The
cysteine proteases, cruzain and TbrCATL (rhodesain),
are therapeutic targets for Chagas disease and Human African Trypanosomiasis,
respectively. Among the known inhibitors for these proteases, we have
described N
4-benzyl-N
2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as
a competitive cruzain inhibitor (K
i =
1.4 μM). Here, we describe the synthesis and biological evaluation
of 22 analogs of 1a, containing modifications in the
quinazoline core, and in the substituents in positions 2 and 4 of
this ring. The analogs demonstrate low micromolar inhibition of the
target proteases and cidal activity against Trypanosoma
cruzi with up to two log selectivity indices in counterscreens
with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations.
During the optimization of 1a, structure-based design
and prediction of physicochemical properties were employed to maintain
potency against the enzymes while removing colloidal aggregator characteristics
observed for some molecules in this series.
Staphylococcus aureus and Staphylococcus epidermidis are the main agents involved with implant-related infections. Their ability to adhere to medical devices with subsequent biofilm formation is crucial to the development of these infections. Herein, we described the antibacterial and antibiofilm activities of a quinazoline-based compound, N 4-benzyl-N 2-phenylquinazoline-2,4-diamine, against both biofilm-forming pathogens. The minimum inhibitory concentrations (MIC) were determined as 25 µM for S. aureus and 15 µM for S. epidermidis. At sub-MIC concentrations (20 µM for S. aureus and 10 µM for S. epidermidis), the compound was able to inhibit biofilm formation without interfere with bacterial growth, confirmed by scanning electron microscopy. Moreover, surfaces coated with the quinazoline-based compound were able to prevent bacterial adherence. In addition, this compound presented no toxicity to human red blood cells at highest MIC 25 µM and in vivo toxicity assay using Galleria mellonella larvae resulted in 82% survival with a high dose of 500 mg/kg body weight. These features evidence quinazoline-based compound as interesting entities to promising applications in biomedical fields, such as antimicrobial and in anti-infective approaches.
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