N-Alkillenmiş Tetrazol Türevi Bileşiklerin Absorpsiyon, Dağılım, Metabolizma ve Atılım (ADME) Özelliklerinin Araştırılması

Yıl 2019, Cilt: 14 Sayı: 2, 384 - 394, 30.11.2019

Hamdi Özkan

https://doi.org/10.29233/sdufeffd.631009

Cited By: 1

Öz

Tetrazoller heterosiklik
bileşiklerdir. Tetrazol halkası içeren
bileşikler, antiviral, antibakteriyel, antifungal, antialerjik, antiülser,
antikonvülsan, antiinflamatuar, antitüberküloz gibi farmakolojik
etkinliklerinden dolayı ilaç sentezinde sıklıkla kullanılır. Tetrazol türevi
bir ilaç olan Losartan yüksek tansiyon, Tomelukast astım tedavisinde
kullanılır. Bu çalışmada, aromatik
halkalar içeren N-alkillenmiş
tetrazol türevleri sentezlendi. Sentezlenen bileşiklerin yapıları spektroskopik
yöntemlerle aydınlatıldı. Aynı zamanda, sentezlenen moleküllerin ADME (absorpsiyon,
dağılım, metabolizma ve atılım) özellikleri in
silico olarak incelendi. Teorik olarak, bileşik 4a, 4b ve 4c'nin ince bağırsağından absorpsiyon
yüzdeleri hesaplandı ve sırasıyla 93,95, 93,95 ve 90,77 gibi çok yüksek
değerler bulundu. Tetrazol halkasını içeren bu bileşikler, merkezi sinir
sistemini etkileyecek moleküller için önemli bir özellik olan kan beyin
bariyerini kolayca geçerler. Bu nedenle, bu bileşiklerin antidepresan ilaçların
sentezi için iyi adaylar oldukları söylenebilir.

Anahtar Kelimeler

Heterosiklik Bileşik, Tetrazol, ADME, Farmakokinetik

Teşekkür

Çalışma sürecinde verdikleri desteklerden dolayı Prof. Dr. Yılmaz Yıldırır, Prof. Dr. Ali Dişli, Doç. Dr. Şevki Adem ve Batuhan Yetim’e teşekkürlerimi sunarım.

N-Alkylated Tetrazole Derivative Compounds and Investigation of Absorption, Distribution, Metabolism and Excretion (ADME) Properties

Öz

Tetrazoles
are heterocyclic compounds. The compounds containing the tetrazole ring are
frequently used in drug synthesis due to their pharmacological activities such
as antiviral, antibacterial, antifungal, antiallergic, antiulcer,
anticonvulsant, anti-inflammatory, antituberculosis. Tetrazole derivated drug
Losartan is used to treat high blood pressure, Tomelukast asthma. In this
study, N-alkylated tetrazole
derivatives containing substituted aromatic rings were synthesized. The
structures of the synthesized compounds were determined by spectroscopic
methods. At the same time, ADME (absorption, distribution, metabolism and
excretion) properties of the synthesized molecules were investigated as silico. Theoretically, the percentages
of absorption from the small intestine of compounds 4a, 4b and 4c were calculated and very high values
were found, such as 93.95, 93.95 and 90.77, respectively. These compounds
containing the tetrazole ring easily cross the blood brain barrier, which is an
important property for molecules that will affect the central nervous system.
Therefore, it can be said that these compounds are good candidates for the
synthesis of antidepressant drugs.

Anahtar Kelimeler

Heterocyclic Compounds, Tetrazole, ADME, Pharmacokinetic

Kaynakça

• [1] J. D. Hepworth, “In Comprehensive Heterocyclic Chemistry” 1nd ed. vol.3, A. R. Katritzky, C. W. Rees, A. J. Boulton, A. McKillop, Ed. Pergamon: Oxford, 1984, pp. 799-810.
• [2] V. A. Ostrovskii, M. S. Pevzner, T. P. Kofman, M. B. Shcherbinin, “Energetic 1,2,4-triazolesand tetrazoles synthesis, structure and properties” Targets Heterocycl. Syst., 3, 467-526, 1999.
• [3] R. N. Butler, “In Comprehensive Heterocyclic Chemistry” 1nd ed. vol.3, A. R. Katritzky and C.W. Rees Ed. Pergamon: New York, 1984, pp. 791-799.
• [4] Y. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T. Komurasaki, K. Sugita, “Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives” J. Med. Chem., 41(4), 640-649, 1998.
• [5] A. Abell, G. Foulds, “Synthesis of a cis-conformationally restricted peptide bond isostere and its application to the inhibition of the HIV-1 protease” J. Chem. Soc. Perkin Trans., 1(17), 2475-2482, 1997.
• [6] O. A. Shemyakina, A. G. Mal’kina, A. I. Albanov, B. A. Trofimov, “Regio-and stereodirection of addition of tetrazole to α, β-acetylenic γ-hydroxy nitrile: synthesis of 1-and 2-(Z)-(2-cyanoethenyl-1-hydroxyalkyl) tetrazoles” Chem Heterocycl Comp., 47(4), 464-469, 2011.
• [7] A. N. Chermahini, A. Ghaedi, A. Teimouri, F. Momenbeik, H.A. Dabbagh, “Density functional theory study of intermolecular interactions of cyclic tetrazole dimers” J. Mol. Struct., 867(1-3), 78-84, 2008.
• [8] H. Özkan, S. Yavuz, A. Dişli, Y. Yıldırır, L. Türker, “Synthesis of Novel 5-Aryl-1H-Tetrazoles” Heteroatom Chem., 18, 255-258, 2007.
• [9] F.H. Dost, Der Blutspiegel; Kinetik der Konzentrationsabläufe in der Krieslaufflüssigkeit, Georg Thieme Verlag, Leipzig, 1953.
• [10] F. H. Dost, Grundlagen der Pharmakokinetik, Georg Thieme Verlag, Leipzig, 1968.
• [11] L. L. Ferreira and A. D. Andricopulo, "ADMET modeling approaches in drug discovery." Drug Discov. Today, 24, 1157–1165, 2019.
• [12] Y. Suzuki, K. Moriyama, H. Togo, “Facile transformation of esters to nitriles” Tetrahedron, 67, 7956-7962, 2011.
• [13] W. Y. Fang, H. L. Qin, “Cascade Process for Direct Transformation of Aldehydes (RCHO) to Nitriles (RCN) Using Inorganic Reagents NH2OH/Na2CO3/SO2F2 in DMSO” J Org Chem, 84, 5803−5812, 2019.
• [14] V. R. Balaji, K. R. Prabhu, “Chemoselective Schmidt Reaction Mediated by Triflic Acid: Selective Synthesis of Nitriles from Aldehydes” J. Org. Chem., 77, 5364−5370, 2012.
• [15] S. R. Paudel, X. B. Min, S. Acharya, D. B. Khadka, G. Yoon, K. M. Kim, S. H. Cheon, “Triple reuptake inhibitors: Design, synthesis and structure–activity relationship of benzylpiperidine–tetrazoles” Bioorg. Med. Chem., 25 5278–5289, 2017.
• [16] Z. P. Demko, K. B. Sharpless, “Preparation of 5-Substituted 1H-Tetrazoles from Nitriles in Water” J. Org. Chem., 66, 7945-7950, 2001.
• [17] A. Daina, O. Michielin and V. Zoete "SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules." Sci. Rep., 7, 42717, 2017.
• [18] Y. H. Zhao, M. H. Abraham, J. Le, A. Hersey, C. N. Luscombe, G. Beck, B. Sherborne and I. Cooper "Rate-limited steps of human oral absorption and QSAR studies." Pharm. Res., 19(10), 1446-1457, 2002.
• [19] M. R. Grimmet, Diazoles, Triazoles, Tetrazoles and Their Benzo-analogues, Comprehensive Heterocyclic Chemistry, Pergamon Press: Oxford, 1979, pp. 357-410.
• [20] J. Elguero, C. Marzın, The Tautomerism of Heterocycles, Advences in Heterocyclic Chemistry, Academic Pres: New York, 1976, pp. 287-291.
• [21] G. B. Barlin, T. J. Batterham, “The proton magnetic resonance spectra of some diazoles, triazoles, and tetrazoles” J. Chem. Soc. B., 516-518, 1967.
• [22] M. Begtrup, “13C-NMR Spectra of Phenyl-substituted Azoles: a Conformational Study” Acta. Chem. Scand., 27, 3101-3110, 1973.
• [23] S. Paudel, S. Acharya, G. Yoon, K.-M. Kim and S. H. Cheon "Exploration of substituted arylpiperazine–tetrazoles as promising dual norepinephrine and dopamine reuptake inhibitors." Bioorg. Med. Chem., 24(21), 5546-5555, 2016.
• [24] S. Paudel, S. Acharya, G. Yoon, K.-M. Kim and S. H. Cheon "Design, synthesis and in vitro activity of 1, 4-disubstituted piperazines and piperidines as triple reuptake inhibitors." Bioorg. Med. Chem., 25(7), 2266-2276, 2017.
• [25] C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings." Adv. Drug Deliv. Rev., 23(1-3), 3-25, 1997.
• [26] A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski "A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases." J. Comb. Chem., 1(1), 55-68, 1999.
• [27] W. J. Egan, K. M. Merz and J. J. Baldwin "Prediction of drug absorption using multivariate statistics." J. Med. Chem., 43(21), 3867-3877, 2000.
• [28] I. Muegge, S. L. Heald and D. Brittelli "Simple selection criteria for drug-like chemical matter." J. Med. Chem., 44(12), 1841-1846, 2001.
• [29] D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W. Ward and K. D. Kopple "Molecular properties that influence the oral bioavailability of drug candidates." J. Med. Chem., 45(12), 2615-2623, 2002.
• [30] P. F. Hollenberg, "Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes." Drug Metab. Rev., 34(1-2), 17-35, 2002.
• [31] J. Kirchmair, A. H. Göller, D. Lang, J. Kunze, B. Testa, I. D. Wilson, R. C. Glen and G. Schneider "Predicting drug metabolism: experiment and/or computation?" Nat. Rev. Drug Discov., 14(6), 387, 2015.