Chiba P, Holzer W, Landau M, Bechmann G, Lorenz K, Plagens B, Hitzler M, Richter E, Ecker G
Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Wien, Austria.
J Med Chem. 1998 Oct 8;41(21):4001-11. doi: 10.1021/jm980121y.
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.
合成了一系列在吡唑N-1（7-20）上连接有3-取代的2-羟基-3-氨基丙基链的4-酰基-3-吡唑啉酮衍生物以及异构的4-酰基-5-（3-取代的3-氨基-2-羟基丙氧基）吡唑衍生物（5,6），并使用柔红霉素外排试验测定了它们的多药耐药性（MDR）调节活性。N1-取代的4-酰基-3-吡唑啉酮（4-酰基-5-羟基吡唑的互变异构体）与过量的环氧氯丙烷反应，然后用适当的胺连续处理，导致N-烷基化，从而得到目标吡唑啉酮衍生物7-20。相反，与1当量的环氧氯丙烷反应并随后用胺处理会发生O-烷基化，生成相应的4-酰基-5-吡唑基醚5和6。定量构效关系（QSAR）研究表明，MDR调节活性与化合物的亲脂性具有良好的相关性。将氢键受体强度和空间参数作为描述符纳入，得到了一个预测能力显著提高的QSAR方程（r2cv = 0.92）。此外，丙醇胺侧链和酰基部分的邻位取代是有利的。对标题化合物进行了详细的核磁共振光谱研究。
