Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile

Abstract

Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde 3 and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds 9a (IC50 = 15.50 nM, 114.77%), 9b (IC50 = 17.50 nM, 101.65%), 12 (IC50 = 17.10 nM, 104.03%), 16b (IC50 = 16.90 nM, 105.26%), and 17 (IC50 = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC50 = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of 9a, 9b, 12, 16b, and 17. These compounds also displayed comparable onset and the duration of action concerning celecoxib and indomethacin in the in vivo studies. No ulcerogenic effects were observed for 9a and 12, whereas 9b, 16b, and 17 showed an insignificant ulcerogenic effect compared to celecoxib. The compounds 9a, 9b, 12, 16b, and 17 displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds 9a (%ABS = 84.09), 9b (%ABS = 84.09), 12 (%ABS = 66.87), 16b (%ABS = 75.02), and 17 (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds 9a, 9b, 11, 16b, and 17 have been recognized and postulated as non-ulcerogenic COX-2 inhibitors with promising physicochemical parameters and gastric safety profile. These compounds may be useful candidates to combat diseases caused by higher levels of COX-2.

Analysis of the Anti-Inflammatory and Analgesic Mechanism of Shiyifang Vinum Based on Network Pharmacology

“…The results show that Shiyifang Vinum and four monomer compounds have a significant inhibitory effect on COX-2, and the IC 50 of quercetin, luteolin, kaempferol, apigenin, and Shiyifang Vinum was 1.198 μ g/ml, 3.102 μ g/ml, 8.774 μ g/ml, 35.518 μ g/ml, and 106.95 μ g/ml, respectively. The IC 50 of celecoxib, a selective COX-2 inhibitor, was 20 nM, which was consistent with the results reported in the kit (IC 50 was approximately 10–100 nM) and the test results (17.79 nM) are reported in the literature [ 19 ].…”

“…The more stable the conformational stability of the compound and protein binding, the lower the energy and the greater the possibility of interaction [ 17 ]. In some studies, the binding energy of ≤ −5.0 kJ/mol was used as the screening standard [ 18 , 19 ]. In this study, 14 core active compounds with a moderate value greater than the average value in the compound target pathway network of Shiyifang Vinum were docked with 11 target proteins.…”

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

“…in vitro analysis of test compounds by performing enzyme immunoassay indicated selective COX‐2 inhibition potential superior to the standard drug celecoxib. Reportedly, the gastric safety of the test compounds arises from the noninhibition of COX‐1 isoenzyme (Khan, Diwan, Thabet, Imran, & Bakht, 2020). The above investigations clearly claimed a robust candidature of thiazolidinone nucleus in rational designing of physiologically benevolent anti‐inflammatory lead molecules focused on the selective inhibition of COX‐2 isoenzyme.…”

Synthetic Approaches toward Certain Structurally Related Antimicrobial Thiazole Derivatives (2010-2020)

“…Thiazole ring is one of the most common heterocycles in biologically active molecules. Thiazole derivatives showed a various biological activities including anticancer, 1 anti-influenza, 2 antiviral, 3 anti-HIV, 4 anti-inflammatory, 5 antidiabetic, 6 antiplatelet, 7 antihypertensive, 8 anti-hyperlipidemic, 9 antileishmanial, 10 and antioxidant. 11 Nowadays the pharmacy is full of thiazole-derived antibiotics.…”