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-hyd roxy-3-aminopropyl chain attached to pyrazole N-1 (7-20) as well as is omeric 4-acyl-5-(3-substituted 3-amino-2-hydroxypropoxy)pyrazole deriv atives (5, 6) were synthesized, and their multidrug resistance (MDR)-m odulating activity was measured using the daunomycin efflux assay; Rea ction of N-1-substituted 4-acyl-3-pyrazolones (tautomer to 4-acyl-5-hy droxypyrazoles) with excessive epichlorohydrin and successive treatmen t with an appropriate amine resulted in N-alkylation and thus afforded the target pyrazolone derivatives 7-20. In contrast, O-alkylation occ urred upon reaction with 1 equiv of epichlorohydrin and subsequent tre atment with amine leading to the corresponding 4-acyl-5-pyrazolyl ethe rs 5 and 6. QSAR studies showed a good correlation of MDR-modulating a ctivity with lipophilicity of the compounds. Inclusion of hydrogen bon d acceptor strength and steric parameters as descriptors led to a QSAR equation with remarkably increased predictive power (r(cv)(2) = 0.92) . Additionally, ortho substitution of the propanolamine side chain and the acyl moiety is favorable. Detailed NMR spectroscopic investigatio ns were carried out with the title compounds.