Structure–Activity Relationship for the 4(3H)-Quinazolinone Antibacterials
| Autor: | Elena Lastochkin, Derong Ding, Mark A. Suckow, Mayland Chang, Renee Bouley, Shahriar Mobashery, Zhihong Peng, Valerie A. Schroeder, Maria Bastian, William R. Wolter, Wei Song |
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| Rok vydání: | 2016 |
| Předmět: |
medicine.drug_class
In silico Antibiotics Microbial Sensitivity Tests Peritonitis Pharmacology Gram-Positive Bacteria 010402 general chemistry medicine.disease_cause 01 natural sciences Article Mice Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics Drug Discovery medicine Animals Humans Structure–activity relationship Quinazolinone Cell Proliferation Quinazolinones Mice Inbred ICR Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Hep G2 Cells Anti-Bacterial Agents 3. Good health 0104 chemical sciences Bioavailability Disease Models Animal Staphylococcus aureus Molecular Medicine Antibacterial activity |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure–activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model. |
| Databáze: | OpenAIRE |
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