Synthesis and biological evaluations of new families of histidine kinases inhibitors

Abstract : Nowadays, the emergence of multidrug resistant bacteria requires interest in the medical field and thereby an urgent need to develop efficient and specific methods in targeting unique bacterial cellular processes. 1,2 Two-component signal transduction systems (TCS) are widely used in bacteria to allow adaptation, osmosis and resistance appearance by translating an external signal into a cellular response. 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. 3 Preliminary modeling work carried out in our laboratory led to a series of thiophene derivatives. Twenty-one new thiophene derivatives were synthesized and evaluated in vitro on bacterial histidine kinases (HK) PhoR, ResE and WalK, from which eight derivatives showed significant inhibitory activity. One compound exhibited broad-spectrum antimicrobial activity with the particularity to restore antibacterial activity of antibiotics ineffective on resistant bacteria treated alone, 4 With the purpose to improve biological activity, amino thiophene derivatives have been developed.
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Submitted on : Monday, October 28, 2019 - 10:21:23 AM
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Valentin Duvauchelle, Miyanou Rosales-Hurtado, Thibaut Boibessot, David Bénimèlis, Catherine Dunyach-Remy, et al.. Synthesis and biological evaluations of new families of histidine kinases inhibitors. GSO-JMJC-JED2019, Oct 2019, Montpellier, France. ⟨hal-02333120⟩

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