Structure-based design and biological profile of (E)-N-(4-Nitrobenzylidene)-2-naphthohydrazide, a novel small molecule inhibitor of IκB kinase-β

Carolina M Avila; Alexandra B Lopes; Arlan S Gonçalves; Leandro L da Silva; Nelilma C Romeiro; Ana Luisa P Miranda; Carlos M R Sant'Anna; Eliezer J Barreiro; Carlos A M Fraga

doi:10.1016/j.ejmech.2011.01.045

Structure-based design and biological profile of (E)-N-(4-Nitrobenzylidene)-2-naphthohydrazide, a novel small molecule inhibitor of IκB kinase-β

Eur J Med Chem. 2011 Apr;46(4):1245-53. doi: 10.1016/j.ejmech.2011.01.045. Epub 2011 Feb 3.

Authors

Carolina M Avila¹, Alexandra B Lopes, Arlan S Gonçalves, Leandro L da Silva, Nelilma C Romeiro, Ana Luisa P Miranda, Carlos M R Sant'Anna, Eliezer J Barreiro, Carlos A M Fraga

Affiliation

¹ Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902 Rio de Janeiro, Brazil.

PMID: 21334796
DOI: 10.1016/j.ejmech.2011.01.045

Abstract

In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-β inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-β active site, and a privileged structure template yielded a novel IKK-β inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-β inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-β inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Benzylidene Compounds / chemical synthesis
Benzylidene Compounds / chemistry*
Benzylidene Compounds / pharmacology*
Benzylidene Compounds / therapeutic use
Catalytic Domain
Cell Line
Drug Design*
Edema / chemically induced
Edema / drug therapy
Female
Humans
Hydrazones / chemical synthesis
Hydrazones / chemistry*
Hydrazones / pharmacology*
Hydrazones / therapeutic use
I-kappa B Kinase / antagonists & inhibitors*
I-kappa B Kinase / chemistry
Ligands
Male
Mice
Molecular Dynamics Simulation
Molecular Sequence Data
Molecular Weight
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use

Substances

Anti-Inflammatory Agents
Benzylidene Compounds
Hydrazones
Ligands
N-(4-nitrobenzylidene)-2-naphthohydrazide
Protein Kinase Inhibitors
I-kappa B Kinase