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

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

  • Bioorg Med Chem Lett. 2022 Mar 1;59:128531. doi: 10.1016/j.bmcl.2022.128531.
Sarah H Megahed 1,  Sari Rasheed 2,  Jennifer Herrmann 2,  Ebaa M El-Hossary 3,  Yahia I El-Shabrawy 4,  Ashraf H Abadi 1,  Matthias Engel 5,  Rolf Müller 6,  Mohammad Abdel-Halim 7,  Mostafa M Hamed 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt.
  • 2 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
  • 3 Drug Radiation Research Department, National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, Ahmed El-Zomor St. 3, El-Zohoor Dist., Nasr City, 11765 Cairo, Egypt.
  • 4 Department of Microbiology and Immunology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt.
  • 5 Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
  • 6 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt. Electronic address: mohammad.abdel-halim@guc.edu.eg.
  • 8 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany. Electronic address: mostafa.hamed@helmholtz-hips.de.
PMID: 35007723 DOI: 10.1016/j.bmcl.2022.128531
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.

Keywords

Antibacterial; Cytotoxicity; Pyrazolo[3,4-d]pyrimidine; Quinazoline; Thieno[2,3-d]pyrimidine.

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