Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1 - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2020

Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

Bogdan Iorga

Résumé

With the aim to develop new chemical tools based on simplified natural metabolites to help deciphering the molecular mechanism of necroptosis, simplified benzazole fragments including 2-aminobenzimidazole and the 2-aminobenzothiazole analogs were prepared during the synthesis of the marine benzosceptrin B. Conpounds inhibiting the RIPK1 protein kinase were discovered. A library of 54 synthetic analogues were prepared and evaluated through a phenotypic screen using the inhibition of the necrotic cell death induced by TNF- in human Jurkat T cells deficient for the FADD protein. This article reports the design, synthesis and biological evaluation of a series of 2-aminobenzazoles on the necroptotic cell death through the inhibition of RIPK1 protein kinase. The 2-aminobenzimidazole and 2-aminobenzothiazole platforms presented herein can serve as novel chemical tools to study the molecular regulation of necroptosis and further develop lead drug candidates for chronic pathologies involving necroptosis.
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Dates et versions

hal-03004425 , version 2 (19-11-2020)
hal-03004425 , version 1 (21-11-2022)

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Mohamed Benchekroun, Ludmila Ermolenko, Minh Quan Tran, Agathe Vagneux, Hristo Nedev, et al.. Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1. European Journal of Medicinal Chemistry, 2020, 201, pp.112337. ⟨10.1016/j.ejmech.2020.112337⟩. ⟨hal-03004425v2⟩
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