Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity

• Main Authors: Souraya A. Domiati (Author), Khaled H. Abd El Galil (Author), Mohammed A. S. Abourehab (Author), Tamer M. Ibrahim (Author), Hanan M. Ragab (Author)
• Format: Book
• Published: Taylor & Francis Group, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/14756366.2022.2109025; 1475-6374; 1475-6366
• Keywords: Inflammation; structure-guided; amide-linked bipyrazoles; COX-2 selective inhibitors; docking; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 2179-2190 (2022)

A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates.