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.
Highlights
The inappropriate and excessive use of antibiotics, without medical supervision, led to the increase and the emergence of lethal human infections that are resistant to multiple antibiotics
In another recently published study, some quinazolin-4-ones were reported as cell wall biosynthesis inhibitors, through their ability to bind to the penicillin-binding protein 22 (PBP)2a
Replacing the benzenoid part of the quinazoline compound I with a thiophene gave the thieno[2,3-d]pyrimidine analogue 20, which displayed good antibacterial activity against S. aureus Newman strain, S. pneumoniae and the effluxdeficient E. coli strain with MIC in the one-digit μg/mL range
Summary
The inappropriate and excessive use of antibiotics, without medical supervision, led to the increase and the emergence of lethal human infections that are resistant to multiple antibiotics. We reported the synthesis and antibacterial activity of an optimized hit compound I (Figure 1) with promising antibacterial activity against Gram-positive bacteria, including drug-resistant strains, the Gram-negative bacterium E. coli TolC as well as Mycobacterium smegmatis, with MIC values ranging from 2-8 μg/mL.[40] Importantly, compound I showed a good safety profile rationalized by the decreased toxicity against A549 and HepG2 cells, in addition to the lack of hemolytic activity at concentrations up to 500 μM.
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