The progress of recent years in a search of potential anticonvulsnts among the derivatives of aza-heterocycles

L Perekhoda

Автор(и)

L Perekhoda National University of Pharmacy,

Ключові слова:

epilepsy, anticonvulsant agent, SAR, QSAR.

Анотація

Introduction.Epilepsy is one of the most common diseases of the nervous system that affects all aspects of life. This fact stimulates an in-depth analysis of the problem of epilepsy from medical and social points of view. The social significance is determined by the prevalence of epilepsy, the possibility of personality and psyche changes in 1/3 patients, and complex social, legal and economic issues associated with the disease. Thus, it is vital to constantly improvethe anticonvulsant drug therapy in order to find the most pharmacologically active and safe anticonvulsants. In addition, one of the priority areas of the pharmaceutical industry in Ukraine is the import substitution, which in turn requires the introduction of production that is not onlygenericdrugs, but also original ones. Analyzing the published data we found that five-membered di(three) aza-heterocycles is quite promising matrix based on which the search of these anticonvulsants can be done. In this paper is introduced the structuresof the synthesized in recent years 1,2,3-triazoles derivatives, 1,2,4-triazoles, 1,3,4-oxadiazoles and 1,3,4-thiadiazole that possess an anticonvulsant effect with bringing of specific models of a convulsive state. Analyzed and summarized published data regarding the qualitative and quantitative relation "structure-activity” (SAR and QSAR analysis) in the series of anticonvulsants that are now widely used - benzodiazepine, barbiturates and hydantoin, and a number of new compounds that are under preclinical trials. Introduced the correlation dependencies in the form of regression equations that connect anticonvulsant effect with structural characteristics of anticonvulsants that are expressed by means of molecular descriptorsof different types. These descriptors consistently affect the amount of anticonvulsant activity, inparticular, dipole moment, molecular weight, Gammet’s constant, Taft’s steric parameter of substituents in certain atoms, atomic charges, electron density, and lower energy of free molecular orbital. Also, there is demonstrated an important role of a lipophilicity for manifestation of anticonvulsant activity and are given equations ofits correlation with retention time, determined by HPLC. There was proved an availability for further study of anticonvulsants’ activity based on derivatives of 1,2,3-triazoles, 1,2,4-triazoles, 1,3,4-oxadiazoles and 1,3,4-thiadiazole and common areas of chemical modification have been identified in order to search for perspective anticonvulsants. Promising methods included an introduction to the structure ofbenzylamine residue (substituted and unsubstituted), carboxamide group, ester groups, free amino and carboxyl groups, sulfonyl groups, aromatic rings and heterocyclic π-redundant heterocyclic systems.In paper there was outlined a question, which is not resolved yet of the described in the literature SAR and QSAR models that are built only for narrow homogeneous samples of compounds that usually belong to the same chemical class. At the same time, the creation of reliable model for various sample compounds that allow using one correlation equation to predict the anticonvulsant properties of compounds of not only homologous, but different chemical structure has not been resolved. In addition, methodological rules for constructing such models are not explicitly formulated. However, in most scientific papers are used either pre-selected descriptors by the authors, or an automatic descriptor selection from a sufficiently large number of them (usually with descriptors implemented in a particular program).

Conclusion. A detailed study of the prospective structures in the series of the five-membered derivatives of di(three) aza-heterocycles and summarizing the progress of recent years in SAR and QSAR analysis will further allow to choose the most promising ways of modification in order to improve the search efficiency of new anticonvulsants.

Посилання

Kharchuk, S. M. Epilepsy Treatment in Ukraine [Тext] / S. M. Kharchuk, A. L. Kompaniets // Ukr. med. newspaper. 2006. № 2. P. 16.

Dubenko, A, E. Application brend and generic antiepileptic drugs [Тext] // Neuro NEWS. –2008. № 3. – P. 13–18.

Voronkov, V. V. Modern Principles of therapy epilepsy[Тext] / V. V. Voronkov, A. S. Pilaeva, E. S. Kosyakova // Journal neurology and psychiatry. 2010. № 6. P. 18-23

Guzeva, V. I. Epilepsy and non-epileptic paroxysmal states in children [Тext] / V. I. Guzeva // M: Medical News Agency, 2007. – 568 p.

Rajasekaran, A. Antibacterial, antifungal and anticonvulsant evaluation of novel newly synthesized 1-[2-(1H-tetrazol-5-yl)ethyl]-1H-benzo[d] [1,2,3]triazoles [Тext] / A. Rajasekaran, S. Murugesan, K. Ananda // Arch.Pharm.Res – 2006. – Vol. 29, № 7. – P. 535–540.

Biagi, G. 1,5-Diarylsubstituted 1,2,3-triazoles as potassium channel activators. [Тext] / G. Biagi, V. Calderone, I. Giorgi // Farmaco. – 2004. – Vol. 59, № 5. – P. 397-404.

Kadaba, P. K. Aminoalkylpyridines (AAPs), triazoline metabolite analogues, as anticonvulsants highly effective in the MES test [Тext] / P.K. Kadaba, T. Dixit // Curr Med Chem. –2003 -10(20) . – P. 2109–21.

Kadaba, P. K. Rational drug design and the discovery of the delta 2-1,2,3-triazolines, a unique class of anticonvulsant and antiischemic agents [Тext] / P. K. Kadaba // Cut. Med. Chem. – 2003. – Vol. 10. –№ 20. – P. 2081–2108.

Satoru, I. Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist [Тext] / S. Atsushi, N. Yasushi [et al.] // Bioorg. Med. Chem. – 2008. – Vol.16. № 22. – Р. 9817-9829.

Kamal, M. D. Synthesis, anticonvulsant, and anti–inflamatory evaluation of some new benzotriazole and benzofuran–based heterocycles [Тext] / M. D. Kamal, A. G. Hassan, A. V. Eman [et al.] // Bioorg. Med. Chem. – 2006. – Vol. 14.–№ 11. – Р. 3672–3680.

Modzelewska–Banachiewicz, B. Synthesis and biological activity of new derivatives of 3-(3,4-diaryl-1,2,4-triazole-5-yl) propenoic acid [Тext] / B. Modzelewska–Banachiewicz, J. Banachiewicz, A. Chodkowska [et al.] // Eur. J. Med. Chem. 2004. – Vol. 39. – №10. – P. 873–877.

Kucukguzel, I. Synthesis of some 3–(arylalkylthio)–4–alkyl/aryl–5–(4–aminophenyl)–4H–1,2,4–triazole derivatives and their anticonvulsant activity / I. Kucukguzel, S. G. Kucukguzel, S. Rollas [et al.] // Farmaco. – 2004. – Vol. 59. –№ 11. – P. 893–901.

Archana, V. K. Synthesis of newer thiadiazolyl and thiazolidinonyl quinazolin–4(3H)–ones as potential anticonvulsant agents [Тext] / V. K. Archana, A. K. Srivastava // Eur. J. Med. Chem. – 2002. – Vol. 37. – № 11. – P. 873–882.

Carling, R. W. 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluoro phenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid (GABA) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models [Тext] / R. W. Carling, A. Madin, A. Guiblin [et al.] // J. Med. Chem. − 2005. – Vol. 48.–№23. – P. 7089-7092.

Atack, J. R. TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl) -1,2,4-triazolo[4,3-b]pyridazine], an agonist for alpha2- and alpha3-containing GABAA receptors, is nonsedating anxiolytic in rodents and primates [Тext] / J. R. Atack, K. A. Wafford, S. J. Tye [et al.] // J. Pharmacol. Exp. Ther. − 2006. – Vol. 316. –№1. – P. 410-422.

Pandey, S. Research anticonvulsant agents: achievements and prospects [Тext] / S. Pandey, І. Srivastava // Russian Chemical Reviews.

№ 9. P. 13-25.

Zarghi, A. .Design and synthesis of new 2-substituted -5- (2-benzylthio phenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists [Тext] / A. Zarghi., M. Faizi, B. Shafaghi [et al.] //Bioorganic. Med. Chem .Lett.- 2005. – №15. P.3126-3129.

Almasirad, A. Synthesis and anticonvulsant activity of new 2–substituted–5–[2–(2–fluorophenoxy)phenyl]–1,3,4–oxadiazoles and 1,2,4–triazoles [Тext] / A. Almasirad, S. A. Tabatabai, M. Faizi [et al.] // Bioorg. Med. Chem. Let. – 2004. – Vol. 14. –№ 24. – P. 6057–6059.

Zarghi, A. Synthesis and anticonvulsant activity of new 2–substituted–5–(2–benzyloxyphenyl]–1,3,4–oxadiazoles [Тext] / A. Zarghi, S. A. Tabatabai, M. Faizi [et al.]. // Bioorg. Med. Chem. Let. – 2005. –№ 7. – P. 1863–1865.

Altintas, H. Synthesis and evaluation of antimicrobial and anticonvulsant activities of some new 3-[2-(5-aryl–1,3,4–oxadiazol–2yl/4–carbethoxymethylthiazol–2–yl)imino–4–thiazolidinon-5-ylidene]-5-substituted/non substituted 1H–indole–2–ones and investigation of their structure–activity relationships [Тext] / H. Altintas, O. Ates, B. S. Uyde–Dogan [et al.] // Arzneimittelforschung. – 2006. – Vol. 56. – № 3. – P. 239–248.

Dogan, H. N. Synthesis of new 2,5–disubstituted–1,3,4–thiadiazoles and preliminary evaluation of anticonvulsant and antimicrobial activities [Тext] / H. N. Dogan, A. Duran, S. Rollas [et al.] // Bioorg. Med. Chem. – 2002. – Vol. 10. – № 9. – P. 2893–2898

New N-substituted sukcinimide as potential anticonvulsants [Тext] / A. V. Velchynska. [et al.] // Actual problems of preventive medicine: Coll. Science. Pr., devote. 95 Anniversary of Birthday. prof. V. Kramarenko: Theses of reports. – Lviv, 2011. – Еdition. 9. – P. 59–63.

Georgiyants, V. A. Features anticonvulsant action and its dependence on the molecular structure of N, N'-dybenzylamides benzylidenmalonіс acids [Тext] / V. A. Georgiyants // Clinical Pharmacy. – 2003. – Т.7. –№ 2. – P.59-64.

Najafi, A Quantitative Structure–Activity Relationship Analysis of the Anticonvulsant Activity of Some Benzylacetamides Based on Genetic Algorithm–Based Multiple Linear Regression [Тext] / A. Najafi, S. A Soheil, M. Mehdi // Tropical Journal of Pharmaceutical Research. 2011. Vol. 10 (4). Р. 483–490

GABAa and GABAc Receptors: Molecular Modelling and QSAR Analysis of Selective Ligands [Тext] / V. A. Palyulin [et al.] // 17th European Symposium on Quantitative Structure–Activity Relationships: Theses of reports. Uppsala. 2008. P. 29–34.

Wilson, T. L. QSAR of the Anticonvulsant Enaminones [Тext] / T. L. Wilson, P. L. Jackson, C. D. Hanson [et al.]. // Journal of molecular modelling. 2009. № 11. P. 371–381

Martinez, J. J. Retention–property relationships of anticonvulsant drugs by biopartitioning micellar chromatography [Тext] / J. J. Martinez, S. Sagrado, R. M. Villanueva-Camanas [et al.] // J. Chromatography. – 2001. – Vol. 757. – № 1. – Р. 89–99.

Puratchikody, A. QSAR Studies on antiepileptic and locomotor in vivo activities of 4,5–diphenyl–1H–imidazoles [Тext] / A. Puratchikody, M. Doble // Chem Biol Drug Des. – 2009.– Vol. 74(2). – Р. 173–82.

Garro Martinez, J. C. Anticonvulsant activity of ringed enaminones: A QSAR study [Тext] / J. C. Garro Martinez, P. R. Duchowicz, M. R. Estrada [et al.] // QSAR Comb. Sci. – 2009.– Vol. 28. – Р. 1376–1385.