Synthesis of thiophene derivatives: Potential new inhibitors of histidine kinases

Abstract : Nowadays, infections caused by multidrug-resistant bacteria represent one of the biggest challenges in the medical field and there is an urgent need to develop efficient and well tolerated antibacterials targeting unique cellular processes.[1,2] Two-component signal transduction systems (TCS) are widely used for bacteria to translate an external signal into a cellular response. They are ubiquitous in bacteria, absent in mammals and are integrated into various pathogenic pathways.[3,4] In order to attenuate these signaling pathways, we aimed at targeting the TCS signal transducer histidine kinase by focusing on their highly conserved ATP-binding domain.[5] Preliminary modeling work carried out in our laboratory led to a series of thiophene derivatives. Twenty-four new molecules were synthesized and evaluated in vitro on bacterial histidine kinases PhoR, ResE and WalK. We identify eight compounds with significant inhibitory activity against these proteins. Nevertheless, only two compounds exhibited broad-spectrum antimicrobial activity.[6] That is the reason why in order to improve the biological activity of the synthesized molecules, a new series of amino thiophene has been developed. The nitro function of the preceding molecules was reduced by hydrogenation in situ using several conditions.
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Miyanou Rosales-Hurtado, Thibaut Boibessot, Christopher Zschiedrich, Alexandre Lebeau, David Bénimélis, et al.. Synthesis of thiophene derivatives: Potential new inhibitors of histidine kinases. Rencontres en Chimie Organique Biologique (Recob 17), Mar 2018, Aussois, France. ⟨hal-01997587⟩

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