The evaluation of the lipophilic characteristics of biologically active agents is indispensable for the rational design of ADMET-tailored structure⁻activity models. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides, and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as a series of compounds with antimycobacterial, antibacterial, and herbicidal activity. As it was found that the lipophilicity of these biologically active agents determines their activity, the hydro-lipophilic properties of all three series were investigated in this study. All 57 anilides were analyzed using the reversed-phase high-performance liquid chromatography method for the measurement of lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, a range of software lipophilicity predictors for the estimation of clogP values of a set of N-alkoxyphenylhydroxynaphthalenecarboxamides was employed and subsequently cross-compared with experimental parameters. Thus, the empirical values of lipophilicity (logk) and the distributive parameters (π) were compared with the corresponding in silico characteristics that were calculated using alternative methods for deducing the lipophilic features. To scrutinize (dis)similarities between the derivatives, a PCA procedure was applied to visualize the major differences in the performance of molecules with respect to their lipophilic profile, molecular weight, and violations of Lipinski’s Rule of Five.

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackeho 1 61242 Brno Czech Republic

Department of Pharmaceutical Chemistry Faculty of Pharmacy Comenius University in Bratislava Odbojarov 10 83232 Bratislava Slovakia

Department of Synthesis Chemistry Faculty of Mathematics Physics and Chemistry University of Silesia Szkolna 9 40007 Katowice Poland

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Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001;46:3–26. doi: 10.1016/S0169-409X(00)00129-0. PubMed DOI

Lipinski C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today Technol. 2004;1:337–341. doi: 10.1016/j.ddtec.2004.11.007. PubMed DOI

Polanski J., Kurczyk A., Bak A., Musiol R. Privileged structures-dream or reality: Preferential organization of azanaphthalene scaffold. Curr. Med. Chem. 2012;19:1921–1945. doi: 10.2174/092986712800167356. PubMed DOI

Veber D.F., Johnson S.R., Cheng H.Y., Smith B.R., Ward K.W., Kopple K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002;45:2615–2623. doi: 10.1021/jm020017n. PubMed DOI

Malik I., Csollei J., Jampilek J., Stanzel L., Zadrazilova I., Hosek J., Pospisilova S., Cizek A., Coffey A., O’Mahony J. The structure–antimicrobial activity relationships of promising class of the compounds containing N-arylpiperazine scaffold. Molecules. 2016;21:1274. doi: 10.3390/molecules21101274. PubMed DOI PMC

Gonec T., Malik I., Csollei J., Jampilek J., Stolarikova J., Solovic I., Mikus P., Keltosova S., Kollar P., O’Mahony J., et al. Synthesis and in vitro antimycobacterial activity of the novel N-arylpiperazines containing ethane-1,2-diyl connecting chain. Molecules. 2017;22:2100. doi: 10.3390/molecules22122100. PubMed DOI PMC

Kubinyi H. QSAR: Hansch Analysis and Related Approaches. Wiley-VCH; Weinheim, Germany: 1993.

Kerns E.H., Di L. Drug-Like Properties: Concepts, Structure Design and Methods: From ADME to Toxicity Optimization. Academic Press; San Diego, CA, USA: 2008.

Pliska V. In: Lipophilicity in Drug Action and Toxicology. 1st ed. Pliska V., Testa B., van der Waterbeemd H., editors. Volume 4 Methods and Principles in Medicinal Chemistry; Wiley-VCH; Weinheim, Germany: 1996.

Avdeef A. Absorption and Drug Development: Solubility, Permeability, and Charge State. 2nd ed. John Wiley & Sons; Hoboken, NJ, USA: 2012.

Hansch C., Mahoney P.P., Fujita T., Muir R.M. Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature. 1962;194:178–180. doi: 10.1038/194178b0. DOI

Hansch C., Fujita T. ρ-σ-π Analysis. A method for the correlation of biological activity and chemical structure. J. Am. Chem. Soc. 1964;86:1616–1626. doi: 10.1021/ja01062a035. DOI

Leo A., Hansch C., Elkins D. partition coefficients and their uses. Chem. Rev. 1971;71:525–616. doi: 10.1021/cr60274a001. DOI

Valko K. Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution. J. Chromatogr. A. 2004;1037:299–310. doi: 10.1016/j.chroma.2003.10.084. PubMed DOI

Carlson R.M., Carlson R.E., Kopperman H.L. Determination of partition coefficients by liquid chromatography. J. Chromatogr. A. 1975;107:219–223. doi: 10.1016/S0021-9673(00)82769-7. DOI

Mirrlees M.S., Moulton S.J., Murphy C.T., Taylor P. Direct measurement of octanol-water partition coefficients by high-pressure liquid chromatography. J. Med. Chem. 1976;19:615–619. doi: 10.1021/jm00227a008. PubMed DOI

Unger S.H., Cook J.R., Holenberg J.S. Simple procedure for determining octanol-aqueous partition, distribution, and ionization coefficients by reversed phase high pressure liquid chromatography. J. Pharm. Sci. 1978;67:1364–1367. doi: 10.1002/jps.2600671008. PubMed DOI

Braumann T. Determination of hydrophobic parameters by reversed-phase liquid chromatography: Theory, experimental techniques, and application in studies on quantitative structure-activity relationships. J. Chromatogr. A. 1986;373:191–225. doi: 10.1016/S0021-9673(00)80213-7. PubMed DOI

Giaginis C., Tsantili-Kakoulidou A. Current state of the art in HPLC methodology for lipophilicity assessment of basic drugs. A review. J. Liq. Chromatogr. Relat. 2008;31:79–96. doi: 10.1080/10826070701665626. DOI

Valko K., Du C.M., Bevan C., Reynolds D.P., Abraham M.H. Rapid method for the estimation of octanol/water partition coefficient (log P(oct)) from gradient RP-HPLC retention and a hydrogen bond acidity term (zetaalpha(2)(H)) Curr. Med. Chem. 2001;8:1137–1146. doi: 10.2174/0929867013372643. PubMed DOI

Cimpan G., Irimie F., Gocan S., Claessens H.A. Role of stationary phase and eluent composition on the determination of log P values of N-hydroxyethylamide of aryloxyalkylen and pyridine carboxylic acids by reversed-phase high-performance liquid chromatography. J. Chromatogr. B. 1998;714:247–261. doi: 10.1016/S0378-4347(98)00228-X. PubMed DOI

Gocan S., Cimpan G., Comer J. Lipophilicity measurements by liquid chromatography. Adv. Chromatogr. 2006;44:79–176. PubMed

Kucerova-Chlupacova M., Opletalova V., Jampilek J., Dolezel J., Dohnal J., Pour M., Kunes J., Vorisek V. New hydrophobicity constants of substituents in pyrazine rings derived from RP-HPLC study. Collect. Czechoslov. Chem. Commun. 2008;73:1–18. doi: 10.1135/cccc20080001. DOI

Musilek K., Jampilek J., Dohnal J., Jun D., Gunn-Moore F., Dolezal M., Kuca K. RP-HPLC determination of the lipophilicity of bispyridinium reactivators of acetylcholinesterase bearing a but-2-ene connecting linker. Anal. Bioanal. Chem. 2008;391:367–372. doi: 10.1007/s00216-008-2018-8. PubMed DOI

Musiol R., Jampilek J., Podeszwa B., Finster J., Tabak D., Dohnal J., Polanski J. RP-HPLC determination of drug lipophilicity in series of quinoline derivatives. Cent. Eur. J. Chem. 2009;7:586–597.

Tengler J., Kapustikova I., Stropnicky O., Mokry P., Oravec M., Csollei J., Jampilek J. Synthesis of New (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties. Cent. Eur. J. Chem. 2013;11:1757–1767. doi: 10.2478/s11532-013-0302-8. DOI

Hartmann T., Schmitt J. Lipophilicity-beyond octanol/water: A short comparison of modern technologies. Drug Discov. Today Technol. 2004;1:431–439. doi: 10.1016/j.ddtec.2004.10.006. PubMed DOI

Nasal A., Siluk D., Kaliszan R. Chromatographic retention parameters in medicinal chemistry and molecular pharmacology. Curr. Med. Chem. 2003;10:381–426. doi: 10.2174/0929867033368268. PubMed DOI

Bak A., Kozik V., Smolinski S., Jampilek J. In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters. SAR QSAR Environ. Res. 2017;28:427–449. doi: 10.1080/1062936X.2017.1327459. PubMed DOI

Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Gonec T., Bobal P., Kauerova T., Oravec M., Kollar P., et al. Antibacterial and herbicidal activity of ring-substituted 3-hydroxynaphthalene-2-carbox-anilides. Molecules. 2013;18:7977–7997. doi: 10.3390/molecules18077977. PubMed DOI PMC

Gonec T., Zadrazilova I., Nevin E., Kauerova T., Pesko M., Kos J., Oravec M., Kollar P., Coffey A., O’Mahony J., et al. Synthesis and biological evaluation of N-alkoxyphenyl-3-hydroxynaphthalene-2-carbox-anilides. Molecules. 2015;20:9767–9787. doi: 10.3390/molecules20069767. PubMed DOI PMC

Gonec T., Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Bobal P., Kollar P., Cizek A., Kralova K., et al. Antimycobacterial and herbicidal activity of ring-substituted 1-hydroxynaphthalene-2-carboxanilides. Bioorg. Med. Chem. 2013;21:6531–6541. doi: 10.1016/j.bmc.2013.08.030. PubMed DOI

Gonec T., Kos J., Zadrazilova I., Pesko M., Govender R., Keltosova S., Chambel B., Pereira D., Kollar P., Imramovsky A., et al. Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1-carboxanilides. Molecules. 2013;18:9397–9419. doi: 10.3390/molecules18089397. PubMed DOI PMC

Gonec T., Pospisilova S., Kauerova T., Kos J., Dohanosova J., Oravec M., Kollar P., Coffey A., Liptaj T., Cizek A., et al. N-Alkoxyphenylhydroxynaphthalenecarboxamides and their antimycobacterial activity. Molecules. 2016;21:1068. doi: 10.3390/molecules21081068. PubMed DOI PMC

Gonec T., Kralova K., Pesko M., Jampilek J. Antimycobacterial N-alkoxyphenylhydroxynaphthalene-carboxamides affecting photosystem II. Bioorg. Med. Chem. Lett. 2017;27:1881–1885. doi: 10.1016/j.bmcl.2017.03.050. PubMed DOI

De Marco A., De Candia M., Carotti A., Cellamare S., De Candia E., Altomare C. Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides. Eur. J. Pharm. Sci. 2004;22:153–164. doi: 10.1016/j.ejps.2004.03.003. PubMed DOI

Opletalova V., Kalinowski D.S., Vejsova M., Kunes J., Pour M., Jampilek J., Buchta V., Richardson D.R. Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: Cellular iron chelation mediating cytotoxic activity. Chem. Res. Toxicol. 2008;21:1878–1889. doi: 10.1021/tx800182k. PubMed DOI

Opletalova V., Dolezel J., Kralova K., Pesko M., Kunes J., Jampilek J. Synthesis and characterization of (Z)-5-arylmethylidenerhodanines with photosynthesis-inhibiting properties. Molecules. 2011;16:5207–5227. doi: 10.3390/molecules16065207. PubMed DOI PMC

Norrington F.E., Hyde R.M., Williams S.G., Wootton R. Physicochemical-activity relations in practice I. A rational and self-consistent data bank. J. Med. Chem. 1975;18:604–607. doi: 10.1021/jm00240a016. PubMed DOI

Dearden J.C. Partitioning and lipophilicity in quantitative structure-activity relationships. Environ. Health Perspect. 1985;61:203–228. doi: 10.1289/ehp.8561203. PubMed DOI PMC

Hansch C., Leo A., Unger S.H., Kim K.H., Nikaitani D., Lien E.J. “Aromatic” substituent constants for structure-activity correlations. J. Med. Chem. 1973;16:1207–1216. doi: 10.1021/jm00269a003. PubMed DOI

Tetko I.V., Gasteiger J., Todeschini R., Mauri A., Livingstone D., Ertl P., Palyulin V.A., Radchenko E.V., Zefirov N.S., Makarenko A.S., et al. Virtual computational chemistry laboratory--design and description. J. Comput. Aided Mol. Des. 2005;19:453–463. doi: 10.1007/s10822-005-8694-y. PubMed DOI

Bak A., Polanski J. Modeling robust QSAR 3: SOM-4D-QSAR with iterative variable elimination IVE-PLS: Application to steroid, azo dye, and benzoic acid series. J. Chem. Inf. Model. 2007;47:1469–1480. doi: 10.1021/ci700025m. PubMed DOI

Centner V., Massart D.L., de Noord O.E., de Jong S., Vandeginste B.M.V., Sterna C. Elimination of uninformative variables for multivariate calibration. Anal. Chem. 1996;68:3851–3858. doi: 10.1021/ac960321m. PubMed DOI

Smolinski A., Drobek L., Dombek V., Bak A. Modeling of experimental data on trace elements and organic compounds content in industrial waste dumps. Chemosphere. 2016;162:189–198. doi: 10.1016/j.chemosphere.2016.07.086. PubMed DOI

Investigation of Permeation of Theophylline through Skin Using Selected Piperazine-2,5-Diones