Molecular docking, ADME study, Cardiovascular biomarkers and gastric safety of new pyrazoles as selective anti-inflammatory agents

Abstract

• Novel pyrazole series were prepared pharmacophored at position 1,4, 5. • Molecular docking and ADME study to exploreThe binding mode of active compounds inside the COX-2 active site was explained. • Structural determination for prepared compounds using NMR, IR, and mass. • Anti-inflammatory activity compounds were evaluated relative to celecoxib , indomethacin , and rofecoxib . • Histopathological study and effect on in-vitro and in-vivo different biomarkers such as IL6, TNFα, MDA , SOD , TGF-β, Nrf2 , COX-1, COX-2, PG-E2, Mucin, AKT, mTOR, CK-MP, and Thrombin for estimation of drug safety. Selective cyclooxygenase-2 inhibitor drugs have major adverse effects, including some myocardial thrombotic events that lead to their market withdrawal. In order to create selective cyclooxygenase-2 inhibitors with cardioprotective effects, we synthesize a novel series of pyrazoles ( 2, 3, 4, 5a, 5b, 6, 7a, 7b, 8a, 8b, 8c, 8d, 9a, and 9b ) that are substituted with oxazole, pyrazole, pyrimidine, and enamine moiety. All synthesized compounds are evaluated in an in-vitro study against cyclooxygenase-1, cyclooxygenase-2, TNF-α, IL-6, CK-MP, and thrombin. Compound (E) -1-(5-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-3-(piperazin-1-yl)prop-2-en-1-one (9b) shows the highest selectivity against cyclooxygenase-2 (cyclooxygenase-1/cyclooxygenase-2 ratio = 57.95), and it reveals strong anti-inflammatory activity with low cardiovascular adverse effects. The future scop of our study to select most active and safe compound and modify it to archive more activity with lowest side effect. An ADME research was conducted and provided a promising activity for all synthesized compounds as new oral anti-inflammatory drugs.