PMID- 14695838
OWN - NLM
STAT- MEDLINE
DCOM- 20040224
LR  - 20031229
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 47
IP  - 1
DP  - 2004 Jan 1
TI  - Folate-synthesizing enzyme system as target for development of inhibitors and 
      inhibitor combinations against Candida albicans-synthesis and biological activity 
      of new 2,4-diaminopyrimidines and 4'-substituted 4-aminodiphenyl sulfones.
PG  - 240-53
AB  - The paper describes the design, synthesis, and testing of inhibitors of 
      folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The 
      target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate 
      reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized 
      and tested as inhibitors of DHFR and compared with their activity against DHFR 
      derived from mycobacteria and Escherichia coli. To test for selectivity, also rat 
      DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for 
      inhibitory activity against SYN and the I(50) values compared to those obtained 
      previously against Plasmodium berghei- and E. coli-derived SYN. Surprisingly, 
      QSAR equations show very similar structural dependencies. To find an explanation 
      for the large difference in the I(50) values observed for enzyme inhibition (SYN, 
      DHFR) and for inhibition of cell cultures of Candida, mutant strains with 
      overexpressed efflux pumps and strains in which such pumps are deleted were 
      included in the study and the MICs compared. Efflux pumps were responsible for 
      the low activity of some of the tested derivatives, others showed no increase in 
      activity after pumps were knocked out. In this case it may be speculated that 
      these derivatives are not able to enter the cells.
FAU - Otzen, Thomas
AU  - Otzen T
AD  - Division of Structural Biochemistry, Research Center Borstel, Leibniz Center for 
      Medicine and Biosciences, Parkallee 1-40, D-23845 Borstel, Germany.
FAU - Wempe, Ellen G
AU  - Wempe EG
FAU - Kunz, Brigitte
AU  - Kunz B
FAU - Bartels, Rainer
AU  - Bartels R
FAU - Lehwark-Yvetot, Gudrun
AU  - Lehwark-Yvetot G
FAU - Hansel, Wolfram
AU  - Hansel W
FAU - Schaper, Klaus-Jurgen
AU  - Schaper KJ
FAU - Seydel, Joachim K
AU  - Seydel JK
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Aminopyridines)
RN  - 0 (Antifungal Agents)
RN  - 0 (Drug Combinations)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Sulfones)
RN  - EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
RN  - EC 2.5.1.15 (Dihydropteroate Synthase)
SB  - IM
MH  - Aminopyridines/*chemical synthesis/chemistry/pharmacology
MH  - Animals
MH  - Antifungal Agents/*chemical synthesis/chemistry/pharmacology
MH  - Candida albicans/*drug effects/genetics/growth & development
MH  - Dihydropteroate Synthase/chemistry/metabolism
MH  - Drug Combinations
MH  - Drug Resistance, Multiple, Fungal
MH  - Folic Acid Antagonists/*chemical synthesis/chemistry/pharmacology
MH  - Microbial Sensitivity Tests
MH  - Mutation
MH  - Quantitative Structure-Activity Relationship
MH  - Rats
MH  - Sulfones/*chemical synthesis/chemistry/pharmacology
MH  - Tetrahydrofolate Dehydrogenase/chemistry/metabolism
EDAT- 2003/12/30 05:00
MHDA- 2004/02/26 05:00
CRDT- 2003/12/30 05:00
PHST- 2003/12/30 05:00 [pubmed]
PHST- 2004/02/26 05:00 [medline]
PHST- 2003/12/30 05:00 [entrez]
AID - 10.1021/jm030931w [doi]
PST - ppublish
SO  - J Med Chem. 2004 Jan 1;47(1):240-53. doi: 10.1021/jm030931w.