Benzimidazole scaffold based hybrid molecules for various inflammatory targets: Synthesis and evaluation.
Bioorg Chem
; 80: 24-35, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-29864685
ABSTRACT
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 IC50â¯=â¯9.85⯵M; COX-2 IC50â¯=â¯1.00⯵M; SIâ¯=â¯9.85; 5-LOX IC50â¯=â¯0.32⯵M; 15-LOX IC50â¯=â¯1.02⯵M) 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.
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MEDLINE
Assunto principal:
Benzimidazóis
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Analgésicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article