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

Abida Khan; Anupama Diwan; Hamdy Kh Thabet; Mohd Imran; Md Afroz Bakht

doi:10.3390/molecules25092002

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

Molecules. 2020 Apr 25;25(9):2002. doi: 10.3390/molecules25092002.

Authors

Abida Khan¹, Anupama Diwan¹, Hamdy Kh Thabet², Mohd Imran³, Md Afroz Bakht⁴

Affiliations

¹ School of Pharmaceutical Sciences, Apeejay Stya University, Sohna - Palwal Road, Sohna 122103, India.
² Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha 91911, Saudi Arabia.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia.
⁴ Department of Chemistry, College of Science and Humanities, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.

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.

Keywords: 4-thiazolidinone; Lipinski’s rule; cyclooxygenase-2; lipid peroxidation; non-ulcerogenic; pyridazine; thiazole.

MeSH terms

Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology*
Anti-Ulcer Agents / chemistry
Anti-Ulcer Agents / pharmacology
Chemical Phenomena
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery* / methods
Hydrogen Bonding
Lipid Peroxidation / drug effects
Models, Molecular
Molecular Conformation
Molecular Structure
Pyridazines / pharmacology*
Spectrum Analysis
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Anti-Ulcer Agents
Cyclooxygenase 2 Inhibitors
Pyridazines
pyridazine