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11:51
Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
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Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.
Renee Bouley1, Derong Ding1, Zhihong Peng1
1Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
Journal of Medicinal Chemistry
|April 19, 2016
Summary
Researchers discovered a novel antibacterial quinazolinone derivative effective against Staphylococcus aureus and methicillin-resistant strains. This compound shows promising oral bioavailability and efficacy in preclinical infection models.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Antimicrobial Research
Background:
- A novel antibacterial compound featuring a 4(3H)-quinazolinone core was previously identified.
- The initial discovery involved in silico screening of 1.2 million compounds targeting a penicillin-binding protein.
Purpose of the Study:
- To explore the structure-activity relationship (SAR) of the 4(3H)-quinazolinone antibacterial scaffold.
- To identify and characterize novel quinazolinone derivatives with potent antimicrobial activity.
Main Methods:
- Evaluation of 77 variants of the quinazolinone scaffold to establish the SAR.
- In vitro toxicity, pharmacokinetic profiling, and efficacy studies in mouse infection models for promising compounds.
Main Results:
- Compound 27, a novel quinazolinone, demonstrated potent activity against methicillin-resistant Staphylococcus aureus (MRSA).
- This compound exhibited favorable pharmacokinetic properties, including low clearance and oral bioavailability.
- Efficacy was confirmed in a mouse neutropenic thigh infection model.
Conclusions:
- The study successfully elucidated the SAR for the 4(3H)-quinazolinone antibacterial scaffold.
- Compound 27 represents a promising lead candidate for developing new treatments against MRSA infections.
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