Abstract:
The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents.
There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked
the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by
discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we
describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3–13 and 36), 2-thio-4-amino
substituted quinazolines (14–33) and 6-substituted 2,4-diamonsubstituted quinazolines (37–39). The synthe-
sized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and
Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus
aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin-
resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds
revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the
2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at
position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously
reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a
successful approach to keep the high antibacterial potency while substantially improving safety profile as
indicated by the reduced activity on different cell lines and a lack of hemolytic activity.
