Design, synthesis, biological evaluation and in silico studies of novel pyrrolo [3,4-d]pyridazinone derivatives with promising anti-inflammatory and antioxidant activity

• Published in: Bioorganic chemistry Vol. 102; pp. 104035 - 104054
• Main Authors: Szczukowski, Lukasz, Redzicka, Aleksandra, Wiatrak, Benita, Krzyzak, Edward, Marciniak, Aleksandra, Gebczak, Katarzyna, Gebarowski, Tomasz, swiatek, Piotr
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier 01.09.2020
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; ACID; PYRIDAZINONE-SUBSTITUTED BENZENESULFONAMIDES; 1,3,4-OXADIAZOLE; Anti-inflammatory agents; Molecular docking; Antioxidants; POTENT; FLUORESCENCE; Cyclooxygenase inhibitors; VASORELAXANT; Pyridazinone; 1,3,4-Oxadiazole-2-thione; Mannich bases; COX-2 INHIBITORS; BINDING; BOVINE SERUM-ALBUMIN
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104035

Novel Mannich base analogues of pyrrolo[3,4-d]pyridazinone 7a,b-13a,b are designed and synthesized as potential anti-inflammatory agents. The title compounds are obtained via convenient one-pot synthesis with good yields. Their structures and properties are described by spectroscopic techniques and elemental analyses. The aim of this study is to evaluate the inhibitory activity of the new derivatives against both cyclooxygenase isoforms COX1 and COX2 as well as their cytotoxicity. The results clearly indicate that the tested compounds 7a,b-13a,b are not toxic, all show better affinity towards isoform COX-2, and some of them act as selective COX-2 inhibitors. Moreover, every examined derivative of pyrrolo[3,4-d]pyridazinone demonstrates better inhibitory activity towards COX-2 and a superior COX-2/COX-1 selectivity ratio compared to the reference drug meloxicam. Molecular docking studies confirm that compounds 7a,b-13a,b preferably bind COX-2 and all of them bind to the active site of cyclooxygenase in a way very similar to meloxicam. Subsequently, taking into account that inflammation is strongly correlated with oxidative stress and both of these processes can potentiate each other, synthesized Mannich bases are evaluated for potential antioxidant activity. Most of the investigated derivatives reduce induced oxidative and nitrosative stress. Moreover, compounds 7a,b, 8a, 10a,b, 11b, 12a,b-13a,b protect chromatin from oxidative stress and decrease the number of DNA strand breaks caused by intracellular growth of free radicals. Finally, a study of the binding mechanism between compounds 7a,b-13a,b and bovine serum albumin (BSA) was carried out. According to spectroscopic and molecular docking studies, all examined derivatives interact with BSA, which suggests their potential long half-life in vivo.