Exploration of the Structural Space in 4(3H)‑Quinazolinone Antibacterials
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 prop...
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Published in | Journal of medicinal chemistry Vol. 63; no. 10; pp. 5287 - 5296 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
28.05.2020
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Y.Q., G.A., and S.T. synthesized the quinazolinones. J.J. conducted the time-kill assays and the mouse neutropenic thigh-infection studies. Z.P. and M.M.N.G. determined plasma protein binding and conducted the PK studies. K.V.M. performed the computational analyses. E.L. determined the MIC. E.L. and R.F. conducted the XTT assays. V.A.S. and W.R.W. conducted the in-life portion of the animal studies. S.M. and M.C. directed all the studies. The manuscript was written and proofread by all authors. Author Contributions |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/acs.jmedchem.0c00153 |