Bazı Heterosiklik Bileşiklerin İyonlaşma/Protonasyon, Lipofilisite ve Çözünürlük Sabitlerinin Belirlenmesi
Yıl 2019,
, 651 - 657, 25.08.2019
Kader Poturcu
,
Ebru Çubuk Demiralay
Öz
B12
vitamini yapısında bulunan benzimidazol halkası ve histidinin yapısında bulunan
imidazol halkası; tıpta, eczacılıkta, ilaç kimyasında önemli biyolojik ve
klinik uygulamalara sahip heterosiklik yapılardır. Bu yapıların anthelmintik,
antifungal, antiviral ve anti-HIV gibi birçok farklı biyolojik aktiviteye sahip
olması ve son zamanlarda antikanser ajan olarak kullanılması dikkatleri bu
yapılar üzerine çekmektedir. Bu çalışmada benzimidazol/imidazol halkası içeren
altı ilaç molekülünün ters faz sıvı kromatografik yöntemle %40 (v/v) ACN:H2O
içeren mobil faz ortamında iyonlaşma/protonasyon sabitleri
belirlenmiştir. Deneysel çalışmalarda Gemini NX C18 (250 x 3.0 mm I.D., 5 µm) kolon kullanılmıştır ve kromatografik analizler 1 mL/dakika
akış hızında, 30°C’de gerçekleştirilmiştir. Abraham çözünen
tanımlayıcıları ve ters faz sıvı kromatografik yöntemle elde edilen bu alıkonma
verileri kullanılarak bu altı ilaç molekülünün lipofilisite ve çözünürlük
değerleri hesaplanmıştır.
Kaynakça
- [1] Gaba, M., Singh, S., Mohan, C. 2014. Benzimidazole: an Emerging Scaffold for Analgesic and Anti-Inflammatory Agents. European Journal of Medicinal Chemistry, 76, 494-505.
- [2] Vitaku, E., Smith, D.T., Njardarson, J.T. 2014. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. Journal of Medicinal Chemistry, 57, 10257-10274.
- [3] Anand, K., Wakod, S. 2017. Development of Drugs Based on Benzimidazole Heterocycle: Recent Advancement and Insights. International Journal of Chemical Studies, 5(2), 350-362.
- [4] Verma, A., Joshi, S., Singh, D. 2013. Imidazole: Having Versatile Biological Activities. Journal of Chemistry, 2013, 1-12.
- [5] Ali, I., Lone, M.N., Aboul-Enein, H.Y. 2017. Imidazoles as Potential Anticancer Agents. Medicinal Chemistry Communications, 8, 1742-1773.
- [6] El Rashedy, A.A., Aboul-Enein, H.Y. 2013. Benzimidazole Derivatives as Potential Anticancer Agents. Mini-Reviews in Medicinal Chemistry, 13(3), 399-407.
- [7] Wan, H., Holmén, A.G., Wang, Y., Linbeg, W., Englund, M., Någård, M.B., Thompson, R.A. 2003. High-Throughput Screening of pKa Values of Pharmaceuticals by Pressure-Assisted Capillary Electrophoresis and Mass Spectrometry. Rapid Communications in Mass Spectrometry, 17(23), 2639-2648.
- [8] Brown, T.N., Mora-Diez, N. 2006. Computational Determination of Aqueous pKa Values of Protonated Benzimidazoles (Part 2). Journal of Physical Chemistry B, 110(41), 20546-20554.
- [9] Rupp, M., Körner, R., Tetko, I.V., 2011. Predicting the pKa of Small Molecules. Combinatorial Chemistry & High Throughput Screening, 14, 307-327.
- [10] Barbosa, J., Bergés, R., Sanz-Nebot, V., 1996. Solvatochromic Parameter Values and pH in Aqueous-Organic Mixtures Used in Liquid Chromatography Prediction of Retention of a Series of Quinolones. Journal of Chromatography A, 719(1), 27-36.
- [11] Demiralay, E.C., Alsancak, G., Ozkan, S.A. 2009. Determination of pKa Values of Nonsteroidal Antiinflammatory Drug‐Oxicams by RP-HPLC and Their Analysis in Pharmaceutical Dosage Forms. Journal of Separation Science, 32(17), 2928-2936.
- [12] Sun, N., Avdeef, A. 2011. Biorelevant pKa (37°C) Predicted from the 2D Structure of the Molecule and Its pKa at 25°C. Journal of Pharmaceutical and Biomedical Analysis, 56, 173-182.
- [13] Wiechers, J.W. 1989. The Barrier Function of the Skin in Percutaneous Absorption of Drugs Relation to Percutaneous Absorption of Drugs. Pharmaceutisch Weekblad Scientific Edition, 11, 185-198.
- [14] Testa, B., Crivori, P., Reist, M., Carrupt, P-A. 2000. The Influence of Lipophilicity on the Pharmacokinetic Behavior of Drugs: Concepts and Examples. Perspectives in Drug Discovery and Design, 19, 179-211.
- [15] Jouyban, A., Fakhree, M.A.A., Shayanfar, A. 2008. Solubility Prediction Methods for Drug/Drug Like Molecules. Recent Patents on Chemical Engineering, 1, 220-231.
- [16] Abraham, M.H., Rosés, A. 1994. Hydrogen Bonding. 38. Effect of Solute Structure and Mobile Phase Composition on Reversed-Phase High-Performance Liquid Chromatographic Capacity Factors. Journal of Physical Organic Chemistry, 7, 672-684.
- [17] Cook, G.C. 1990. Use of Benzimidazole Chemotherapy in Human Helminthiases: Indications and Efficacy. Parasitology Today, 6 (4), 133-136.
- [18] Sasaki, J.I., Ramesh, R., Chada, S., Gomyo, Y., Roth, J.A., Mukhopadhyay, T. 2002. The Anthelmintic Drug Mebendazole Induces Mitotic Arrest and Apoptosis by Depolymerizing Tubulin in Non-Small Cell Lung Cancer Cells. Molecular Cancer Therapeutics, 1(13), 1201-1209.
- [19] Ludwig, J., Terlau, H., Wunder, F., Bruggemann, Pardo, L.A., Marquardt, A., Stuhmer, W., Pongs, O. 1994. Functional Expression of a Rat Homologue of the Voltage Gated ether á go-go Potassium Channel Reveals Differences in Selectivity and Activation Kinetics between the Drosophila Channel and Its Mammalian Counterpart. The EMBO Journal, 13(19), 4451-4458.
- [20] Izumi-Nakaseko, H., Nakamura, Y., Cao, X., Wada, T., Ando, K., Sugiyama, A. 2016. Possibility as an Anti-Cancer Drug of Astemizole: Evaluation of Arrhythmogenicity by the Chronic Atrioventricular Block Canine Model. Journal of Pharmacological Sciences, 131, 150-153.
- [21] Garcia-Quiroz, J., Camacho, J. 2011. Astemizole: an Old Anti-Histamine as a New Promising Anti-Cancer Drug. Anti-Cancer Agents in Medicinal Chemistry, 11(3), 307–314.
- [22] Davidse, L.C., Flach, W. 1978. Interaction of Thiabendazole with Fungal Tubulin. Biochimica et Biophysica Acta (BBA)- General Subjects, 543(1), 82-90.
- [23] Abdel-Moety, E.M., Khattab, F.I., Kelani, K.M., AbouAl-Alamein, A.M. 2002. Chromatographic Determination of Clotrimazole, Ketoconazole and Fluconazole in Pharmaceutical Formulations. II Farmaco 57, 931-938.
- [24] Kümmerer, K., Al-Ahmad, A., Mersch-Sundermann, V. 2000. Biodegradability of Some Antibiotics, Elimination of the Genotoxicity and Affection of Wastewater Bacteria in a Simple Test. Chemosphere, 40, 701-710.
- [25] Abraham, M.H. 1993. Scales of Solute Hydrogen-Bonding: Their Construction and Application to Physicochemical and Biochemical Processes. Chemical Society Reviews, 22, 73-83.
- [26] Rondinini, S., Mussini, P.R, Mussini, T. 1987. Reference Value Standards and Primary Standards for pH Measurements in Organic Solvents and Water+Organic Solvent Mixtures of Moderate to High Permittivities. Pure and Applied Chemistry, 59, 1549-1560.
- [27] Sundberg, R.J., Martın, R.B. 1974. Interactions of Histidine and Other Imidazole Derivatives with Transition Metal Ions in Chemical and Biological Systems. Chemical Reviews, 74(4), 471-517.
- [28] Chemicalize, 2019. Kimyasal Hesaplama https://chemicalize.com/#/calculation (Erişim Tarihi: 11.01.2019).
- [29] Wright, J.B. 1951. The Chemistry of the Benzimidazoles. Chemical Reviews, 48(3), 397-541.
- [30] Seybold, P.G., Shields, G.C. 2015. Computational Estimation of pKa Values. WIREs Computational Molecular Science, 5, 290-297.
- [31] Sherrod, P.H. 1993. NLREG version 4.0. http://www.nlreg.com/ (Erişim tarihi: 21.01.2019).
- [32] Takács-Novák, K., Jozan, M., Szasz, G. 1995. Lipophilicity of Amphoteric Molecules Expressed by the True Partition Coefficient. International Journal of Pharmaceutics, 113 (1), 47-55.
- [33] Shalaeva, M., Kenseth, J., Lombardo, F., Bastin, A. 2008. Measurement of Dissociation Constants (pKa Values) of Organic Compounds by Multiplexed Capillary Electrophoresis Using Aqueous and Cosolvent Buffers. Journal of Pharmaceutical Sciences, 97(7), 2581-2606.
- [34] Tam, K.Y., Avdeef, A., Tsinman, O., Sun, N. 2010. The Permeation of Amphoteric Drugs through Artificial Membranes − An in Combo Absorption Model Based on Paracellular and Transmembrane Permeability. Journal of Medicinal Chemistry, 53(1), 392-401.
- [35] Koner, A.L., Ghosh, I., Saleh, N., Nau, W.M. 2011. Supramolecular Encapsulation of Benzimidazole derived Drugs by Cucurbit[7]uril. Canadian Journal of Chemistry, 89, 139-147.
- [36] Stovall, D.M., Givens, C., Keown, S., Hoover, K.R., Rodriguez, E., Acree Jr Jr, W.E., Abraham, M.H. 2005. Solubility of Crystalline Nonelectrolyte Solutes in Organic Solvents: Mathematical Correlation of Ibuprofen Solubilities with the Abraham Solvation Parameter Model. Physics and Chemistry of Liquids, 43(3), 261–268.
- [37] Lombardo, F., Shalaeva, M.Y., Tupper, K.A., Gao, F., Abraham, M.H. 2000. ElogPoct: A Tool for Lipophilicity Determination in Drug Discovery. Journal of Medicinal Chemistry, 43, 2922-2928.
- [38] Abraham, M.H., Rupert P. Austin, R.P. 2012. The Effect of Ionized Species on Microsomal Binding. European Journal of Medicinal Chemistry, 47, 202-205.
- [39] Abraham, MH, Gola, JMR, Ibrahim A, William, E Acree, Jr., Liu, X. 2014. The Prediction of Blood-Tissue Partitions, Water-Skin Partitions and Skin Permeation for Agrochemicals. Pest Management Science. 70(7), 1130-1137.
- [40] Santaladchaiyakit, Y., Srijaranai, S. 2012. A Simplified Ultrasound-Assisted Cloud-Point Extraction Method Coupled with High Performance Liquid Chromatography for Residue Analysis of Benzimidazole Anthelmintics in Water and Milk Samples. Analytical Methods, 4, 3864-3873.
- [41] Box, K.J., Comer, J.E.A. 2008. Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Current Drug Metabolism, 9, 869-878.
- [42] ChemDraw Ultra Software Version 6.0.1, 2007. CambridgeSoft, 100 Cambridge Park Drive, MA 02140, USA.
- [43] Brogi, S., Brindisi, M., Joshi, B.P., Coccone, S.S., Parapini, S., Basilico, N., Novellino, E., Campiani, G., Gemma, S., Butin, S. 2015. Exploring Clotrimazole-Based Pharmacophore: 3D-QSAR Studies and Synthesis of Novel Antiplasmodial Agents. Bioorganic & Medicinal Chemistry Letters, 25 (22), 5412-5418.
Evaluation of Ionization/Protonation, Lipophilicity and Solubility Constants for Some Heterocyclic Compounds
Yıl 2019,
, 651 - 657, 25.08.2019
Kader Poturcu
,
Ebru Çubuk Demiralay
Öz
The
benzimidazole ring in the structure of B12 vitamin and the imidazole ring in
the structure of histidine are heterocyclic structures with important
biological and clinical applications in medicine, pharmacy and pharmaceutical
chemistry. These structures have
many different biological activities such as anthelmintic, antifungal,
antiviral and anti-HIV and have recently been used as an anticancer agent,
draws attention to these structures. In this study, the ionization/protonation constants of six drug
molecules which have containing benzimidazole/imidazole moiety were determined
in mobile phase media containing 40% (v/v) ACN:H2O by reversed phase
liquid chromatographic method. Gemini NX C18 (250 mm
× 3.0 mm I.D., 5 µm) column was used in
experimental studies and chromatographic analyzes were performed at a flow rate
of 1 mL/min and at 30°C. The lipophilicity and solubility values of these six
drug molecules were calculated using the Abraham solute descriptor values and the
retention data obtained by the reversed phase liquid chromatographic method
Kaynakça
- [1] Gaba, M., Singh, S., Mohan, C. 2014. Benzimidazole: an Emerging Scaffold for Analgesic and Anti-Inflammatory Agents. European Journal of Medicinal Chemistry, 76, 494-505.
- [2] Vitaku, E., Smith, D.T., Njardarson, J.T. 2014. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. Journal of Medicinal Chemistry, 57, 10257-10274.
- [3] Anand, K., Wakod, S. 2017. Development of Drugs Based on Benzimidazole Heterocycle: Recent Advancement and Insights. International Journal of Chemical Studies, 5(2), 350-362.
- [4] Verma, A., Joshi, S., Singh, D. 2013. Imidazole: Having Versatile Biological Activities. Journal of Chemistry, 2013, 1-12.
- [5] Ali, I., Lone, M.N., Aboul-Enein, H.Y. 2017. Imidazoles as Potential Anticancer Agents. Medicinal Chemistry Communications, 8, 1742-1773.
- [6] El Rashedy, A.A., Aboul-Enein, H.Y. 2013. Benzimidazole Derivatives as Potential Anticancer Agents. Mini-Reviews in Medicinal Chemistry, 13(3), 399-407.
- [7] Wan, H., Holmén, A.G., Wang, Y., Linbeg, W., Englund, M., Någård, M.B., Thompson, R.A. 2003. High-Throughput Screening of pKa Values of Pharmaceuticals by Pressure-Assisted Capillary Electrophoresis and Mass Spectrometry. Rapid Communications in Mass Spectrometry, 17(23), 2639-2648.
- [8] Brown, T.N., Mora-Diez, N. 2006. Computational Determination of Aqueous pKa Values of Protonated Benzimidazoles (Part 2). Journal of Physical Chemistry B, 110(41), 20546-20554.
- [9] Rupp, M., Körner, R., Tetko, I.V., 2011. Predicting the pKa of Small Molecules. Combinatorial Chemistry & High Throughput Screening, 14, 307-327.
- [10] Barbosa, J., Bergés, R., Sanz-Nebot, V., 1996. Solvatochromic Parameter Values and pH in Aqueous-Organic Mixtures Used in Liquid Chromatography Prediction of Retention of a Series of Quinolones. Journal of Chromatography A, 719(1), 27-36.
- [11] Demiralay, E.C., Alsancak, G., Ozkan, S.A. 2009. Determination of pKa Values of Nonsteroidal Antiinflammatory Drug‐Oxicams by RP-HPLC and Their Analysis in Pharmaceutical Dosage Forms. Journal of Separation Science, 32(17), 2928-2936.
- [12] Sun, N., Avdeef, A. 2011. Biorelevant pKa (37°C) Predicted from the 2D Structure of the Molecule and Its pKa at 25°C. Journal of Pharmaceutical and Biomedical Analysis, 56, 173-182.
- [13] Wiechers, J.W. 1989. The Barrier Function of the Skin in Percutaneous Absorption of Drugs Relation to Percutaneous Absorption of Drugs. Pharmaceutisch Weekblad Scientific Edition, 11, 185-198.
- [14] Testa, B., Crivori, P., Reist, M., Carrupt, P-A. 2000. The Influence of Lipophilicity on the Pharmacokinetic Behavior of Drugs: Concepts and Examples. Perspectives in Drug Discovery and Design, 19, 179-211.
- [15] Jouyban, A., Fakhree, M.A.A., Shayanfar, A. 2008. Solubility Prediction Methods for Drug/Drug Like Molecules. Recent Patents on Chemical Engineering, 1, 220-231.
- [16] Abraham, M.H., Rosés, A. 1994. Hydrogen Bonding. 38. Effect of Solute Structure and Mobile Phase Composition on Reversed-Phase High-Performance Liquid Chromatographic Capacity Factors. Journal of Physical Organic Chemistry, 7, 672-684.
- [17] Cook, G.C. 1990. Use of Benzimidazole Chemotherapy in Human Helminthiases: Indications and Efficacy. Parasitology Today, 6 (4), 133-136.
- [18] Sasaki, J.I., Ramesh, R., Chada, S., Gomyo, Y., Roth, J.A., Mukhopadhyay, T. 2002. The Anthelmintic Drug Mebendazole Induces Mitotic Arrest and Apoptosis by Depolymerizing Tubulin in Non-Small Cell Lung Cancer Cells. Molecular Cancer Therapeutics, 1(13), 1201-1209.
- [19] Ludwig, J., Terlau, H., Wunder, F., Bruggemann, Pardo, L.A., Marquardt, A., Stuhmer, W., Pongs, O. 1994. Functional Expression of a Rat Homologue of the Voltage Gated ether á go-go Potassium Channel Reveals Differences in Selectivity and Activation Kinetics between the Drosophila Channel and Its Mammalian Counterpart. The EMBO Journal, 13(19), 4451-4458.
- [20] Izumi-Nakaseko, H., Nakamura, Y., Cao, X., Wada, T., Ando, K., Sugiyama, A. 2016. Possibility as an Anti-Cancer Drug of Astemizole: Evaluation of Arrhythmogenicity by the Chronic Atrioventricular Block Canine Model. Journal of Pharmacological Sciences, 131, 150-153.
- [21] Garcia-Quiroz, J., Camacho, J. 2011. Astemizole: an Old Anti-Histamine as a New Promising Anti-Cancer Drug. Anti-Cancer Agents in Medicinal Chemistry, 11(3), 307–314.
- [22] Davidse, L.C., Flach, W. 1978. Interaction of Thiabendazole with Fungal Tubulin. Biochimica et Biophysica Acta (BBA)- General Subjects, 543(1), 82-90.
- [23] Abdel-Moety, E.M., Khattab, F.I., Kelani, K.M., AbouAl-Alamein, A.M. 2002. Chromatographic Determination of Clotrimazole, Ketoconazole and Fluconazole in Pharmaceutical Formulations. II Farmaco 57, 931-938.
- [24] Kümmerer, K., Al-Ahmad, A., Mersch-Sundermann, V. 2000. Biodegradability of Some Antibiotics, Elimination of the Genotoxicity and Affection of Wastewater Bacteria in a Simple Test. Chemosphere, 40, 701-710.
- [25] Abraham, M.H. 1993. Scales of Solute Hydrogen-Bonding: Their Construction and Application to Physicochemical and Biochemical Processes. Chemical Society Reviews, 22, 73-83.
- [26] Rondinini, S., Mussini, P.R, Mussini, T. 1987. Reference Value Standards and Primary Standards for pH Measurements in Organic Solvents and Water+Organic Solvent Mixtures of Moderate to High Permittivities. Pure and Applied Chemistry, 59, 1549-1560.
- [27] Sundberg, R.J., Martın, R.B. 1974. Interactions of Histidine and Other Imidazole Derivatives with Transition Metal Ions in Chemical and Biological Systems. Chemical Reviews, 74(4), 471-517.
- [28] Chemicalize, 2019. Kimyasal Hesaplama https://chemicalize.com/#/calculation (Erişim Tarihi: 11.01.2019).
- [29] Wright, J.B. 1951. The Chemistry of the Benzimidazoles. Chemical Reviews, 48(3), 397-541.
- [30] Seybold, P.G., Shields, G.C. 2015. Computational Estimation of pKa Values. WIREs Computational Molecular Science, 5, 290-297.
- [31] Sherrod, P.H. 1993. NLREG version 4.0. http://www.nlreg.com/ (Erişim tarihi: 21.01.2019).
- [32] Takács-Novák, K., Jozan, M., Szasz, G. 1995. Lipophilicity of Amphoteric Molecules Expressed by the True Partition Coefficient. International Journal of Pharmaceutics, 113 (1), 47-55.
- [33] Shalaeva, M., Kenseth, J., Lombardo, F., Bastin, A. 2008. Measurement of Dissociation Constants (pKa Values) of Organic Compounds by Multiplexed Capillary Electrophoresis Using Aqueous and Cosolvent Buffers. Journal of Pharmaceutical Sciences, 97(7), 2581-2606.
- [34] Tam, K.Y., Avdeef, A., Tsinman, O., Sun, N. 2010. The Permeation of Amphoteric Drugs through Artificial Membranes − An in Combo Absorption Model Based on Paracellular and Transmembrane Permeability. Journal of Medicinal Chemistry, 53(1), 392-401.
- [35] Koner, A.L., Ghosh, I., Saleh, N., Nau, W.M. 2011. Supramolecular Encapsulation of Benzimidazole derived Drugs by Cucurbit[7]uril. Canadian Journal of Chemistry, 89, 139-147.
- [36] Stovall, D.M., Givens, C., Keown, S., Hoover, K.R., Rodriguez, E., Acree Jr Jr, W.E., Abraham, M.H. 2005. Solubility of Crystalline Nonelectrolyte Solutes in Organic Solvents: Mathematical Correlation of Ibuprofen Solubilities with the Abraham Solvation Parameter Model. Physics and Chemistry of Liquids, 43(3), 261–268.
- [37] Lombardo, F., Shalaeva, M.Y., Tupper, K.A., Gao, F., Abraham, M.H. 2000. ElogPoct: A Tool for Lipophilicity Determination in Drug Discovery. Journal of Medicinal Chemistry, 43, 2922-2928.
- [38] Abraham, M.H., Rupert P. Austin, R.P. 2012. The Effect of Ionized Species on Microsomal Binding. European Journal of Medicinal Chemistry, 47, 202-205.
- [39] Abraham, MH, Gola, JMR, Ibrahim A, William, E Acree, Jr., Liu, X. 2014. The Prediction of Blood-Tissue Partitions, Water-Skin Partitions and Skin Permeation for Agrochemicals. Pest Management Science. 70(7), 1130-1137.
- [40] Santaladchaiyakit, Y., Srijaranai, S. 2012. A Simplified Ultrasound-Assisted Cloud-Point Extraction Method Coupled with High Performance Liquid Chromatography for Residue Analysis of Benzimidazole Anthelmintics in Water and Milk Samples. Analytical Methods, 4, 3864-3873.
- [41] Box, K.J., Comer, J.E.A. 2008. Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Current Drug Metabolism, 9, 869-878.
- [42] ChemDraw Ultra Software Version 6.0.1, 2007. CambridgeSoft, 100 Cambridge Park Drive, MA 02140, USA.
- [43] Brogi, S., Brindisi, M., Joshi, B.P., Coccone, S.S., Parapini, S., Basilico, N., Novellino, E., Campiani, G., Gemma, S., Butin, S. 2015. Exploring Clotrimazole-Based Pharmacophore: 3D-QSAR Studies and Synthesis of Novel Antiplasmodial Agents. Bioorganic & Medicinal Chemistry Letters, 25 (22), 5412-5418.