Evaluation of phenylaminopyrimidines as antifungal protein kinase inhibitors.
The effects of diverse phenylaminopyrimidines (PAP), namely PAP-pyridines (type A), PAP-pyrazoles (type B) and PAP-thiazoles (type C), on Neurospora crassa Shear & Dodge has been investigated. The results revealed that type A strongly inhibit the in vitro growth of N crassa, whereas types B and C are much less active. A significant correlation was observed between the Neurospora growth inhibition and the intrinsic activity of type A compounds on the cyclin-dependent protein kinase p34(CDC2) of starfish, suggesting that the target of phenylaminopyrimidines in fungi is a cyclin-dependent protein kinase (CDK). The phenylaminopyrimidine-binding CDKs Phoss (major band) and CDC2 (minor band) involved in phosphorus uptake, glycogen synthesis and the cell cycle were identified from N crassa by affinity chromatography on phenylaminopyrimidine-sepharose. Comparative experiments with different protein kinases revealed the importance of the side chain of phenylaminopyrimidines for their target selectivity. A type B compound was found to selectively inhibit the MAP-kinase OS-2 involved in the osmoregulatory pathway of Neurospora.
Pillonel
Christian
C
Syngenta Crop Protection AG, Basel, Switzerland. chrispill@bluewin.ch
D005659:Fungicides, Industrial / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009491:Neurospora / Q000187:drug effects / Q000201:enzymology; D010080:Oxazoles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D013329:Structure-Activity Relationship
D005659:Fungicides, Industrial; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C437165:fenpiclonil; C025643:vinclozolin