Estimation of the lipophilicity of antiarrhytmic and antihypertensive active 1-substituted pyrrolidin-2-one and pyrrolidine derivatives

Department of Pharmaceutical Chemistry, Medical College, Jagiellonian University 30-688 Kraków, Medyczna 9, Poland.
Biomedical Chromatography (Impact Factor: 1.72). 07/2003; 17(5):318-24. DOI: 10.1002/bmc.246
Source: PubMed


The lipophilicity of some antiarrhythmic and antihypertensive active 1-[2-hydroxy- or 1-[2-acetoxy-3-(4-aryl-1-piperazinyl)propyl]pyrrolidin-2-one derivatives (1-12) has been investigated. Their lipophilicity (R(MO) and log k') was determined by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography with mixtures of acetonitrile and Tris buffer as mobile phases. The partition coefficients of compounds 1-12 (log P(ScilogP)) were also calculated with the ScilogP program. Comparison of R(MO), log k' and calculated log D(7.0 ScilogP) values enabled calculation of clog D(7.0 TLC) and clog D(7.0 HPLC) values. Preliminary quantitative structure-activity relationship studies indicated that for active compounds there is a dependence between affinity for alpha(2)-adrenoceptors and their clog D(7.0 HPLC) values.

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    • "Computational methods 1-[3-(4-Arylpiperazin-1-yl)propyl]pyrrolidin-2-one derivatives Thirty-three analogs of 1-[3-(4-(aryl)piperazin-1-yl)pro- pyl]pyrrolidin-2-one were chosen from the reports published by us between 2002 and 2009 (Kulig et al., 2003, 2004, 2007, 2009; Malawska et al., 2002, 2005). The source publications concern the synthesis of over 70 arylpiperazine derivatives and their pharmacological test results. "
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    ABSTRACT: The activity of a number of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one antiarrhythmic (AA) agents was described using the quantitative structure–activity relationship model by applying it to 33 compounds. The molecular descriptors of the AA activity were obtained by quantum chemical calculations combined with molecular modeling calculations. The resulting model explains up to 91% of the variance and it was successfully validated by four tests (LOO, LMO, external test, and Y-scrambling test). Statistical analysis shows that the AA activity of the studied compounds depends mainly on the PCR and JGI4 descriptors. Electronic supplementary material The online version of this article (doi:10.1007/s00044-010-9540-x) contains supplementary material, which is available to authorized users.
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    ABSTRACT: A molecule library containing 42 1-[3-(arylpiperazin-1-yl)-propyl]-pyrrolidin-2-one derivatives has been designed and synthesized. The phospholipophilicity of the obtained compounds has been determined using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC). The performed analysis allowed the calculation of log k(we) values for each of the tested compounds. Experimental phospholipophilicity data (log k(we)) has been compared with the affinity of the tested compounds to alpha(2)-adrenoceptors. Performed quantitative structure-activity relationship studies indicated that, for the tested compounds, there are dependences between affinity for alpha(2)-adrenoceptors and their log k(we) values. The obtained results confirmed that the applied chromatographic IAM-HPLC method could be useful in fast characterization of the phosholipophilicity of structurally closely related compounds as well as for larger series of compounds, such as drug candidates. It could also be used as a tool for further research into this group of compounds.
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    ABSTRACT: The relative lipophilicity (R(M)(0)) of fourteen 1-substituted pyrrolidin-2-one derivatives has been measured by use of RP-TLC plates and mixtures of acetonitrile and pH 7.0 Tris buffer with volume fractions of acetonitrile between 20 and 80% were used as mobile phases. Retention data (R(M)) obtained by this method were exponentially dependent on acetonitrile concentration and enabled estimation of the relative lipophilicity corresponding to pH 7.0 Tris buffer as mobile phase. 1-{2-Hydroxy-3-[4-(3-methoxyphenyl)piperazin-1-yl]propyl}pyrrolidin-2-one had the highest relative lipophilicity (1.33) and butylcarbamic acid 1-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-2-(2-oxopyrrolidin-1-yl)ethyl ester had the lowest (0.72). Comparison of R(M)(0) values obtained with the affinity of the compounds tested for alpha-adrenoceptors enable formulation of preliminary equations for quantitative structure-activity relationships (QSAR).
    JPC - Journal of Planar Chromatography - Modern TLC 04/2009; 22(2):141-144. DOI:10.1556/JPC.22.2009.2.12 · 0.67 Impact Factor
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