دورية أكاديمية
1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors
| العنوان: | 1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors |
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| المؤلفون: | Verdirosa, Federica, Gavara, Laurent, Sevaille, Laurent, Tassone, Giusy, Corsica, Giuseppina, Legru, Alice, Feller, Georges, Chelini, Giulia, Mercuri, Paola, Tanfoni, Silvia, Sannio, Filomena, Benvenuti, Manuela, Cerboni, Giulia, De Luca, Filomena, Bouajila, Ezeddine, Hoang, Yen Vo, Licznar-Fajardo, Patricia, Galleni, Moreno, Pozzi, Cecilia, Mangani, Stefano, Docquier, Jean-Denis, Hernandez, Jean-François |
| المصدر: | ChemMedChem, 17 (7), e202100699 (2022-01-20) |
| بيانات النشر: | Chemistry Europe Wiley-VCH GmbH, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | antibiotic resistance, beta-lactamase, medicinal chemistry, carbapenem, 1,2,4-triazole-3-thione, bacterial resistance, beta-lactam antibiotic, metallo-beta-lactamase inhibitor, Life sciences, Microbiology, Biochemistry, biophysics & molecular biology, Human health sciences, Immunology & infectious disease, Sciences du vivant, Microbiologie, Biochimie, biophysique & biologie moléculaire, Sciences de la santé humaine, Immunologie & maladie infectieuse |
| الوصف: | Metallo-β-lactamases (MBLs) are increasingly involved as amajor mechanism of resistance to carbapenems in relevantopportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medicalneed. We previously reported several series of compoundsbased on the 1,2,4-triazole-3-thione scaffold. In particular, Schiffbases formed between diversely 5-substituted-4-amino com pounds and 2-carboxybenzaldehyde were broad-spectruminhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately,these compounds were unable to restore antibiotic suscepti bility of MBL-producing bacteria, probably because of poorpenetration and/or susceptibility to hydrolysis. To improve theirmicrobiological activity, we synthesized and characterizedcompounds where the hydrazone-like bond of the Schiff baseanalogues was replaced by a stable ethyl link. This small changeresulted in a narrower inhibition spectrum, as all compoundswere poorly or not inhibiting NDM-1 and IMP-1, but showed asignificantly better activity on VIM-type enzymes, with Ki valuesin the μM to sub-μM range. The resolution of the crystallo graphic structure of VIM-2 in complex with one of the bestinhibitors yielded valuable information about their bindingmode. Interestingly, several compounds were shown to restorethe β-lactam susceptibility of VIM-type-producing E. coli labo ratory strains and also of K. pneumoniae clinical isolates. Inaddition, selected compounds were found to be devoid oftoxicity toward human cancer cells at high concentration, thusshowing promising safety. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article peer reviewed |
| اللغة: | English |
| Relation: | urn:issn:1860-7179 |
| DOI: | 10.1002/cmdc.202100699 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/268398 |
| حقوق: | restricted access http://purl.org/coar/access_right/c_16ec info:eu-repo/semantics/restrictedAccess |
| رقم الأكسشن: | edsorb.268398 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1002/cmdc.202100699 |
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