Benzimidazole scaffold based hybrid molecules for various inflammatory targets: Synthesis and evaluation

• Published in: Bioorganic chemistry Vol. 80; pp. 24 - 35
• Main Authors: Kaur, Gaganpreet, Silakari, Om
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.10.2018; Elsevier
• Subjects: Anti-inflammatory; Benzimidazole scaffold; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; COXs; Hybrid drugs; Life Sciences & Biomedicine; LOXs; Multitarget profile; Physical Sciences; Science & Technology; TNF-α; Multitarget profile; TNF-α; COXs; Anti-inflammatory; Hybrid drugs; LOXs; Benzimidazole scaffold; DESIGN; ASSAY; TNF-alpha; RATS; INDOMETHACIN; IDENTIFICATION; DISCOVERY; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INHIBITORS; 5-LIPOXYGENASE; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.05.014

[Display omitted] •Benzimidazole scaffold based hybrids provided multitargeting potential by influencing various inflammation-related targets such as COX-1, COX-2, 5-LOX, 15-LOX and TNF-α.•Most active compound was selected and tested for in vivo anti-inflammatory profile in conjuction with analgesic, ulcerogenic and lipid peroxidation activities.•Additionally, active compound further exposed to molecular docking studies to deduce out binding mode with target proteins. Designing of hybrid drugs with specific multitarget profile is a promising line of attack against inflammation. In light of this, a series of benzimidazole scaffold based hybrid molecules were designed by integrating benzimidazoles (containing pharmacophoric elements for COXs and LOXs inhibitors) with phthalimide subunit of thalidomide (pharmacophore element for TNF-α inhibitor) under one construct via molecular hybridization strategy. The designed molecules were synthesized and evaluated for their inhibitory activity against COXs (COX-1, COX-2), LOXs (5-LOX, 15-LOX) enzymes as well as TNF-α inhibitory effect. The results revealed that, compounds (3a–l) obtained showed inhibition in submicromolar range against COXs and LOXs targets whereas milder inhibitory activity was obtained against lipopolysaccharides (LPS)-induced TNF-α secretion by murine macrophage-like cells (RAW264.7). Within this class of compounds, 3j emerged as having alluring multiple inhibitory effects on set of COX-1/2 and 5-/15-LOX enzymes (COX-1 IC50 = 9.85 µM; COX-2 IC50 = 1.00 µM; SI = 9.85; 5-LOX IC50 = 0.32 µM; 15-LOX IC50 = 1.02 µM) in conjunction with a good anti-inflammatory and analgesic activities. Additionally, compound 3j showed gastrointestinal safety with reduced lipid peroxidation. Docking results of compound 3j with COX-2 and 5-LOX were also consistent with the in vivo anti-inflammatory results.