Academic Journal
The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases
| العنوان: | The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases |
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| المؤلفون: | Boibessot, Thibaut, Zschiedrich, Christopher, Lebeau, Alexandre, Bénimélis, David, Dunyach-Remy, Catherine, Lavigne, Jean-Philippe, Szurmant, Hendrik, Benfodda, Zohra, Meffre, Patrick |
| المساهمون: | Détection, évaluation, gestion des risques CHROniques et éMErgents (CHROME) / Université de Nîmes (CHROME), Université de Nîmes (UNIMES), Institut des Biomolécules Max Mousseron Pôle Chimie Balard (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), College of Osteopathic Medicine, Department of Basic Medical Sciences, Western University of Health Sciences, Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, San Diego, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM) |
| المصدر: | ISSN: 0022-2623. |
| بيانات النشر: | HAL CCSD American Chemical Society |
| سنة النشر: | 2016 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | Inhibitory activities, Thiophene derivatives, Bacterial histidine kinase (HK), Two-component signal transduction systems (TCSs), Multidrug-resistant bacteria, [CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry |
| الوصف: | International audience ; The emergence of multidrug-resistant bacteria emphasizes the urgent need for novel antibacterial compounds targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved adenosine triphosphate-binding domain. We used a structure-based drug design strategy that begins from an inhibitor-bound crystal structure and includes a significant number of structurally simplifiying “intuitive” modifications to arrive at the simple achiral, biaryl target structures. Thus, ligands were designed, leading to a series of thiophene derivatives. These compounds were synthesized and evaluated in vitro against bacterial HKs. We identified eight compounds with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compounds were also evaluated as adjuvants for the treatment of resistant bacteria. One compound was found to restore the sensivity of these bacteria to the respective antibiotics. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | hal-01543599; https://hal.science/hal-01543599; https://hal.science/hal-01543599/document; https://hal.science/hal-01543599/file/2016_Benfodda%20J.Med.Chem_AD%C3%A9poser05072017.pdf |
| DOI: | 10.1021/acs.jmedchem.6b00580 |
| الاتاحة: | https://hal.science/hal-01543599 https://hal.science/hal-01543599/document https://hal.science/hal-01543599/file/2016_Benfodda%20J.Med.Chem_AD%C3%A9poser05072017.pdf https://doi.org/10.1021/acs.jmedchem.6b00580 |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.7253EB58 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.6b00580 |
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