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.