Substituted 4-acylpyrazoles and 4-acylpyrazolones: synthesis and multidrug resistance-modulating activity.
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 (r2cv = 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.
Chiba
P
P
Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Wien, Austria.
Holzer
W
W
Landau
M
M
Bechmann
G
G
Lorenz
K
K
Plagens
B
B
Hitzler
M
M
Richter
E
E
Ecker
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D001692:Biological Transport; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012044:Regression Analysis; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005456:Fluorescent Dyes; D011720:Pyrazoles; D020112:Rhodamine 123; D003630:Daunorubicin