Abstract

Mohd Imran^1*, Abida Ash Mohd¹, Naira Nayeem¹, Nawaf M. Al-Otaibi², Malik Homoud³, Muhannad Thafi Alshammari ³

DOI : http://dx.doi.org/10.13005/ojc/390504

This work aimed to discover safe and effective pyridazine-based cyclooxygenase-2 (COX-2) inhibitors. Thirty-three pyridazine-based compounds (compounds 1 to 33) were designed. The in silico studies were conducted to predict their toxicity, docking scores (DS), pharmacokinetic parameters, and drug-likeliness properties compared to celecoxib. Based on the safety and efficacy data obtained by in silico studies, four compounds (7, 12, 16, and 24) were synthesized, and the spectral analysis confirmed their chemical structures. Additionally, the in vitro COX-2 inhibitory activity of these four compounds was evaluated. Eleven compounds were predicted as non-toxic compounds. The DS of four compounds, 7 (DS = -9.72 kcal/mol), 12 (DS = -10.48 kcal/mol), 16 (DS = -9.71 kcal/mol), and 24 (DS = -9.46 kcal/mol), was better than celecoxib (DS = -9.15). These compounds (7, 12, 16, and 24) also demonstrated better oral absorption (83.53% each) than celecoxib (79.20%) in addition to their promising drug-likeliness properties. The compounds 7 (101.23%; p < 0.05), 12 (109.56%; p < 0.05), 16 (108.25%; p < 0.05), and 24 (103.90%; p < 0.05) also exhibited superior COX-2 inhibition to celecoxib (100%; p < 0.05). Compounds 7, 12, 16, and 24 are useful lead compounds in developing drugs for various diseases in which high levels of COX-2 are implicated.

Benzothiazole; COX-2 inhibition; in silico studies; Pyridazine; synthesis

[ View HTML Full Text]