Substituted 4-acylpyrazoles and 4-acylpyrazolones
- Author(s)
- Peter Chiba, Wolfgang Holzer, Marion Landau, Gerhard Bechmann, Karin Lorenz, Brigitte Plagens, Manuela Hitzler, Elisabeth Richter, Gerhard Ecker
- Abstract
A series of 4-acyl-3-pyrazolone derivatives with a 3-substituted 2- hydroxy-3-aminopropyl chain attached to pyrazole N-1 (7-20) as well as isomeric 4-acyl-5-(3-substituted 3-amino-2-hydroxypropoxy)pyrazole derivatives (5, 6) were synthesized, and their multidrug resistance (MDR)- modulating activity was measured using the daunomycin efflux assay. Reaction of N1-substituted 4-acyl-3-pyrazolones (tautomer to 4-acyl-5- hydroxypyrazoles) with excessive epichlorohydrin and successive treatment with an appropriate amine resulted in N-alkylation and thus afforded the target pyrazolone derivatives 7-20. In contrast, O-alkylation occurred upon reaction with 1 equiv of epichlorohydrin and subsequent treatment with amine leading to the corresponding 4-acyl-5-pyrazolyl ethers 5 and 6. QSAR studies showed a good correlation of MDR-modulating activity with lipophilicity of the compounds. Inclusion of hydrogen bond acceptor strength and steric parameters as descriptors led to a QSAR equation with remarkably increased predictive power (r2(cv) = 0.92). Additionally, ortho substitution of the propanolamine side chain and the acyl moiety is favorable. Detailed NMR spectroscopic investigations were carried out with the title compounds.
- Organisation(s)
- Journal
- Journal of Medicinal Chemistry
- Volume
- 41
- Pages
- 4001-4011
- No. of pages
- 11
- ISSN
- 0022-2623
- DOI
- https://doi.org/10.1021/jm980121y
- Publication date
- 10-1998
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301207 Pharmaceutical chemistry
- ASJC Scopus subject areas
- Molecular Medicine, Drug Discovery
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/56f87d22-056a-462f-b5fc-e848bcf07aca