Trimethoxyphenyl containing compounds: Synthesis, biological evaluation, nitric oxide release, modeling, histochemical and histopathological studies

Abstract

Novel series of trimethoxy phenyl containing chalcone 3, 5, 6, 7, pyrazoline 4a&b, 9a-h and pyrazole 10a&b scaffolds were designed and synthesized. They were characterized by spectral data and elemental analyses. All newly synthesized compounds were screened for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity. All the target compounds showed COX-2 inhibitory activity over COX-1. Compound 5c was the most active derivative with higher COX-2 inhibitory activity (IC50 = 0.039 µM) than celecoxib (IC50 = 0.045 µM), and selectivity index value of 321.28 nearly equal to that of celecoxib (S.I. = 326.66). Four additional derivatives 5a, 6, 8b and 9f exhibited excellent COX-2 inhibitory activity (IC50 = 0.041 – 0.049 µM) if compared to the reference drug, celecoxib, with selectivity index values (S.I. = 230.61 – 278.05). Additionally, prolonged in vivo A.I activity was observed in compounds 9e, 9 g, 10a and 10b with % inhibition ranged from 33.21 to 44.52%, after 7 h from carrageenan injection. Compound 9e appeared normal without degeneration similar to celecoxib as resulted from histolopathogical study. Compounds containing NO releasing moieties, 7, 10a and 10b were assesses to overcome the gastrointestinal side effects. Molecular modeling study was operated and achieved a parallel correlation with in vitro COX-2 assay results. Pharmacokinetic study for all the prepared compounds was developed.