and inducible NOS (iNOS) 10 , 11 . Consequently, inhibition of iNOS-mediated NO and PGE 2 generation is a favourable therapeutic target in the discovery of effective anti-inflammatory agents for the therapy of inflammatory diseases 10 .…”

“…Among these estimated derivatives, IV and V were the targets having remarkable inhibitory potencies; furthermore, compound V is the most potent as COX-2 inhibitor with approximately 6.6-folds higher than the reference drug, celecoxib and compound V has bestowed with the strongest 15-LOX inhibitory activity. Moreover, and very recently we have studied the effects of aryl carboximidamides appended indomethacin as dual iNOS/PGE2 inhibitors 10 . Most of the target indomethacin/aryl carboximidamides displayed powerful inhibitory action against LPS-prompted NO production.…”