Exploration of the Structural Space in 4(3H)-Quinazolinone Antibacterials
| Autor: | Kiran V. Mahasenan, Jeshina Janardhanan, Sara Tejera, Elena Lastochkin, Shahriar Mobashery, Yuanyuan Qian, William R. Wolter, Giuseppe Allegretta, Zhihong Peng, Melissa Malia N. Gozun, Mayland Chang, Rhona Feltzer, Valerie A. Schroeder |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
biology Chemistry medicine.drug_class Antibiotics Allosteric regulation In vitro toxicology Active site biochemical phenomena metabolism and nutrition medicine.disease_cause 01 natural sciences 0104 chemical sciences Microbiology 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Staphylococcus aureus In vivo Drug Discovery medicine biology.protein Molecular Medicine Structure–activity relationship Quinazolinone 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 63:5287-5296 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant Staphylococcus aureus (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73 ((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the β-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence. |
| Databáze: | OpenAIRE |
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