- Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines
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Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim (TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4- diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains.
- Li, Xiaoming,Hilgers, Mark,Cunningham, Mark,Chen, Zhiyong,Trzoss, Michael,Zhang, Junhu,Kohnen, Lucy,Lam, Thanh,Creighton, Chris,Gc, Kedar,Nelson, Kirk,Kwan, Bryan,Stidham, Mark,Brown-Driver, Vickie,Shaw, Karen J.,Finn, John
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scheme or table
p. 5171 - 5176
(2011/10/09)
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- Further Studies on the Synthesis of Quinazolines from 2-Fluorobenzonitriles
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Recently, we reported that appropriately substituted 2-fluorobenzonitriles undergo cyclization with guanidine carbonate to afford 2,4-diaminoquinazolines usually in good to excellent yield.This paper describes the preparation of a variety of new 2,4-diaminoquinazolines substituted at positions five or seven.In addition, the reactions of selected 2-fluorobenzonitriles with formamidine acetate or acetamidine acetate were examined.The results obtained demonstrate that the analogous 4-amino- and 2-methyl-4-aminoquinazolines can be prepared by this approach but that yields are considerably lower than when guanidine carbonate is employed as the cyclization reagent.
- Hynes, John B.,Tomazic, Alenka,Parrish, Christie A.,Fetzer, Oliver S.
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p. 1357 - 1364
(2007/10/02)
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