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Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part.

Megahed, Sarah H
; 
Rasheed, Sari
; ; 
El-Hossary, Ebaa M
; 
El-Shabrawy, Yahia I
; 
Abadi, Ashraf H
; 
Engel, Matthias
; 
Müller, Rolf
; 
Abdel-Halim, Mohammad
; 
Hamed, Mostafa M
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Issue Date
2022-01-07
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Abstract
Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.
Citation
Bioorg Med Chem Lett. 2022 Mar 1;59:128531. doi: 10.1016/j.bmcl.2022.128531. Epub 2022 Jan 7.
Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Publisher
Elsevier Ltd.
Journal
Bioorganic & medicinal chemistry letters
URI
http://hdl.handle.net/10033/623169
DOI
10.1016/j.bmcl.2022.128531
PubMed ID
35007723
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Article
Language
en
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1464-3405
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Attribution 4.0 International
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publications of the research group drug design and optimization(HIPS]DDOP)
publications of the research group of microbial natural substances([HIPS]MINS)