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

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.
Carolina M Avila 1 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
Affiliations

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.
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.

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