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Pyrimido-Pyrimidines: A Novel Class of Dihydrofolate Reductase Inhibitors

Mihailo Banjanac1*, Iva Tatic1, Zrinka Ivezic2, Sanja Tomic3 and Jerka Dumic4


1
CEMDD, GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia

2Nabriva Therapeutics AG, Leberstrasse 20, AT-1112 Vienna, Austria
3Physical Chemistry Department, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
4Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovačića 1, HR-10000 Zagreb, Croatia

Article history:

Received October 29, 2008
Accepted April 14, 2009

Key words:

dihydrofolate reductase, docking, inhibitors, pyrimido[4,5-d]pyrimidine-2,4-diamine, structure-activity relationship

Summary:

Inhibitors of dihydrofolate reductase (DHFR), an enzyme that catalyzes 5,6,7,8-tetrahydrofolate synthesis, have been used as antimicrobial as well as antimetabolite drugs for a long time. Although structurally belonging to different classes, the majority of DHFR inhibitors contain 2,4-diamino substitution in pyrimidine ring. With the aim to introduce pyrimido-pyrimidines as a novel class of bacterial DHFR (bDHFR) inhibitors, 42 compounds belonging to that class have been tested and compared with 18 pteridines using cell and enzyme models and docking studies. A few pyrimido-pyrimidine compounds showed high potency (IC50≤0.05 μM) and selectivity as inhibitors of bDHFR. These properties seem to be dependent on the stringent structure freedom and flexibility, based on the specific combination of prerequisite structural motifs that enable pyrimido-pyrimidine compounds to fit into bDHFR active site in a relatively specific manner. The presented results will help to set the basis for designing new small molecules, inhibitors of DHFR, with interesting and potentially selective antibacterial properties.

 


*Corresponding author:           mihailo.z.banjanac@gsk.com
                                               ++385 1 6051 114
                                             
 ++385 1 6051 091

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