STUDYING RETENTION BEHAVIOR, LIPOPHILICITY AND PHARMACOKINETIC CHARACTERISTICS OF N-SUBSTITUTED PHENYL-2-CHLOROACETAMIDES
Abstract
The biological activity of compounds is mostly determined by its physical and structural characteristics. Among the many molecular descriptors that may indicate a potential biological activity of a compound, lipophilicity occupies the most important place. Since chloroacetamides show a variety of physiological activity, the task of this study was to investigate the potential biological activity of newly synthesized derivatives of selected N-substituted phenyl-2-chloroacetamides. Analysis was performed by thin layer chromatography on reversed phase (RP18 F254s TLC), and the mobile phase consisted of mixtures of water-acetic acid and water-dimethylformamide. By varying the volume fraction of organic modifier chromatographic retention constants, RM0, of the compounds were determined. Тhen RM0 were correlated with the software calculated partition coefficient, log P, as a standard measure of lipophilicity. Also, RM0 were correlated with selected pharmacokinetic parameters: intestinal absorption, HIA, the ability to bind to plasma proteins, PPB, and the distribution through the blood-brain barrier, BBB.References
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[29] R. F. Rekker, R. Mannhold, G. Bijloo, G. De Vries, K. Dross, The lipophilic behaviour of or¬ganic compounds: 2. The development of an ali¬pha¬tic hydrocarbon/water fragmental system via interco¬nnection with octanol-water partitioning data, Quantitative Structure-Activity Relationships, Vol. 17 (1998) 537548.
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[2] A. A. Oauf, M. A. Eldawy, H. H. Farag, New compounds: synthesis of certain p-alkoxy¬phe-ny¬lacetamide derivatives as potential analgesic ag¬ents, Journal of Pharmaceutical Sciences, Vol. 60 (1971) 158–159.
[3] D. Ü. Özkay, Y. Özkay, Ö. D. Can, Synthe¬sis and analgesic effects of 2-(2-carboxyphenylsul¬fa¬nyl)-N-(4- substitutedphenyl)acetamide deriva¬tives, Medicinal Chemistry Research, Vol. 20 (2011) 152157.
[4] I. M. Gabr, Synthesis, characterization, ther¬¬mal studies, and antimicrobial activity of 2-(2-(3,4-dihydronaphthalenylidene)-hydrazinyl)-2-oxo-N-phenylacetamide (H2NHPA) and its transition metal complexes, Journal of Coordination Chemis¬try, Vol. 62 (2009) 32063216.
[5] C. M. Jamkhandi, J. I. Disouza, Synthesis and antimicrobial evaluation of 2-(1H-1,2,3-Ben-zot¬ri¬azol-1-yl)-N-phenylacetamide derivatives, Re¬sea¬r¬ch Journal of Pharmacy and Technology, Vol. 5 (2012) 10721075.
[6] H. Li, S. Matsunaga, N. Fusetani, Simple an¬tifungal metabolites from a marine sponge, Hali-chondria sp., Comparative Biochemistry and Physi¬ology − Biochemistry and Molecular Biology, Vol. 107 (1994) 261264.
[7] M. Haramoto, H. Yamanaka, H. Sano, S. Sa¬no, H. Otani, Fungicidal activities of cy-flufenamid ag¬ainst various plant-pathogenic fungi, Journal of Pe¬sti¬cide Science, Vol. 31 (2006) 95101.
[8] M. Kalyanasundaram, N. Mathew, N,N-di¬ethyl phenylacetamide (DEPA): A safe and effective repellent for personal protection against hemato¬phagous arthropods, Journal of Medical Entomol¬ogy, Vol. 43 (2006) 518525.
[9] R. Sawant, D. Kawade, Synthesis and biolo¬gical evaluation of some novel 2-phenyl ben¬zimi-da¬zole-1-acetamide derivatives as potential anthel¬min¬tic agent, Acta Pharmaceutica, Vol. 61 (2011) 353−361.
[10] D. Kadadevar, K. C. Chaluvaraju, M. S. Niranjan, C. Sultanpur, S.K. Madinur, M. Nagaraj, Hegde, M. Smitha, K. Chakraborty, Synthesis of N-(substituted phenyl)-2 [5- phenyl-2H-1, 2, 4-triazol-3ylamino] acetamide as anticonvulsant, Interna¬tional Journal of ChemTech Research, Vol. 3 (2011) 1064-1069.
[11] V. R. Khairullina, G. P. Tarasov, A. Ya. Gerchikov, F. S. Zarydiy, L. A. Tyurina, Study "structu¬re-anti-arrhythmic activity" relationship of n-phe¬nyl acetamide derivatives and amides of aro-matic car¬bonic acids, Biomeditsinskaya Khimiya, Vol. 56 (2010) 471479.
[12] I. Roufos, S. Hays, R. D. Schwarz, A struc¬ture-activity relationship study of novel phenyl-ace¬tamides which are sodium channel block¬ers, Jou¬rnal of Medicinal Chemistry, 39 (1996) 15141520.
[13] K. Lee, S. H. Roh, Y. Xia, K. W. Kang, Synthesis and biological evaluation of phenoxy-N-phenyl¬acetamide derivatives as novel P-glycoprotein inhibitors, Bulletin of the Korean Chemical Society, 32 (2011) 36663674.
[14] R. C. Dash, S. H. Bhosale, S. M. Shelke, M.R. Suryawanshi, K.R. Mahadik, Design, synthe-sis, pharmacological evaluation and descriptor ba¬sed similarities study of N,N-diphenyl-2-[4-(sub-stituted phenyl)piperazin-1-yl] acetamides as poten¬tial antipsychotics, Medicinal Chemistry 8 (2012) 10691075.
[15] A. Tomar, S. Kumar, M. Mall, Synthesis, computational studies and preliminary pharmacol¬ogi¬cal evaluation of new acetamides: Potential an¬tip¬sychotics, Der Pharma Chemica, Vol. 4 (2012) 8592.
[16] H. S. Lv, X. Q. Kong, Q. Q. Ming, X. Jin, J. Y. Miao, B. X. Zhao, Synthesis of 5-benzyl-2-phenylpyrazolo[1,5-a]pyrazin-4,6(5H,7H)-dione derivatives and discovery of an apoptosis inducer for H322 lung cancer cells, Bioorganic and Medici¬nal Chemistry Letters, Vol. 22−2 (2012) 844849.
[17] I. L. Chen, J. J. Chen, Y. C. Lin, C. T. Peng, S. H. Juang, T. C. Wang, Synthesis and anti-pro¬liferative activities of N-(naphthalen-2-yl)ace¬ta¬mi¬de and N-(substituted phenyl)acetamide bearing qui¬nolin-2(1H)-one and 3,4-dihydroquino¬lin-2(1H)-one derivatives, European Journal of Me¬dicinal Che¬mistry, Vol. 59 (2013) 227234.
[18] N. Perišić-Janjić, Gy. Vaštag, J. Tomić, S. Petrović, Effect of the physicochemical properties of N,N-disubstituted-2- phenylacetamide derivatives on their retention behavior in RP-TLC, Journal of Planar Chromatography, Vol. 20 (2007) 353359.
[19] K. Heberger, Quantitative structure-(chro¬matographic) retention relationships, Journal of Chro¬matography A, Vol. 1158 (2007) 273−305.
[20] R. Kaliszan, P. Haber, T. Baczek, D. Si¬luk, Gradient HPLC in the determination of drug lipo¬philicity and acidity, Pure and Applied Chemis¬try, Vol. 73 (2001) 1465-1475.
[21] M. A. C. Perez, M. B. Sanz, L. R. Torres, R. G. Evalos, M. P. Gonzales, H. G. Diaz, A topo-logical sub-structural approach for predicting hu¬man intestinal absorption of drugs, European Jour-nal of Medicinal Chemistry, Vol. 39 (2004) 905916.
[22] M. H. Abraham, K. Takacs-Novak, R. C. Mitchell, On the partition of ampholytes: Applica-tion to blood-brain distribution, Journal of Pharma¬ceutical Sciences, Vol. 86 (1997) 310315.
[23] http://www.vcclab.org Accessed May 2011
[24] http://www.chemsilico.com Accessed May 2011
[25] S. M. Petrović, E. Lončar, N. U. Perišić-Ja¬¬njić, M. Lazarević, Normal and reversed-phase thin-layer chromatography of thiourea derivatives, Journal of Planar Chromatography - Modern TLC, Vol. 10 (1997) 2630.
[26] L. C. Tan, P. W. Carr, Study of retention in reversed-phase liquid chromatography using lin¬ear solvation energy relationships II. The mobile pha¬se, Journal of Chromatography A, Vol. 799 (1998) 119.
[27] R. Kaliszan, M. A. van Straten, M. Mar¬kusyewski, C. A. Crames, C. A. Claessens, Mo-lecular mechanism of retention in reversed-phase high-performance liquid chromatography and clas-sification of modern stationary phases by using quantitative structure-retention relationships, Jour¬nal of Chromatography A, Vol. 855 (1999) 455486.
[28] G. L. Biagi, A. M. Barbaro, A. Sapone, M. Recanatini, Determination of lipophilicity by means of reversed-phase thin-layer chromatography I. Basic aspects and relationship between slope and intercept of TLC equations, Journal of Chromatog¬raphy A, Vol. 662 (1994) 341361.
[29] R. F. Rekker, R. Mannhold, G. Bijloo, G. De Vries, K. Dross, The lipophilic behaviour of or¬ganic compounds: 2. The development of an ali¬pha¬tic hydrocarbon/water fragmental system via interco¬nnection with octanol-water partitioning data, Quantitative Structure-Activity Relationships, Vol. 17 (1998) 537548.
[30] G. E. Kellogg, G. S. Joshi, D. J. Abra¬ham, New tools for modeling and understanding hy-drophobicity and hydrophobic interactions, Medici¬nal Chemistry Research, Vol. 1 (1992) 444453.
[31] D. Vaštag, N. Perišić-Janjić, J. Tomić, S. Petrović, Evaluation of the lipophilicity and pre-dic¬tion of biological activity of some N-cyclohexyl-N-substituted-2-phenylacetamide derivatives using RP-TLC, Journal of Planar Chromatogaphy − Modern TLC, Vol. 24 (2011) 435440.
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2014-09-26
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