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

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Benchekroun, Mohamed | Ermolenko, Ludmila | Tran, Minh Quan | Vagneux, Agathe | Nedev, Hristo | Delehouzé, Claire | Souab, Mohamed | Baratte, Blandine | Josselin, Béatrice | Iorga, Bogdan | Ruchaud, Sandrine | Bach, Stéphane | Al-Mourabit, Ali

Edité par CCSD ; Elsevier -

International audience. 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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